Synthesis of vinyl thioethers and bis-thioethenes from calcium carbide and disulfides

Article abstract of DOI:10.1016/j.mencom.2017.09.015

Bis-thioethenes and vinyl thioethers were obtained from the reaction of disulfides and calcium carbide in good to high yields using a simple synthetic procedure and common laboratory setup. The tolerance of the reaction was investigated by the examples of aliphatic, aromatic, heteroaromatic and sesquiterpenic substrates.

Full text of DOI:10.1016/j.mencom.2017.09.015

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 476–478
Synthesis of vinyl thioethers and bis-thioethenes
from calcium carbide and disulfides
Konstantin S. Rodygin,*a Yuliya V. Gyrdymovaa and Vladimir V. Zarubaevb
a Institute of Chemistry, St. Petersburg State University, 198504 St. Petersburg, Russian Federation.
Fax: +7 812 363 6722; e-mail: k.rodygin@spbu.ru
b Influenza Research Institute, 197376 St. Petersburg, Russian Federation
DOI: 10.1016/j.mencom.2017.09.015
Bis-thioethenes and vinyl thioethers were obtained from the
H2O, base
R
R
S
+
+
CaC2
reaction of disulfides and calcium carbide in good to high yields
using a simple synthetic procedure and common laboratory
setup. The tolerance of the reaction was investigated by the
examples of aliphatic, aromatic, heteroaromatic and ses-
quiterpenic substrates.
S
S
R
DMSO,
100–130 °C
RS
SR
up to 95% yields
12 examples
R = alkyl, (het)aryl, sesquiterpenyl
Nucleophilic addition to triple C≡C bond is a key tool to the
broad scope of organic compounds and materials.1 Gaseous
acetylene is not widely used in common laboratory technique
because of safety and equipment requirements.2 These limita-
tions motivate searching for its substitute with two sp hybridized
carbon atoms. Calcium carbide has enormous potential in inser-
tion, addition and click-like reactions.3 Moreover, it is inexpensive
and industrially available.
The reaction started also in DMF and mixtures of DMSO and
DMF with dioxane, while nonpolar solvents were not suitable.
The process required the action of bases, e.g., KOH, which
i
R
S
R
+
CaC2
+
S
R
S
R
S
S R
1a–k
2a–k
3a–k
Me
O
Recently, we have developed a new access to vinyl sulfides
through calcium carbide and thiols.4 Vinyl sulfides can undergo
cycloaddition,5 Heck reaction,6 hydrosilylation,7 diimide reduc-
tion8 and asymmetric oxidation.9 They are also promising pre-
cursors to functionalized monomers.10 Sulfur-containing polymers
are used in optoelectronics because of high refractive index.11
Thioether-containing styrene derivatives were tested in com-
binatorial screening and biomedical diagnostics,12 synthesis of
gold nanocomposites,13 and catalysis.14
Previously described synthetic procedures for vinyl sulfides
require metal catalysts,15 special synthetic protocols16 or the use
of toxic thiols.4 Herein, we present an original access to vinyl
sulfides through addition of organic disulfides to acetylene
generated in situ from calcium carbide. Thus, toxic thiols can
be replaced with the corresponding disulfides. Disulfides 1 are
more suitable for common laboratory practice due to better
stability in air and absence of nasty smell. The reaction was
carried out in DMSO in the presence of potassium hydroxide
and stoichiometric amounts of water on heating in a sealed
vessel, no organometal catalyst having been used (DMSO was
chosen as a medium since gaseous acetylene is well soluble in it
and would evaporate slowly from the solutions4). Surprisingly,
the reaction afforded, along with expected vinyl thioethers, some
bis(1,2-organyl thio)ethenes. Both products were isolated in
good total yields after simple isolation procedure (Scheme 1).†
S
Me
Me
2
1e
Total isolated
yield (%)
R
2 : 3 ratio
a
n-dodecyl
n-hexyl
Bu
93
90
60
64
1 : 0
1 : 3
0 : 1
1 : 1
1 : 1
1 : 0
1 : 0
1 : 0
1 : 0
1 : 3
1 : 0
b
c
d
e
f
g
h
i
cyclohexyl
4,5-epoxycaryophyll-9-ylmethyl 95
Ph
93
69
60
64
84
92
4-MeC6H4
4-ClC6H4
4-FC6H4
3-MeC6H4
2-pyridyl
j
k
i
Se
Ph
Ph
+
+
CaC2
Se
63%
Se
Ph
Ph Se
Se Ph
4
5
1 : 1
6
Scheme 1 Reagents and conditions: i, H2O, base, DMSO, 100°C, 3 h.
KF (69 mg, 1.2 mmol, 130°C) or CsF (90 mg, 0.6 mmol) were used as an
additive in the cases of 1e and 4, respectively.
This operation was repeated twice, and, totally, the product was extracted
three times. All hexane extracts were combined and washed with 10% aq.
KOH (2×10 ml), brine, dried over MgSO4, and concentrated in vacuo. The
crude material was purified by column chromatography on neutralized
silica gel (hexane or/and diethyl ether–hexane as the eluents). For further
purification, if necessary, the products were bulb-to-bulb distilled in vacuo
and kept cold under argon. In the case of volatile products, pentane was
used for extraction instead of hexane.
†
Synthesis of vinyl sulfides. Potassium hydroxide (67 mg, 1.5 mmol),
disulfide 1 (0.4 mmol) and DMSO (1.5 ml) were placed into 8 ml pressure
