Convenient one-pot syntheses of 1,2-dithiole-3-thiones and 3-imino-1,2-dithioles from terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2014.07.104

The reaction of acetylide anions with carbon disulfide or phenyl isothiocyanate followed by addition of sulfur in the presence of a protonating agent such as a primary amine or alcohol affords 1,2-dithiole-3-thiones or 3-imino-1,2-dithioles in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.07.104

Tetrahedron Letters 55 (2014) 5283–5285
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient one-pot syntheses of 1,2-dithiole-3-thiones
and 3-imino-1,2-dithioles from terminal alkynes
⇑
Harry Adams, Amelia J. Hughes, Michael J. Morris , Sophia I. A. Quenby
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of acetylide anions with carbon disulfide or phenyl isothiocyanate followed by addition of
sulfur in the presence of a protonating agent such as a primary amine or alcohol affords 1,2-dithiole-
3-thiones or 3-imino-1,2-dithioles in good to excellent yields.
Received 22 May 2014
Revised 30 June 2014
Accepted 24 July 2014
Available online 30 July 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Alkyne
1,2-Dithiole-3-thione
3-Imino-1,2-dithiole
Sulfur
Carbon disulfide
Isothiocyanate
Compounds containing the 3H-1,2-dithiole-3-thione ring
system have attracted longstanding interest because of their
biological activity.1 The best known example, Oltipraz [4-methyl-
5-(2-pyrazinyl)-3H-1,2-dithiole-3-thione], originally developed as
an anti-schistosomiasis drug, has also been investigated as a cancer
chemopreventive agent and, more recently, as a way of ameliorat-
ing insulin resistance in chronic liver disease.2,3 Other compounds
of the same class display cancer chemoprevention properties as
good as, if not better than, Oltipraz.4 Another example, anethole
trithione [5-(4-methoxyphenyl)-3H-1,2-dithiole-3-thione] is used
as a salivation enhancer for conditions such as dry mouth.
Although less explored than the thiones, the corresponding
3-imino-1,2-dithiole compounds also display biological activity;
for example, 3-imino-5-phenyl-1,2-dithiole (PDTI) has been shown
to inhibit the replication of poliovirus, an effect suggested to be
due to disruption of viral RNA synthesis.5
involve the use of undesirable reagents such as liquid H2S or
hexamethyldisilathiane.6
Several years ago we reported a new route to this ring system in
which the only sources of sulfur are carbon disulfide and elemental
sulfur, and all the reactions take place at or below room tempera-
ture.7 Our strategy was based on that previously used by Mayer
and subsequently modified by Otsubo, who prepared the isomeric
4-substituted 1,3-dithiole-2-thiones by the sequential reaction of
acetylides with sulfur and CS2 followed by reprotonation with
aqueous acid.8 We demonstrated that simply reversing the order
of addition of the reagents produced the desired 1,2-dithiole-3-thi-
one ring by way of alkynyldithiocarboxylate anions, which proved
sufficiently stable at room temperature to undergo cyclisation on
addition of sulfur (Scheme 1). However the products were not
the expected 1,2-dithiole-3-thiones 2, but instead their 4-mer-
capto derivatives 3, formed by the reaction of the presumed inter-
mediate anion 4 with the excess of sulfur present. Attempts to
produce 2 by using only one equivalent of sulfur appeared unen-
couraging at the time, leading to complex mixtures of products.
Eventually, however, we reasoned that if we carried out the
cyclisation reaction in the presence of a proton donor that would
protonate the vinylic anion 4 (pKa ꢀ45) but not the acetylide
anion (pKa ꢀ25) or the alkynyldithiocarboxylate (pKa ꢀ2),
we might be able to intercept and protonate 4 before it had the
opportunity to incorporate the extra sulfur atom. A primary amine
(pKa 35) seemed an ideal choice. We now demonstrate that this
Although various methods for the synthesis of 1,2-dithiole-3-
thiones are known, most involve heating a suitable substrate with
a sulfurising agent such as sulfur and/or P2S5, or Lawesson’s
reagent.1 Some of these methods suffer from problems such as
low yields, generation of large amounts of waste relative to the
desired compound, and difficult purification procedures; others
⇑
Corresponding author. Tel.: +44 114 2229363; fax: +44 114 2229346.
