Synthesis of Symmetrical and Unsymmetrical Thiosulfonates from Disulfides through Electrochemically Induced Disulfide Bond Metathesis and Site-Selective Oxidation

Article abstract of DOI:10.1002/ejoc.202101007

The anodic generation of symmetrical and unsymmetrical thiosulfonates is presented. First, the oxidation of disulfides yielding symmetrical thiosulfonates was realized. The direct synthesis is performed using a simple quasi-divided cell design, whereby using a supporting electrolyte is unnecessary. Its principle was then expanded to the conversion of unsymmetrical disulfides that were generated in situ through metathesis of two symmetrical disulfides. This enables a direct access to unsymmetrical thiosulfonates without any pre-functionalization or elaborate synthesis of the starting materials for the first time. The reaction scope was investigated by converting differently functionalized aliphatic and aromatic disulfides in moderate to very good yields. Furthermore, a sensitivity assessment for an improved reproducibility and a robustness screen to determine the compatibility of the reaction against functional groups were performed.

Full text of DOI:10.1002/ejoc.202101007

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of Symmetrical and Unsymmetrical Thiosulfonates
from Disulfides via Electrochemical Induced Disulfide Bond
Metathesis and Site-Selective Oxidation
Authors: Julia Strehl and Gerhard Hilt
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202101007
Link to VoR: https://doi.org/10.1002/ejoc.202101007
01/2020

10.1002/ejoc.202101007
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Symmetrical and Unsymmetrical Thiosulfonates from
Disulfides via Electrochemical Induced Disulfide Bond Metathesis
and Site-Selective Oxidation
Julia Strehl and Gerhard Hilt*[a]
[a]
MSc. J. Strehl, Prof. Dr. G. Hilt
Institut für Chemie, Universität Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26111 Oldenburg, Germany
Fax: +49 441 798 3329
email: gerhard.hilt@uni-oldenburg.de
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The electrochemical, oxidative generation of symmetrical
and unsymmetrical thiosulfonates is presented. First, the oxidation of
disulfides yielding symmetrical thiosulfonates was realised. The direct
synthesis is performed using a simple quasi-divided cell design,
whereby the usage of a supporting electrolyte is unnecessary. Its
principle was then expanded to the conversion of unsymmetrical
disulfides that were in situ generated via metathesis of two
symmetrical disulfides. This enables a direct access to unsymmetrical
thiolsulfonates without any pre-functionalisation or elaborate
synthesis of the starting materials for the first time. The scope of the
reaction was investigated by converting different functionalised
aliphatic and aromatic disulfides in moderate to very good yields.
Furthermore, a sensitivity assessment for an improved reproducibility
and a robustness screen to determine the compatibility of the reaction
against functional groups were performed.
economical point of view. Furthermore, the preparation of sulfonyl
chlorides and hydrazines classically requires the usage of
hazardous reagents as well (e.g. PCl5, POCl3 or SOCl2,
N2H4).[20,49-54]
To avoid the stoichiometric usage of redox reagents and/or toxic
reagents Guan and Wu et al. developed an electrochemical
method for the oxidation of disulfides to thiosulfonates (Scheme
1a).[55] However, it has still some severe drawbacks: Only the
generation of symmetrical thiosulfonates was realised, the usage
of a supporting electrolyte is unavoidable and long reaction times
of 20 hours are necessary, which again diminishes the ecological
and economical attraction for this procedure. In addition, the
statement of the terminal voltage has only a limited informative
value regarding the actual applied voltage, which complicates the
reproducibility of the reaction. Shortly after, two methods for the
electrochemical generation of unsymmetrical thiosulfonates were
developed as well using sulfonyl hydrazines or sulfinic esters
(Scheme 1 b and c).[56,57]
In general, organo-sulphur compounds are widespread in nature
and do exhibit many biological active properties. One
representative of this substance class are thiosulfonates that act
antimicrobial, antifungal, and antiviral.[1-4] In addition, they might
be applied in cancer treatment or as antidote in case of cyanide
poisoning.[5-8] In the synthetic, organic chemistry these
compounds are used as popular sulfenylating agents.[9-14] As
opposed to sulfinyl halides, thiosulfonates exhibit a higher stability
and compared to disulfides are accompanied by a higher
reactivity at the same time.[15]
Due to the significance of this substance class, many synthetic
strategies have been developed during the past decades.[15]
Symmetrical thiosulfonates can be prepared by oxidative
dimerisation of thiols,[16-21] oxidation of disulfides,[16,22-26] reduction
of sulfonyl chlorides[27-32] or the decomposition of sulfonyl
hydrazines.[22,33,34]
The
generation
of
unsymmetrical
thiosulfonates is more challenging and can be accomplished for
example by cross-coupling of sodium sulfinates with thiols,[35,36]
disulfides[37-40] or N-arylthiosuccinimides.[41,42] Alternatively, they
can be synthesised by reaction of thiols with sulfonyl
hydrazines[43-45] or by the addition of thiols to sulfonyl halides via
a nucleophilic substitution.[46-48] All of these methods require the
stoichiometric use of oxidants (e.g. H2O2, NaIO4, PIFA, I2, oxone,
CAN), reductants (e.g. Zn, Sm, LiAlH4) or the application of
transition metals (e.g. Zn(II), Ag(I), Cu(I), TiCl4), which is highly
problematic and disadvantageous from both an ecological and an
Scheme 1. Procedures for the electrochemical preparation of thiosulfonates.
