Electrochemical Formation of 3,5-Diimido-1,2-dithiolanes by Dehydrogenative Coupling

Article abstract of DOI:10.1021/acs.orglett.8b02904

A synthetic approach to the cyclic disulfide moiety of 3,5-diimido-1,2-dithiolane derivatives starting with readily available precursors including the electrochemical coupling of dithioanilides is developed. The electrochemical key step provides sustainab

Full text of DOI:10.1021/acs.orglett.8b02904

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Formation of 3,5-Diimido-1,2-dithiolanes by
Dehydrogenative Coupling
Valentina M. Breising,† Tile Gieshoff,†,‡ Anton Kehl,† Vincent Kilian,† Dieter Schollmeyer,†
and Siegfried R. Waldvogel*,†,‡
†Institute of Organic Chemistry, Johannes Gutenberg University Mainz, 55128 Mainz, Germany
‡Graduate School Materials Science in Mainz, 55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: A synthetic approach to the cyclic disulfide
moiety of 3,5-diimido-1,2-dithiolane derivatives starting with
readily available precursors including the electrochemical
coupling of dithioanilides is developed. The electrochemical
key step provides sustainable synthetic access in high yields,
using a very simple electrolysis setup.
of imidothioates and 1,2-dithiolanes results in 3,5-diimido-1,2-
nterest in sulfur-containing heterocycles has been growing
Isince the discovery of their potential applications as dithiolanes. There is only a single report dedicated to these
structures which was given by Schmidt in the 1950s. By
oxidation of dithiomalonimides with iodine, he could isolate
the corresponding 3,5-diamino-dithiylium iodide.13
antioxidants, chemotherapeutics, radioprotectives, and cancer
chemoprotectives.1 The 1,2-dithiolane moiety is a disulfide-
containing thiaheterocycle which was first reported in the late
19th century.2 In 1950, α-lipoic acid had been discovered as
the first natural product containing a 1,2-dithiolane moiety.3
Further investigations revealed that the dithiolane performs a
vital task in a redox system within mitochondria.4 Owing to
this moiety, asparagusic acid is supposed to be metabolized in a
similar way resulting in odorous urine after consumption of
asparagus.5 Other 1,2-dithiolanes isolated from mangroves
have shown antibacterial properties in biological studies.6
Based on the antioxidant behavior of α-lipoic acid, several
analogues of this natural antioxidant have been investigated for
pharmaceutical applications.7 Furthermore, disulfides have
been investigated as part of target drug delivery systems,
since the cleavage of the disulfide bond is both pH and redox
dependent.8 1,2-Dithiolane motifs also occur in lipoic acid-
PEG which is used as a precursor for anchoring groups in the
functionalization of nanoparticles. The corresponding dithiol is
released after reduction, and the liberated bidentate structure
shows a higher affinity toward the nanoparticle surface.9
Conventional synthetic approaches to 1,2-dithiolanes are
based on the construction of the disulfide moieties. Several
possibilities exist such as nucleophilic substitutions, reduction
of sulfonyl halides, and oxidation of thiols, which have a severe
stench and are toxic.10 Specifically, the oxidation of thiols to
disulfides is employed frequently. These methods often require
metals (e.g., RSLi), strong oxidants (e.g., PIDA, CAN), harsh
conditions (e.g., H2O2), halogens or toxic reagents (e.g.,
CrO2(OTMS)2).10,11 Furthermore, thioamides can be em-
ployed as starting materials in these reactions as reported by
Lo et al., who applied various oxidizers being limited to
substituted aromatic rings.12 The combination of the moieties
However, those synthetic approaches are questionable
concerning either the use of toxic reagents for pharmaceutical
applications, generation of large amounts of waste, or the
tolerance of labile moieties. In contrast, electrochemistry offers
a more sustainable and cost-efficient methodology.14 The
substitution of the oxidizers by electric current avoids reagent
waste and results in better atom economy.15 Hence electro-
organic reactions can be considered as “green chemistry”.16
Recently, several developments had been made in the
electrochemical coupling of heteroatoms. Huang et al. have
shown the general applicability of electrochemistry on thiol-
coupling reactions.17 Further, the oxidative intramolecular
cyclization of anilides had been successfully conducted in the
Waldvogel group.18−20 Utilizing TEMPO-catalyzed electro-
chemical C−H thiolation, the Xu group developed an access to
benzothiazoles and its analogs using thioanilides.21
We herein report an electrochemical dehydrogenative
approach for the S−S coupling of dithioanilides in order to
construct 3,5-diimido-1,2-dithiolane derivatives 5 in a simple
synthetic protocol. Symmetrical derivatives can be easily
obtained by a condensation reaction of dimethylmalonic
chloride (1′) and a collection of anilines.20 In the case of
mixed dianilides, an easy to conduct strategy was applied which
was developed within our N−N bond formation studies.22
These diamides 3 are converted to the corresponding
dithioamides 4 by thionation with phosphorus pentasulfide
as a cost-efficient reagent under mild reaction conditions.
