A convenient route to 4-mercapto-1,2-dithiole-3-thiones from terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2004.08.091

Sequential treatment of terminal alkynes with n-butyllithium, carbon disulfide and elemental sulfur gives 4-mercapto-1,2-dithiole-3-thiones in good yields after acidic workup.

Full text of DOI:10.1016/j.tetlet.2004.08.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7671–7674
A convenient route to 4-mercapto-1,2-dithiole-3-thiones
from terminal alkynes
Harry Adams, Lai-Ming Chung, Michael J. Morris* and Penelope J. Wright
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
Received 24 June 2004; revised 11 August 2004; accepted 17 August 2004
Abstract—4-Mercapto-1,2-dithiole-3-thiones are easily prepared by deprotonation of terminal alkynes followed by sequential treat-
ment with carbon disulfide, sulfur and acid; addition of alkylating agents at the last stage gives 4-alkylthio-1,2-dithiole-3-thiones
instead.
Ó 2004 Elsevier Ltd. All rights reserved.
Compounds containing the 3H-1,2-dithiole-3-thione
ring system have been known for many years, and have
recently attracted interest as cancer preventive agents. In
particular, Oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-
3-thione), a compound originally developed as an anti-
schistosomal agent, has undergone large scale clinical
trials in this respect, and simpler derivatives can also
be effective.1 There are many methods available for the
synthesis of such compounds,2 the majority of which
require the use of sulfurising agents such as P2S5,3
LawessonÕs reagent, H2S4 or sulfur at high tempera-
tures.5 Our involvement in this area began when we
recently discovered an interesting organometallic route
to an otherwise inaccessible example.6 We now report
an extremely useful one-pot route to simple 5-substi-
tuted 4-mercapto-1,2-dithiole-3-thiones from terminal
alkynes. The advantages of this method are twofold:
all the stages of the reaction take place at or below room
temperature, and the only sources of sulfur involved are
carbon disulfide and elemental sulfur itself.
A recent paper by Otsubo and co-workers described the
synthesis of 1,3-dithiole-2-thiones by sequential addition
of sulfur and CS2 to deprotonated terminal alkynes
(Scheme 1).7 We reasoned that it might be possible to
produce the isomeric 1,2-dithiole-3-thiones by addition
of the same reagents in the opposite order (Scheme 2).
At first this idea did not look promising: we were able
to find only one literature example of the addition of
an alkynyl-lithium (MesCꢀCLi) to CS2,8 and although
methylation of the resulting anion gave a stable dithio-
carboxylate ester, those derived from smaller aryl
groups were described as thermally unstable. However,
our initial investigations revealed that simple alkynyl-
lithiums do add readily to CS2 to give red solutions,
which are stable at room temperature for at least several
Scheme 1. OtsuboÕs synthesis of 1,3-dithiole-2-thiones (Ref. 7).
Keywords: 1,2-Dithiole-3-thiones; Alkynes; Carbon disulfide; Sulfur.
*
Corresponding author. Tel.: +44 114 2229363; fax: +44 114 2229346; e-mail: m.morris@sheffield.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.091

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H. Adams et al. / Tetrahedron Letters 45 (2004) 7671–7674
Scheme 2. Synthesis of 4-mercapto-1,2-dithiole-3-thiones.
hours, from which the alkynyldithiocarboxylates can be
isolated by coordination to metal centres.9
and H2S, though to our knowledge a full report of this
reaction has never appeared.10
When a red solution formed by addition of CS2 to
PhCꢀCLi in THF was treated with elemental sulfur, a
rapid colour change to red-purple occurred. After stir-
ring for 1h, the reaction was subjected to acidic work-
up and extraction into dichloromethane, followed by
column chromatography, from which an orange powder
Crystallisation of compound 2a from THF/ethanol pro-
vided dark orange crystals suitable for X-ray diffraction.
The resulting structure is shown in Figure 1. While con-
firming our identification of 2a, the result was slightly
unexpected in that the compound had been oxidised
during crystallisation to the corresponding disulfide 3
(a reaction well documented for the isomeric 4-substi-
tuted-5-mercapto-1,2-dithiole-3-thiones).11,12 Although
the disulfide is much less soluble than 2a, we were able
to confirm the absence of the –SH proton resonance in
the 1H NMR spectrum of the crystals used for the struc-
ture determination.
1
was isolated. However its H NMR spectrum did not
match that of 5-phenyl-1,2-dithiole-3-thione,4 and the
mass spectrum indicated the incorporation of an extra
sulfur atom. Moreover the peak at d 5.98 in the 1H
NMR spectrum, integrating as 1H, disappeared when
the sample was treated with a drop of D2O. We there-
fore identified the product as 5-phenyl-4-mercapto-1,2-
dithiole-3-thione (2a), formed by further attack of the
intermediate anion I on sulfur prior to work-up. This
compound was briefly mentioned in the literature as a
product of the sulfuration of 1-phenylpropene by sulfur
Extension of the reaction to other terminal alkynes re-
sulted in the preparation of the analogous mesityl (2b)
and t-butyl (2c) derivatives in comparable yields. More-
over, when the reaction mixtures were quenched with
˚
Figure 1. Molecular structure of [PhCSSC(@S)CS]2 3 in the crystal. Selected bond lengths (A): S(1)–S(6) 2.057(3), S(1)–C(8) 1.761(10), S(2)–C(9)
1.647(10), S(5)–C(7) 1.734(11), S(5)–S(7) 2.066(4), S(7)–C(9) 1.716(9), C(7)–C(8) 1.390(14).