Unfortunately, these procedures are limited to the use of aromatic
starting materials so that only aryl sulfinic esters and aromatic
sulfonyl hydrazines can be converted with a small range of thiols.
1
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10.1002/ejoc.202101007
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COMMUNICATION
Moreover, an elaborate preparation of the starting materials is
necessary, which requires harsh reaction conditions and toxic
reagents.
It was noted that good yields of the mixed disulfide 1c of 71% in
the anodic and 59% in the cathodic compartment are already
generated at a ratio of 1a:1b of 1:2. A further increase of one
disulfide only slightly increased the yield of 1c, although this
should be possible from a statistical point of view. This indicates
that the formation of the mixed disulfides reaches a kinetic limit.
Fortunately, around 10% higher yields were generated in the
anode compartment than in the cathode compartment, which can
be explained by an increased appearance of electrode fouling at
the cathode. This observation is adjuvant for the aimed
thiosulfonate generation.
Before the development of a method for the generation of
unsymmetrical thiosulfonates was started, the oxidation of a
symmetrical disulfide to a thiosulfonate was optimised using
diphenyl disulfide (1a) as test system (Table 1). The quasi-divided
cell design combines a relatively large surface area with a low
current density for the desired transformation (metathesis and
oxidation of one sulphur atom) while on the counter electrode,
which is typically just a Pt wire, the solvent is electrolysed, based
on the relatively high current density when applying constant
current electrolysis conditions, which might be advantageous for
the aimed reaction.
Although, these works represent a good beginning for the
electrochemical synthesis of thiosulfonates, the procedures have
severe drawbacks. For this reason, the aim of this work was the
development of an oxidative, electrochemical method that
enables the ecologically and economically efficient access to
symmetrical and unsymmetrical thiosulfonates in a short period of
time by oxidation of disulfides (Scheme 1d). For the generation of
unsymmetrical thiosulfonates the required unsymmetrical
disulfides should be generated in situ from a matrix of two
symmetrical disulfides via electrochemically initiated sulfide
metathesis reaction.
In our working group, the electrochemically catalysed preparation
of mixed disulfides by sulphur-sulphur bond metathesis using
alternating current electrolysis has already been investigated.[58]
The generation of mixed disulfides can be achieved in principle
also by using direct current. However, for longer lasting
electrolysis the formation of a polymeric film at the electrode
(electrode fouling) with concomitant diminished yields were
observed, which is
a common problem in electroorganic
synthesis.[59-62] Herein, this expertise should be used to develop a
method for the in situ generation of mixed disulfides via sulphur-
sulphur bond metathesis with subsequent oxidation to the
corresponding thiosulfonates under constant current conditions.
At first, the generation of mixed disulfides via metathesis reaction
was investigated utilising catalytic amounts of electricity in a
divided cell in order to determine the efficiency of the
electrochemical part reactions for the metathesis (Scheme 2).[58]
Table 1. Selected examples of the optimisation of the reaction conditions.
Entry
Variations from above
None
Yield[a]
76%
1
2
3
4
5
6
Undivided cell
Divided cell
15 mA
52%
Scheme 2. Test reaction for the formation of unsymmetrical disulfides via
electro-catalytic metathesis reaction.
75%
73%
Thus, for an initial screening only 0.1 F were used to transform
diphenyl disulfide (1a) and di-n-butyl disulfide (1b) to the mixed
disulfide 1c, at which different excess of di-n-butyl disulfide (1b)
were used (Figure 1).
25 mA
69%
CH3CN : HCl : H2O =
7.5 : 0.25 : 0.25 mL[b]
>99%
(93% isol.)
7
8
Graphite anode
Stainless steel anode
0 °C
88%
0%
80
70
60
50
40
30
20
9
88%
84%
93%
93%
10
11
12
40 °C
Stirring at 250 rpm
Stirring at 650 rpm
The reactions were performed in a quasi-divided cell on a 0.5 mmol scale using
a glassy carbon anode (surface area: 1.0 ∙ 3.0 cm2) and a platinum wire cathode
(electrode distance: 11 mm; diameter: 1.0 mm; depth of immersion: 14 mm) at
room temperature. Concentrated HClaq. (37%) was used. [a] The yield was
determined by GC-FID analysis of the crude reaction mixture using mesitylene
as internal standard. [b] This change was kept for entries 7-12.