E-mail address: M.Morris@sheffield.ac.uk (M.J. Morris).
http://dx.doi.org/10.1016/j.tetlet.2014.07.104
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5284
H. Adams et al. / Tetrahedron Letters 55 (2014) 5283–5285
several other alkynes (Scheme 2), though Me3SiC„CH underwent
desilylation during the reaction to produce a moderate yield of
the parent heterocycle 2e. On most occasions no other products
were observed.9
To obtain the best yields, the order and timing of the addition of
reagents are important. When the sulfur was added to the
PhC„CCSÀ2 solution a few minutes after the addition of the amine,
a lower yield of product 2a (37%) was obtained. Amines are known
to react with activated alkynes, and it is possible that the
alkynyldithiocarboxylate anion is slowly attacked in this way. To
i
avoid this problem, the PrNH2 can be replaced by ethanol (pKa
ꢀ16), which gives a comparable yield of the heterocycle, though
the reaction is not as clean.
Scheme 1. Synthesis of 4-mercapto-1,2-dithiole-3-thiones.
When the sulfur was added first and the mixture allowed to stir
for a few minutes before addition of the amine, a red solution was
obtained, which again produced a lower yield of 2a (43%). Surpris-
ingly, in the latter reaction, a 12% yield of the isomeric 1,3-dithiole-
2-thione was also obtained as a by-product;10 this implies that the
reaction of the acetylide anion with CS2 was either incomplete, or
was to some extent reversible. It is notable, however, that we did
not observe this product in any of our previous reactions where
an excess of sulfur was used.
Unfortunately, attempts to produce 4,5-disubstituted 1,2-
dithiole-3-thiones by quenching the proposed intermediate anion
4 with other electrophiles such as MeI, MeCOCl and Me3SiCl were
largely unsuccessful. A major problem is that electrophiles that
would also react with the alkynyldithiocarboxylate anion cannot
be added before the sulfur. It should be noted however that Otsubo
has experienced similar difficulties when trying to functionalise
the isomeric 1,3-dithiole-2-thiones prepared from acetylides, sul-
fur and CS2.11
Scheme 2. Synthesis of 1,2-dithiole-3-thiones.
Isothiocyanates are known to undergo attack by organolithiums
or Grignard reagents exclusively at the central carbon atom. For
example, treatment of ArNCS (Ar = 2,6-xylyl) with PhLi and BuI
gave an 82% yield of the thioimide, PhC(@NAr)SBu.12 This regiose-
lectivity has also been demonstrated for alkynyllithiums by Brand-
sma, leading to a synthesis of aminothiophenes.13 We therefore
explored whether isothiocyanates would react in the same way
as CS2 with alkynyllithium reagents and sulfur, initially under
the conditions of our original reaction in which an excess of sulfur
was employed.7 Addition of sulfur to the orange solution formed
by reaction of the acetylide with PhNCS [presumably containing
RC„CC(@NPh)SLi] at low temperature, followed by warming, gave
a red-purple solution which could be alkylated by MeI to give rea-
sonable yields of the 4-methylthio-3-phenylimino-1,2-dithioles 5
(Scheme 3). The structure of compound 5a was confirmed by
X-ray diffraction and is shown in Figure 1.14
Scheme 3. Synthesis of 4-methylthio-3-imino-1,2-dithioles.
methodology is successful not only for the thiones but also for the
analogous iminodithioles.
Deprotonation of phenylacetylene followed by reaction with
CS2 generated a solution of the alkynyldithiocarboxylate as previ-
ously described.7 At this point iPrNH2 (3 equiv) was added at
À78 °C, followed immediately by one equivalent of elemental sul-
fur. On warming, the solution turned orange-red (as opposed to the
magenta colour observed in the absence of amine) and purification
by column chromatography produced the orange-yellow desired
product, 5-phenyl-3H-1,2-dithiole-3-thione in 68% yield. The cor-
responding 1,2-dithiole-3-thiones were successfully formed from
We then tried to extend this synthesis to the corresponding 3-
imino-1,2-dithiole heterocycles 6, which are usually prepared by
the action of amines on dithiolium salts derived by alkylation of
Figure 1. Molecular structure of compound 5a in the crystal (ORTEP plot, 50% probability ellipsoids). Hydrogen atoms have been omitted for clarity.

H. Adams et al. / Tetrahedron Letters 55 (2014) 5283–5285
5285
J.; Joyner, H. H. Tetrahedron Lett. 1993, 34, 7231; (g) Curphey, T. J.; Libby, A. H.
Tetrahedron Lett. 2000, 41, 6977.