H. Adams et al. / Tetrahedron Letters 45 (2004) 7671–7674
7673
˚
Figure 2. Molecular structure of PhCSSC(@S)C(SMe) 4a in the crystal. Selected bond lengths (A): S(1)–C(3) 1.741(3), S(1)–S(3) 2.0518(10), S(2)–
C(2) 1.766(3), S(3)–C(1) 1.737(3), S(4)–C(3) 1.651(3), C(1)–C(2) 1.376(4).
1
methyl iodide rather than HCl, work-up afforded 4-
methylthio-5-substituted-1,2-dithiole-3-thiones 4a–c,
116–118°C. H NMR d 7.75–7.55 (m, 5H, Ph), 5.98 (s,
1H, SH). 13C NMR: d 206.0 (C@S), 160.9, 139.1
(C@C), 134.1–128.8 (m, Ph). Found: C, 44.60; H, 2.21;
S, 52.69%. Calcd for C9H6S4: C, 44.60; H, 2.50; S,
52.89%. MS m/z 242 (M+), 209 (MÀSH)+.
again in similar yields. Of these, 4a is the only one pre-
pared previously, most effectively by a reaction involv-
ing sequential treatment of PhCOCH2SMe with KH,
CS2, S(SiMe3)2 and C2Cl6.13 To confirm the nature of
the product, the crystal structure of 4a was also deter-
mined and is shown in Figure 2, with selected bond
lengths and angles given in the caption. The heterocyclic
ring lies almost coplanar with the phenyl substituent,
with the methyl group attached as expected to S(2).
Bond lengths within the ring are typical for this type
of heterocycle.
1
Compound 2b: yield 61%. Mp 119–121°C. H NMR:
7.05 (s, 2H, CH), 5.35 (s, 1H, SH), 2.37 (s, 3H, Me),
2.15 (s, 6H, 2 Me). 13C NMR: d 207.1 (C@S), 160.3,
140.5 (C@C), 140.8 (CMe), 136.8 (2CMe), 129.0 (CH),
21.2 (Me), 19.5 (2Me). Found: C, 50.88; H, 4.49; S,
43.63%. Calcd for C12H12S4: C, 50.67; H, 4.25; S,
45.07%. MS m/z 284 (M+), 269 (MÀMe)+.
1
In conclusion we have described a general synthesis of
4-thio-5-substituted-3H-1,2,-dithiole-3-thiones from read-
ily available, relatively innocuous, and inexpensive start-
ing materials, which occurs under unusually mild
conditions in THF solution. Further investigations of
the chemistry of these heterocycles are continuing.
Compound 2c: yield 44% of an orange-brown oil. H
NMR: d 6.65 (1H, SH), 1.55 (9H, Me). 13C NMR:
d 207.0 (C@S), 174.9, 137.5 (C@C), 39.0 (CMe3), 27.4
(Me). MS m/z 222 (M+), 207 (MÀMe)+. HRMS (electro-
spray) m/z 222.9735 (M+H+); calcd for C7H11S4:
222.9744.
Typical experimental procedure (synthesis of 2a). A solu-
tion of phenylacetylene (0.29mL, 2.64mmol) in THF
(18mL), at À78°C, was treated dropwise with n-BuLi
(1.65mL of a 1.6M solution in hexanes) and allowed
to warm to room temperature. After 30min stirring
the solution was cooled again to À78°C and CS2
(0.15mL, 2.5mmol) was added. The pale yellow solution
was allowed to warm to room temperature and then stir-
red for 1h, giving a red solution of the alkynyldithio-
carboxylate, to which was added sulfur (0.25g,
7.92mmol), causing a rapid further colour change to
magenta. After stirring for a further 1h, an excess of
2M HCl was added, giving an orange-red mixture.
The solvent was removed and the residue partitioned be-
tween CH2Cl2 and water; the organic layer was dried
(Na2SO4) and evaporated, then chromatographed (silica
gel). Elution with light petroleum–CH2Cl2 (9:1) afforded
a yellow band, which produced an orange powder of 2a
on evaporation. Yield 0.3409g, 53%.
Compound 4a: yield 50%. Mp 68–72°C. 1H NMR:
7.70–7.50 (m, 5H, Ph), 2.25 (s, 3H, Me). 13C NMR: d
213.6 (C@S), 174.3, 139.4 (C@C), 133.2–128.8 (m, Ph),
16.7 (Me). Found: C, 47.98; H, 3.16; S, 47.28%. Calcd
for C10H8S4: C, 46.87; H, 3.13; S, 50.00%. MS: m/z
256 (M+), 241, 223. HRMS m/z 255.9510; calcd for
C10H8S4: 255.9509.
1
Compound 4b: yield 49%. Mp 72–75°C. H NMR: d
7.00 (2H, CH), 2.35 (3H, Me of mes), 2.25 (3H, SMe),
2.10 (6H, Me). 13C NMR: d 213.9 (C@S), 174.3
(C@C), 140.5 (CMe + C@C), 136.6 (2CMe), 128.9
(CH), 21.5, 20.3 (Me), 15.6 (SMe). Found: C, 52.67;
H, 4.74; S, 43.39%. Calcd for C13H14S4: C, 52.31; H,
4.73; S, 42.97%. MS m/z 298 (M+), 283 (MÀMe)+.
1
Compound 4c: yield 38% of an orange-brown oil. H
NMR: d 2.40 (3H, SMe), 1.45 (9H, Me). 13C NMR: d
211.1 (C@S), 157.7, 129.6 (C@C), 38.0 (CMe3), 30.6
(3Me), 21.3 (SMe). MS m/z 236 (M+), 221 (MÀMe)+.
HRMS (electrospray) m/z 236.9903 (M+H+); calcd for
C8H13S4: 236.9900.
Selected spectroscopic data (1H NMR 250.13MHz, 13C
NMR 62.9MHz, all in CDCl3). Compound 2a: mp