10
Anode compartment
Cathode compartment
0
0
1
2
3
4
5
Equiv. di-n-butyl disulfide (1b)
We started our investigation using a mixture of acetonitrile and
aqueous concentrated (37%) hydrochloric acid (7:1) as solvent
and a quasi-divided cell design with a platinum wire cathode and
a glassy carbon anode applying a constant current of 20 mA and
Figure 1. Screening of the required disulfide ratio for an efficient disulfide
metathesis reaction in a divided cell. The yields were determined by GC-FID
analysis of the crude reaction mixture using mesitylene as internal standard.
2
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10.1002/ejoc.202101007
European Journal of Organic Chemistry
COMMUNICATION
observed the formation of the desired product 2a in a good yield
of 76% (Table 1, entry 1). Afterwards, different cell designs were
tested as well (entries 2,3) but to no significant prevail. While the
yield could be reproduced in a divided cell, the yield decreased to
52% using an undivided cell. Neither the increase nor the
decrease of the current ameliorated the yield of 2a (entries 4-5).
By the addition of 0.25 mL water and adjusting the amount of
CH3CN and hydrochloric acid to 7.5 mL and 0.25 mL respectively,
thiosulfonate 2a was isolated in an excellent yield of 93% (entry
6). The variation of the anode material (graphite, stainless steel),
the temperature (0 °C, 40 °C) or the stirring rate (250 rpm,
650 rpm) did not result in a further improvement of the yield
(entries 7-12).
disulfides were converted according to the optimised reaction
conditions. While the methyl-substituted product 2b and the
methoxyphenyl-substituted compound 2c were isolated in very
good yields (85% and 88% respectively), 4-nitrophenyl disulfide
could not be converted to product 2d and stayed unaffected. Alkyl
substituted disulfides were converted to thiosulfonates as well.
Dibenzyl disulfide yielded the desired product 2e in a good yield
of 82%. While dicyclohexyl disulfide yielded product 2f in 83%, di-
n-butyl thiosulfonate (2g) was isolated in an almost quantitative
yield (99%).
Due to its many advantages (e.g. less waste, mild reaction
conditions and only electrons as reagents)[63-68] electro-organic
synthesis has experienced a renaissance during the past decade
and is focused in different research areas. As recently reported
by Waldvogel,[69] this might lead to reproducibility issues, since
researches with various scientific backgrounds report the applied
parameters differently. To ensure the reproducibility of this
reaction, a sensitivity assessment was performed in addition to
the reaction optimisation (Figure 2).[70]
Scheme 3. Substrate scope of the electrochemical generation of symmetrical
thiosulfonates.
After these encouraging results the aimed synthesis for the
generation of unsymmetrical thiosulfonates should be realised.
For this, the reaction conditions for the synthesis of symmetrical
thiosulfonates were adopted, but the amount of charge of the
electrolysis was increased (Scheme 4).
Following the results of the required disulfide ratio (see Figure 1),
the disulfides were applied in a ratio of 1:2 (for further information
see SI). As a first example, the conversion of diphenyl disulfide
and bis(4-methoxyphenyl) disulfide gave the unsymmetrical
aromatic compound 2h in 45%. The identity of the oxidised
sulphur atom of the products was determined by 13C NMR spectra
and the fragmentation patterns of the GCMS spectra. The
synthesis of compound 2i by using bis(4-nitrophenyl) disulfide as
starting material failed, probably due to the strong electron-
withdrawing character of the nitro group. It is interesting to note,
that mixtures of thiosulfonates are obtained when aryl disulfides
are reacted with dialkyl disulfides as in the case of the products
2j/2j´-2l/2l´. For the products 2j/2j´ and 2k/2k´ the preference for
one regioisomer is inverted from 1:4 in favour of 2j´ to almost 4:1
(2k). The cross-combination gave the thiosulfonate 2n (as well as
2o) as a pure regioisomer, although in moderate (to acceptable)
yield. While a benzyl group and a n-butyl group have the same
effect on the regioselectivity of the thiosulfonate formation
resulting in a 1:1 mixture (2l/2l´), it is surprising that the product
2q was isolated as single regioisomer. As expected, the same can
be observed for n-dodecyl and n-butyl (2m:2m’ = 1:1), which
create the same electronic environment at the sulphur atom. The
Figure 2. Sensitivity assessment for the electrochemical generation of
thiosulfonates.
This test is based on the adoption, that small variations of the
reaction conditions, that can be made accidently by other
researches, might have an impact on the reproducibility of the
reaction.[70] Here, parameters have been investigated, that are
often neglected in common electrochemical optimisations.