Received: September 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Finally, the S−S coupling of the dithioamides 4 is achieved by
Table 1. Influence of Solvent onto the Yield of 5c
electrochemical oxidation (Scheme 1).
b
entry
solvent
yield [%]
1
2
3
acetonitrile
HFIP
methanol
81
87
92
Scheme 1. Three-Step Synthesis of Symmetrical (I) and
Unsymmetrical (II) Dithiolane Derivatives Using Easily
Accessible Precursors
a
0.2 mmol of substrate, anode: graphite, cathode: platinum, current
density: 0.5 mA cm−2, charge: 2 F, 0.01 M NBu4PF6, 5 mL of solvent,
b
undivided cell. 1H NMR yield, standard: 2,4,6-triiodophenol.
a
Table 2. Influence of Current Density onto the Yield of 5c
b
entry
current density (mA cm−2
)
yield (%)
1
2
3
4
5
6
0.2
0.5
2.5
5
10
20
60
92
88
83
78
64
a
0.2 mmol of substrate, anode: graphite, cathode: platinum, charge: 2
F, 0.01 M NBu4PF6, solvent: 5 mL of methanol, undivided cell.
b
1H NMR yield, standard: 2,4,6-triiodophenol.
Tetrabutylammonium hexafluorophosphate (NBu4PF6) and
tetrabutylammonium tetrafluoroborate (NBu4BF4) were inves-
tigated as supporting electrolytes.
Interestingly, the yield drops by increasing the concentration
of NBu4PF6, due to the increase of the Helmholtz layer. The
low concentration of 0.01 M is beneficial due to its better atom
efficiency and simplification of the workup. By further lowering
of the concentration of NBu4PF6, the terminal voltage rises
about 1 V and the yield drops dramatically. Because of the
better yield compared to tetrafluoroborate, the work was
continued with hexafluorophosphate at a concentration of
0.01 M as the supporting electrolyte (Table 3).
a
EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), HOBt
(hydroxybenzotriazole), PCC (pyridinium chlorochromate).
Initial screenings were conducted to evaluate the influence
of different solvents, electrode materials, current densities, and
supporting electrolytes. As part of this setup, small undivided
Teflon cells were used to conduct several reactions at the same
time.23 2,2-Dimethyl-N,N′-di-(4-methylphenyl)malonic di-
thioamide 4c was chosen as a test substrate for the oxidative
coupling (Scheme 2).
Table 3. Influence of Supporting Electrolyte (SE) and Its
a
Concentration onto the Yield of 5c
b
entry
SE
concentration (mol/L)
yield (%)
Scheme 2. Anodic Cyclization to N,N′-(4,4-Dimethyl-1,2-
dithiolane-3,5-diylidene)-bis(4-methylaniline) (5c)
1
2
3
4
NBu4PF6
NBu4PF6
NBu4PF6
NBu4BF4
0.1
76
94
22
76
0.01
0.001
0.01
a
0.2 mmol of substrate, anode: graphite, cathode: platinum, current
density: 0.5 mA cm−2, charge: 2 F, solvent: 5 mL of methanol,
b
undivided cell. 1H NMR yield, standard: 2,4,6-triiodophenol.
Another investigated parameter was the cathode material
which has a significant influence on the conversion by
controlling the hydrogen evolution as a counter reaction.