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H. Adams et al. / Tetrahedron Letters 45 (2004) 7671–7674
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X-ray crystal structure data for 3: C9H5S4, M = 241.37,
trigonal, space group P32, a = b = 8.0049(9),
3
˚
˚
c = 26.433(4)A, a = b = 90°, c = 12 0°, V = 1466.9(3)A ,
Z = 6. MoKa radiation, l = 0.914mmÀ1, T = 150(2)K,
9370 reflections collected, 3401 independent reflections
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X-ray crystal structure data for 4a: C10H8S4,
M = 256.40, monoclinic, space group C2/c, a =
˚
23.651(4), b = 5.5964(9), c = 16.126(3)A, a = c = 90,
3
˚
b = 90.781°, V = 2134.3(6)A , Z = 8. Moa radiation,
l = 0.843mmÀ1, T = 150(2)K, 6163 reflections col-
lected, 2577 independent reflections (Rint = 0.0655),
R1 = 0.0422, wR2 = 0.1033. Final R indices (all data)
R1 = 0.0640, wR2 = 0.1127.
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Crystallographic data for the structure determinations
of 3 and 4a have been deposited with the Cambridge
Crystallographic data centre, CCDC reference numbers
240542 and 240543, respectively. Copies of this informa-
tion may be obtained free of charge from The Director,
CCDC, 12Union Road, Cambridge CB21EZ, UK (fax:
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Acknowledgements
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We thank Joanne Hinsley and Paul McHugh for prelim-
inary experiments and the Nuffield Foundation for
financial support of initial aspects of the work, which
led to this paper. Some of the results described here were
first presented at the 19th International Symposium on
the Organic Chemistry of Sulfur, held in Sheffield in
June 2000.
References and notes
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