7. (a) Adams, H.; Chung, L.-M.; Morris, M. J.; Wright, P. J. Tetrahedron Lett. 2004,
45, 7671; (b) Adams, H.; McHugh, P. E.; Morris, M. J.; Spey, S. E.; Wright, P. J. J.
Organomet. Chem. 2001, 619, 209.
8. (a) Takimiya, K.; Morokami, A.; Otsubo, T. Synlett 1997, 319; (b) Mayer, R.;
Gebhardt, B.; Fabian, J.; Müller, A. K. Angew. Chem., Int. Ed. Engl. 1964, 3, 134; (c)
Mayer, R.; Hunger, B.; Prousa, R.; Müller, A. K. J. Prakt. Chem. 1967, 35, 294.
9. Typical experimental procedure: 5-phenyl-1,2-dithiole-3-thione (2a).
A solution of phenylacetylene (0.29 mL, 2.64 mmol) in THF (10 mL) was cooled
to À78 °C and treated with n-BuLi (1.65 mL of a 1.6 M solution in hexanes,
2.64 mmol), then warmed to room temperature and stirred for 30 min. At
À78 °C again, CS2 (0.16 mL, 2.72 mmol) was added; on warming to room
temperature and stirring for 1 h, the solution gradually turned a dark orange-
Scheme 4. Synthesis of 3-imino-1,2-dithioles.
the thiones 2.15 Our initial attempts using phenyl isothiocyanate in
place of CS2 with isopropylamine as the protonating agent were
frustrated by the isolation of by-products containing isopropyl
groups. However, on changing the protonating agent to ethanol,
we were pleased to find that the 3-imino-1,2-dithioles 6a–c were
formed in yields approaching quantitative (Scheme 4).16,17 In con-
trast, the reaction failed in the case of R = SiMe3, where the desily-
lated product appeared to be formed in low yield but could not be
successfully purified.
In conclusion, we have described a one-pot synthesis of 5-
substituted 1,2-dithiole-3-thiones and 3-imino-1,2-dithioles from
terminal alkynes. The good yields, mild conditions and simplicity
of the procedure make this an attractive route, especially in cases
where the alkyne is commercially available or easily synthesised.
i
red colour. It was cooled to À78 °C for a third time and PrNH2 (0.75 mL) and
sulfur (86.9 mg, 2.72 mmol of S) were added in quick succession, causing a
colour change to bright orange-yellow. The solution was warmed to room
temperature and allowed to stir for 1 h, then the solvent was removed in vacuo,
the residue absorbed on a small amount of silica and introduced to the top of a
silica column made up in light petroleum. Elution with light petroleum–CH2Cl2
(7:3) produced a large bright orange-yellow band of 2a (354.6 mg, 68%). Mp
122–124 °C (Lit. 124–125 °C).6d 1H NMR (250 MHz, CDCl3): d 7.71–7.47 (m, 6 H,
Ph+CH). 13C NMR (62.8 MHz, CDCl3): d 215.6 (C@S), 172.9 (CPh), 135.9, 132.2
(Cpara, CH), 131.7 (Cipso), 129.6, 126.9 (Cortho, Cmeta). MS (EI): m/z 210 (M+), 145
(MÀS2H)+.
10. Data for 4-phenyl-1,3-dithiole-2-thione: 1H NMR (250 MHz, CDCl3): d 7.45 (s,
5H, Ph), 7.13 (s, 1H); 13C NMR (62.8 MHz, CDCl3): d 212.3 (C@S), 146.3 (CPh),
131.1-126.5 (m, Ph), 122.0 (CH). MS (EI): m/z 210 (M+), 134 (MÀPh)+. The two
isomers are easily distinguished by their 1H NMR spectra and also by the
fragmentation pattern in their mass spectra. See Ref. 8 and also. Plavac, N.; Still,
I. W. J.; Chauhan, M. S.; McKinnon, D. M. Can. J. Chem. 1975, 53, 836.
11. (a) Morikami, A.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 1999, 1, 23; (b)
Otsubo, T.; Takimiya, K.; Aso, Y. Phosphorus Sulfur Silicon 2001, 171, 231.
12. Maeda, H.; Kambe, N.; Sonoda, N.; Fujiwara, S.; Shin-Ike, T. Tetrahedron 1996,
52, 12165. and references therein.
Acknowledgements
13. Tarasova, O. A.; Klyba, L. V.; Vvedensky, V. Y.; Nedolya, N. A.; Trofimov, B. A.;
Brandsma, L.; Verkruijsse, H. D. Eur. J. Org. Chem. 1998, 253.