Within the investigated materials the yields vary drastically.
Presumably, the best yields had been achieved by using
platinum because of the low overpotential for hydrogen
evolution which is needed as a counter reaction of the
dehydrogenative coupling (Table 4).
As well as the N−N coupling of dianilides the electrolysis of
dithioanilides offers a compelling synthetic approach due to
the fact that the reaction conditions provide a simple
electrolysis setup and low amounts of supporting electrolyte.
Providentially, the best results had been shown in methanol
which is beneficial owing to its cost efficiency and easy
In initial experiments, the reaction parameters which had
been elaborated in N−N coupling reactions of pyrazolidine-
3,5-diones were applied.20 From comparison of three solvents
(acetonitrile, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), and
methanol) commonly used in electrochemistry, methanol
revealed the best yield. This is advantageous since methanol
is an inexpensive, environmentally friendly, and easy-to-handle
solvent (Table 1).
The investigation of the current density shows a similar
result as observed for the N−N coupling reactions.19,20 The
highest yields in the intramolecular coupling of dithioanilides
were obtained at a low current density of 0.5 mA cm−2 (Table
2).
B
DOI: 10.1021/acs.orglett.8b02904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 4. Influence of Cathode Material onto the Yield of 5c
b
entry
material
platinum
stainless steel
nickel
yield (%)
1
2
3
4
92
83
78
47
c
graphite
a
0.2 mmol of substrate, anode: graphite, current density: 0.5 mA
cm−2, charge: 2 F, 0.01 M NBu4PF6, solvent: 5 mL of methanol,
b
c
undivided cell. 1H NMR yield, standard: 2,4,6-triiodophenol. A5
stainless steel (VA 1.4571).
handling. The optimized reaction parameters are shown in
Scheme 3.
Scheme 3. Optimized Parameters of the Anodic Cyclization
to N,N′-(4,4-Dimethyl-1,2-dithiolane-3,5-diylidene)-bis(4-
methylaniline) (5c)
These reaction parameters were applied to a collection of
dithioanilides with different substitution patterns. Dehydrogen-
ative coupling leading to dithiolanes 5e, 5i, and 5l was
conducted in acetonitrile, resulting in substantially improved
yields due to the better solubility of the starting materials. The
formation of the S−S coupled product has additionally been
confirmed by X-ray structure analysis of 5c (Figure 1).
Furthermore, an up-scaling reaction (1 mmol) using 5c was
conducted, demonstrating the scalability of the electrochemical
conversion.
All derivatives could be isolated in moderate to very good
yields tolerating various functional groups (Figure 1). Halo
substituents (5d−5f) which enable follow-up reactions are well
tolerated. The iodo derivative 5f could be isolated in an
excellent yield of 87%. Remarkably as well is the good total
yield of 68% over three steps starting with malonic dichloride.
Furthermore, substituted rings with electron-withdrawing (5g,
5i, 5k) and -releasing (5h, 5j) moieties could be obtained. In
the case of 5g−5i multiple substituted aromatic systems had
been applied, which showed promising yields. Interestingly,
nonsubstituted anilines (5a) are achieved in good yields.
Hence, it could be anticipated that the radicals are not located
at the nitrogen (see the Supporting Information), which
reduces the possibility of side reactions in the aromatic system
as occurring in the conversion of anilidic analogues.22 Despite
the conversion of oxygenated substrates, the sulfur moieties are
not blocked by a hydrogen bonding network of the solvent,
allowing an efficient coupling.24 These results indicate a broad
applicability of this method on aromatic substituted
dithioanilides.
Figure 1. Scope of the electrochemical S−S coupled dithiolane
derivatives and X-ray structure of N,N′-(4,4-dimethyl-1,2-dithiolane-
3,5-diylidene)-bis(4-methylaniline) (5c). a Solvent: methanol. b Sol-
vent: acetonitrile. c Undivided cell, 5 mL of solvent, 0.2 mmol of
substrate. d Undivided cell, 4.5 mL of solvent, 0.18 mmol of substrate.
e Undivided cell, 25 mL of solvent, 1.0 mmol of substrate.
studies, a broad variety of substituents including electron-
withdrawing and -releasing, labile moieties, and even
unsubstituted phenyl rings, had been tolerated and good
yields had been achieved. Extraordinary are the high yields up
to 75% over three steps of condensation reaction, thionation,
and oxidative coupling. In particular, the final step enables an
effective conversion to 3,5-diimido-1,2-dithiolanes with up to
an 87% yield. Additionally, halide and nitrile moieties are
included which offer the possibility for further modifications.