Special attention has been paid to the electrochemical set-up,
because most working groups use their individually manufactured
equipment.[69] The electrochemical generation of thiosulfonates is
insensitive against many parameters, but the enlargement of the
anode leads to a bisection of the yield. On a larger scale the yield
was decreased by 23%, which can be rationalised by physical
adsorption at the electrode surface due to the increased
concentration, resulting in a reduced reaction rate. This is
confirmed by the recovery of the starting material 1a based on
which the yield of 2a is the same as for the optimal reaction
conditions.
4-methoxyphenyl has
a
strong directing effect on the
regioselectivity of the oxidation of one sulphur atom as in 2o and
2p. However, the benzyl group inverted this regioselectivity
completely, resulting in the formation of 2q in 46% yield. The
regioselective formation of 2r can be attributed to the stronger
electron-donating effect of the t-butyl group over the n-butyl group.
With the optimised reaction conditions in hand, the substrate
scope for the generation of symmetrical thiosulfonates was
investigated (Scheme 3). First, different functionalised diphenyl
3
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10.1002/ejoc.202101007
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COMMUNICATION
Table 2. Functional group tolerance test using diphenyl disulfide as substrate.
Entry
Additive
None
Yield (2a)
>99%
64%
Yield (additive)
1
2
3
4
5
6
7
8
9
---
octanenitrile
bromobenzene
1-chlorooctane
heptanone
87%
96%
91%
71%
0%
79%
82%
74%
dodecylamine
2,6-lutidine
56%
70%
0%
n-octanal
43%
14%
40%
1,2-epoxy-n-octane
59%
1,3-dimethoxy-
benzene
10
51%
14%
11
12
13
1-octanol
86%
100%
71%
70%
73%
0%
methyl benzoate
benzothiazole
Colour code: green: yields >66%, yellow: yields between 34-66%, red: yields
<34%. [a] The yield was determined by GC-FID analysis of the crude reaction
mixture using mesitylene as internal standard.
In conclusion, an electrochemical method for the oxidative
synthesis of symmetrical thiosulfonates is described. Its principle
was then successfully expanded for the synthesis of
unsymmetrical thiosulfonates starting from two different
symmetrical disulfides. Compared to the known electrochemical
methods for the synthesis of thiosulfonates, the reaction time was
reduced significantly, the reaction set-up was simplified and
unsymmetrical thiosulfonates can be generated directly without
the need of an elaborate starting material synthesis. Thereby, the
use of alkyl and aryl substituted disulfides is possible. On top of
this, the generation of unsymmetrical thiosulfonates can be
accomplished in high regioselectivity: Due to the mild oxidative
conditions of the electrochemical procedure, the selective
oxidation of one sulphur atom can be controlled in some cases by
the electronic character of the residue. The scope and limitations
of both reactions were investigated. Thereby, the conversion of
alkyl and aryl substituted disulfides works well. Lastly, a sensitivity
assessment and a robustness screen according to Glorius were
performed to ensure a good reproducibility and to determine the
group tolerance of the reaction.
Scheme 4. Substrate scope of the electrochemical generation of
unsymmetrical thiosulfonates.
Thereafter, the tolerance of the electrochemical reaction for the
thiosulfonate formation towards functional groups was tested by
applying a functional group compatibility test.[71,72] Selected
results of this investigation are summarised in Table 2 (for further
information see SI).
Overall, several functional groups are compatible to the reaction
conditions of the electrochemical generation of thiosulfonates.
Nitriles, alkyl/ aryl halides, alkyl ketones, alcohols and esters were
not converted and detected in good yields after the
electrochemical reaction, whereas the formation of the desired
product was not significantly inhibited. In general, functional
groups that lack redox or acid stability, only showed a moderate
or bad compatibility: Amines are protonated by the hydrochloric
acid and precipitated of the solution, which slightly diminished the
product formation (Table 2, entries 6-7). However, n-octanal was
converted to several side-products due to its redox lability, the
epoxide was protonated by the hydrochloric acid and some side
reactions occurred. 1,3-Dimethoxybenzene representing an
electron-rich arene was chlorinated. Benzothiazole was not stable
under the reaction conditions, so that no additive was found after
the reaction took place, but the formation of product 2a stayed
unaffected.
Acknowledgements
The support by the German Science Foundation (GRK 2226) is
gratefully acknowledged.
Keywords: Disulfides• Electrochemistry • Metathesis • Oxidation
• Thiosulfonates
4
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10.1002/ejoc.202101007
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COMMUNICATION
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The electrochemical, oxidative generation of symmetrical and unsymmetrical thiosulfonates is presented. The principle of the oxidation of
symmetrical disulfides was expanded to the conversion of in situ generated unsymmetrical disulfides yielding the respective thiosulfonates. A
strong dependency of the regioselectivity for the formation of the unsymmetrical thiosulfonates was encountered and allows their regioselective
formation in the future.
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