We thank the University of Sheffield for support, and Prof. Fred
Wudl of the University of California, Santa Barbara for a useful dis-
cussion about this chemistry.
14. 5-Phenyl-4-methylthio-3-phenylimino-1,2-dithiole
phenylacetylene (0.29 mL, 2.64 mmol) in THF (18 mL) was deprotonated
with n-BuLi (1.65 mL of 1.6 M solution in hexanes, 2.64 mmol), then
(5a).
As
above,
a
treated with PhNCS (0.3 mL, 2.5 mmol) at À78 °C and allowed to warm to rt
and stir for 1 h. At À78 °C elemental sulfur (0.25 g, 7.8 mmol) was added,
causing an immediate colour change from orange-brown to dark red-purple.
After stirring for 1 h at room temperature, MeI (0.47 mL, 7.5 mmol) was added
Supplementary data
Crystallographic data for the structure determination of 5a have
been deposited with the Cambridge Crystallographic Data Centre,
reference number CCDC 1003706. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Supplementary data (char-
acterisation data for all compounds prepared) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.07.104.
and after stirring for a further 18 h the solvent was removed. Column
chromatography of the residue with an eluting solvent of light petroleum–
CH2Cl2 (2:3) produced an orange-brown oil which was recrystallised from a
mixture of the same solvents to give 5a as a yellow solid. Yield 374 mg, 45%. 1
H
NMR (250 MHz, CDCl3): d 7.58–7.14 (m, 10 H, Ph), 2.41 (s, 3 H, Me). 13C NMR
(62.8 MHz, CDCl3): d 168.1 (C@N), 160.8 (CPh), 151.7 (Cipso of NPh), 133.6,
125.4 (Cipso), 130.5-119.9 (m, Ph+C@C), 17.0 (Me). MS (EI): m/z 315 (M+).
Analysis Found: C, 60.60; H, 4.02; N, 4.27; S, 30.54. Calcd for C16H13NS3: C,
60.92; H, 4.15; N, 4.44; S, 30.49.
15. (a) Mollier, Y.; Lozac’h, N. Bull. Soc. Chim. Fr. 1961, 614; (b) Paulmier, C.; Mollier,
Y.; Lozac’h, N. Bull. Soc. Chim. Fr. 1965, 2463.
16. 3-Phenylimino-5-phenyl-1,2-dithiole (6a). A solution of LiC„CPh in THF (20 mL)
was prepared as above from phenylacetylene (0.29 mL, 2.64 mmol) and n-BuLi
(1.65 mL of a 1.6 M solution in hexanes, 2.64 mmol), then treated with PhNCS
(0.3 mL, 2.5 mmol) and allowed to stir for 1 h as above. The dark orange
solution was cooled to À78 °C again, and absolute ethanol (1.5 mL) and
elemental sulfur (86.4 mg, 2.7 mmol of S) were added in quick succession. The
now bright orange solution was allowed to warm to rt, then stirred overnight.
Work-up was done by column chromatography as above. Elution with light
petroleum–CH2Cl2 (4:1) removed two very faint yellow bands, followed by the
major orange-yellow fraction in a 1:1 mixture of the same solvents. Although
this band appears initially to split into two slightly different coloured zones,
the NMR spectra of all parts of the band are the same. We attribute this to slow
E/Z isomerisation at the imine nitrogen. The compound was recrystallised from
CH2Cl2 and light petroleum or from hot EtOH. Yield: 698.2 mg, 93%. Mp 128–
References and notes
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(e) Curphey, T. J.; Joyner, H. H. Tetrahedron Lett. 1993, 34, 3703; (f) Curphey, T.
130 °C (Lit. 131.5 °C).15 1H NMR (250 MHz, CDCl3):
d 7.62–7.09 (m, 11H,
Ph+CH). 13C NMR (62.8 MHz, CDCl3): d 170.3 (C@N), 160.2 (CPh), 151.9 (Cipso of
NPh), 132.6 (Cipso of CPh), 130.9–120.0 (7 peaks, Ph+CH). MS (EI): m/z 269 (M+),
204 (MÀS2H)+. HRMS: Found: 269.034186; calcd for C15H11NS2: 269.033293.
Analysis Found: C, 66.75; H, 4.07; N, 5.19; S, 23.64. Calcd for C15H11NS2: C,
66.91; H, 4.09; N, 5.20; S, 23.79.
17. In the case of ferrocenyl acetylene, a second product is formed in 21% yield and
will be reported elsewhere.