In summary, we established synthetic access to 3,5-diimido-
1,2-dithiolanes by dehydrogenative anodic oxidation of
dithioanilides. By combining the sustainability of electro-
chemistry with the easy accessibility of the starting materials
this protocol offers an interesting approach to this promising
class of heterocycles and a favorable, oxidizer-free alternative to
conventional methods for the disulfide formation. During the
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02904.
C
DOI: 10.1021/acs.orglett.8b02904
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
General information, experimental and analytical details,
Letter
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Vasquez-Medrano, R. Green Chem. 2010, 12, 2099−2119. (b) Wald-
NMR spectra, and crystallographic data (PDF)
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vogel, S. R. Beilstein J. Org. Chem. 2015, 11, 949−950. (c) Schafer, H.-
Accession Codes
J. C. R. Chim. 2011, 14, 745−765.
(17) Huang, P.; Wang, P.; Tang, S.; Fu, Z.; Lei, A. Angew. Chem., Int.
Ed. 2018, 57, 8115−8119.
CCDC 1866690 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(18) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.;
Waldvogel, S. R. Chem. Commun. 2017, 53, 2974−2977.
(19) Kehl, A.; Gieshoff, T.; Schollmeyer, D.; Waldvogel, S. R. Chem.
- Eur. J. 2018, 24, 590−593.
(20) Gieshoff, T.; Schollmeyer, D.; Waldvogel, S. R. Angew. Chem.,
Int. Ed. 2016, 55, 9437−9440.
AUTHOR INFORMATION
(21) Qian, X.-Y.; Li, S.-Q.; Song, J.; Xu, H.-C. ACS Catal. 2017, 7,
2730−2734.
■
Corresponding Author
*E-mail: waldvogel@uni-mainz.de.
ORCID
(22) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.;
Waldvogel, S. R. J. Am. Chem. Soc. 2017, 139, 12317−12324.
(23) Gutz, C.; Klockner, B.; Waldvogel, S. R. Org. Process Res. Dev.
̈
̈
2016, 20, 26−32.
Siegfried R. Waldvogel: 0000-0002-7949-9638
Notes
(24) (a) Wiebe, A.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.;
Waldvogel, S. R. Angew. Chem., Int. Ed. 2016, 55, 11801−11805.
(b) Lips, S.; Frontana-Uribe, B. A.; Dorr, M.; Schollmeyer, D.;
̈
The authors declare no competing financial interest.
Franke, R.; Waldvogel, S. R. Chem. - Eur. J. 2018, 24, 6057−6061.
(c) Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel,
S. R. Angew. Chem., Int. Ed. 2014, 53, 5210−5213. (d) Elsler, B.;
Wiebe, A.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S.
R. Chem. - Eur. J. 2015, 21, 12321−12325. (e) Lips, S.; Wiebe, A.;
Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S.
R. Angew. Chem., Int. Ed. 2016, 55, 10872−10876. (f) Waldvogel, S.
R.; Lips, S.; Selt, M.; Riehl, B.; Kampf, C. Chem. Rev. 2018, 118,
6706−6765. (g) Lips, S.; Schollmeyer, D.; Franke, R.; Waldvogel, S.
R. Angew. Chem., Int. Ed. 2018, 57, 12980. (h) Wiebe, A.; Lips, S.;
Schollmeyer, D.; Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed.
2017, 56, 14727−14731.
ACKNOWLEDGMENTS
■
T.G. is a recipient of a DFG fellowship by the Excellence
Initiative by the Graduate School Materials Science in Mainz
(GSC 266). S.R.W. gratefully acknowledges financial support
by the DFG (Wa 1276/17-1).
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DOI: 10.1021/acs.orglett.8b02904
Org. Lett. XXXX, XXX, XXX−XXX