vessel, and the mixture was stirred at room temperature for 20 min. Freshly
powdered calcium carbide (256 mg, 4 mmol) and water (144 ml, 8 mmol)
were added, the vessel was immediately sealed and heated to 100°C for
3 h. The mixture was allowed to cool to room temperature and extracted
with hexane (3×20 ml). Then, new portions of calcium carbide and water
were added into the reaction tube which was sealed and heated again.
For characteristics of the products, see Online Supplementary Materials.
© 2017 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2017, 27, 476–478
would cleave S–S bond. The thus formed nucleophile adds at
Caryophyllane molecular core is known for its biological
activity.22 In particular, being a minor component of essential oils,
caryophyllene confers high antiviral properties against herpes
viruses of various strains including those resistant to acyclovir,23
and influenza virus on animal model.24 Based on these results, we
tested caryophyllane derivatives obtained herein for their ability
to suppress influenza virus. Cytotoxic and antiviral properties
of compounds 2e and 3e were tested in MDCK cells against
influenza virus A/Puerto Rico/8/34 (H1N1).¶ The compounds
under investigation possessed close cytotoxicity. The highest
virus-inhibiting activity was demonstrated by 3e (CC50 = 17 mm,
IC50 = 2 mm, SI = 9). Importantly, the corresponding vinyl thio-
ether 2e revealed similar toxicity (CC50 = 6 mM, IC50 = 7 mm,
SI = 1) but lack of virus-directed selectivity. This suggests sym-
metric bis-thioethene 3e based on caryophyllane scaffold may be
further optimized for enhancing antiviral properties. No data on
anti-influenza activity of pure caryophyllene in vitro are available.
For comparison, the values of C50, IC50 and SI for b-caryo-
phyllene against herpes virus type 1 were found to be 35 mg ml–1,
0.25 mg ml–1 and 140, respectively.
triple bond, which leads to vinyl sulfide. On the other hand,
acetylene insertion into S–S bond of the disulfide is not impos-
sible. The rates of two reactions depend on the nature of an initial
substrate. The vinylation reaction mechanism is known,17 but the
mechanism of insertion reaction is not completely clear. We also
found an optimal reactant ratio of CaC2 :H2O:KOH:disulfide
being 4:8:1.2:0.4. Generally, the addition is preferable in the case
of excess of calcium carbide. Deficiency of calcium carbide causes
incomplete conversion, and some amounts of the starting disulfide
remain unchanged. At higher temperatures, destruction of formed
vinyl thioethers and bis-thioethenes does occur. To investigate
the scope of the reaction, we tested aliphatic, cycloaliphatic,
aromatic, heteroaromatic and sesquiterpenoid disulfides‡ (see
Scheme 1), with the product composition having been dependent
on the nature of the disulfide.
Interestingly, the elongation of aliphatic chain length leads to
growth of the vinyl sulfide (products 2a–c) fraction. In the case
of diphenyl disulfide 1f and its para-substituted analogues 1g–i, as
well as di(2-pyridyl) disulfide 1k, the vinylated products 2f–i,k
are exclusively formed. Meantime, with secondary cycloaliphatic
(1d), sterically hindered terpenoid (1e) and meta-substituted
aromatic (1j) disulfides mainly insertion products 3d,e,j were
obtained; the same phenomenon took place with diphenyl
diselenide 4 (see Scheme 1). We also developed the triple vinyla-
tion procedure. After the first cycle, the product is extracted, new
portions of calcium carbide and water are added, and the reaction
is run again. This procedure allows one to raise the product
yields by 10–30%.
In conclusion, calcium carbide was successfully employed in
new access to vinyl thioethers and bis-1,2-thioethenes. The syn-
thetic procedure is simple and does not require special laboratory
equipment. We replaced toxic and easily oxidized thiols with
stable disulfides. Cytotoxicity and antiviral activity of selected
substrates were estimated.
This work was supported by the Russian Science Founda-
tion (grant no. 16-13-10301). Authors acknowledge Centers of
St. Petersburg State University: Magnetic Resonance, Chemical
Analysis and Materials Research, and X-ray Diffraction Methods.
The structure of compound 3e was proved with X-ray dif-
fraction analysis (Figure 1).§ According to X-ray analysis data,
its double bond has Z-configuration.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2017.09.015.
O(1)
C(4)
O(2)
C(22)
C(23)
C(14)
C(3)
C(2)
C(31)
C(24)
C(5)
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C(21)
C(6)
C(17)
C(16)
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C(7)
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‡
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§
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Received: 26th December 2016; Com. 16/5135
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