Synthesis of 1,4-dithiins from pentathiepins

Article abstract of DOI:10.1021/ol0617042

Fused aromatic and heterocyclic 1,2,3,4,5-pentathiepins react with triphenylphosphine and alkynes bearing electron-withdrawing groups to give the corresponding 1,4-dithiins in high yields. Unsymmetrical alkynes add regioselectively to afford products in agreement with the electron distribution in a proposed reaction intermediate. A mechanism for these reactions is proposed.

Full text of DOI:10.1021/ol0617042

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4529-4532
Synthesis of 1,4-Dithiins from
Pentathiepins
Stanislav A. Amelichev,† Lidia S. Konstantinova,† Natalia V. Obruchnikova,†
Oleg A. Rakitin,*,† and Charles W. Rees*,‡
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky
Prospect, 47, 119991 Moscow, Russia, and Department of Chemistry, Imperial College
London, London SW7 2AZ, U.K.
orakitin@ioc.ac.ru; c.rees@imperial.ac.uk
Received July 11, 2006
ABSTRACT
Fused aromatic and heterocyclic 1,2,3,4,5-pentathiepins react with triphenylphosphine and alkynes bearing electron-withdrawing groups to
give the corresponding 1,4-dithiins in high yields. Unsymmetrical alkynes add regioselectively to afford products in agreement with the electron
distribution in a proposed reaction intermediate. A mechanism for these reactions is proposed.
1,2,3,4,5-Pentathiepins are of particular interest among
polysulfur heterocycles because of their unusual stability,
stereochemistry, occurrence in nature, and significant bio-
logical activity.1 Many benzopentathiepins, including natural
products, possess strong anticancer, antimicrobial, and an-
tifungal activity resulting from the polysulfur moiety.1
Furthermore the use of pentathiepins in technical devices as
cathodic material in battery systems has recently been
proposed.2
intermediates such as 2a,b (Scheme 1), which may add
alkenes or alkynes to give 1,4-dithianes or 1,4-dithiins,
respectively.4 1,4-Dithiins have attracted considerable atten-
tion because of their biological activity, particularly as
fungicides and antibacterials.5
Given our ready one-pot preparation of heterofused
pentathiepins by treatment of nucleophilic heterocycles with
The chemistry of pentathiepins has been investigated
mainly for the benzo fused system 1.3 Its reactions are often
associated with the loss of from one to all five sulfur atoms.
Most frequently three sulfurs are extruded, possibly via
Scheme 1
† Russian Academy of Sciences.
‡ Imperial College London.
(1) Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W. Chem. ReV. 2004,
104, 2617.
(2) Tsutsumi, H.; Higashiyama, H.; Onimura, K.; Oishi, T. J. Power Sci.
2005, 146, 345.
(3) Chenard, B. L.; Harlow, R. L.; Johnson, A. L.; Vladuchick, S. A. J.
Am. Chem. Soc. 1985, 107, 3871.
10.1021/ol0617042 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/02/2006

disulfur dichloride,6 we wished to extend this work to the
mild formation of fused 1,4-dithiins generally, to develop
their chemistry and biological activity further.
Scheme 3
6-Methyl-6H-[1,2,3,4,5]pentathiepino[6,7-b]pyrrole 3, readily
prepared from N-methylpyrrole or N-methylpyrrolidine with
S2Cl2 and Dabco in dichloromethane,6 was treated with
DMAD with reagents to remove sulfur atoms from the
penathiepin ring. Compound 3 was shown not to react with
DMAD (5 equiv) alone on heating under reflux for 10 h in
dichloromethane or chloroform.
In the presence of DMAD, sodium phenylsulfinate (PhSO2-
Na), sodium cyanide, and triphenylphosphine each removed
three atoms of sulfur from pentathiepin 3 to form sodium
phenylthiosulfinate (PhSO2SNa), sodium thiocyanate (NaSCN),
and triphenylphosphine sulfide in high yield (94-99%). With
PhSO2Na, dithiin 4 was not formed, and only oligomeric
products (NMR and mass spectra) were isolated from the
reaction mixture. DMAD reacted smoothly with pentathiepin
3 and NaCN or Ph3P to give 4 in 83 and 80% yields,
respectively, after 1 h at room temperature (Scheme 2).
Scheme 2
Treatment of N-isopropylpyrrolidine with S2Cl2 and Dabco
gave the only characterized bis-pentathiepin 11;6 with
DMAD/Ph3P this could give a bis-dithiin, 12, possibly via
the monopentathiepin 15. When bis-pentathiepin 11 (1 equiv)
was treated with DMAD (10 equiv) and Ph3P (6 equiv) in
DCM at room temperature for 1 h it gave only the red bis-
dithiin 12 in 78% yield. With 11 (1 equiv), DMAD (1 equiv),
and Ph3P (3 equiv), we isolated a lower yield (54%) of the
same bis-dithiin 12, together with recovered 11 (18%). The
unsymmetrical product 15 was not obtained nor detected,
suggesting that attack by Ph3P and DMAD on the second
pentathiepin ring of 11 started before that on the first was
complete (see reaction mechanism).
Although both reagents gave high yields of the dithiin,we
chose triphenylphosphine as our standard because it is less
toxic and required much less organic solvent than NaCN.
Triphenylphosphine alone does react smoothly with 3 in
DCM at room temperature to remove three atoms of sulfur;
more than 3 equiv of triphenylphosphine leaves the excess
of reagent unchanged and isolable by column chromatog-
raphy, together with 3 equiv of Ph3PdS. The best conditions
for conversion of 3 into dithiin 4 (yield 86%) were stirring
3 in DCM with Ph3P (4 equiv) and DMAD (3 equiv) at room
temperature for 1 h. These conditions were employed for
the heterofused pentathiepins 5, 7, 9, and 11 recently
prepared6,7 and for benzopentathiepin 13;8 all of the corre-
sponding fused mono- and bis-1,4-dithiins 6, 8, 10, 12, and
14 were isolated in the high yields shown (Schemes 3 and
4).9
Another alkyne with two electron-withdrawing groups,
dibenzoylacetylene, reacted in the same way as DMAD,
under the same conditions, to give the dibenzoyldithiins 16-
19 from 5, 7a, 9, and 13, respectively, in the yields shown
in Figure 1.
Scheme 4
(4) Sato, R.; Chino, K.; Saito, M. Sulfur Lett. 1990, 10, 233.
(5) Guillaumet, G. ComprehensiVe Heterocyclic Chemistry II; Boulton,
A. J., Ed.; Pergamon: Oxford, 1996; Vol. 6, p 448.
(6) Amelichev, S. A.; Konstantinova, L. S.; Lyssenko, K. A.; Rakitin,
O. A.; Rees, C. W. Org. Biomol. Chem. 2005, 3, 3496.
(7) Rewcastle, G. W.; Janosik, T.; Bergman, J. Tetrahedron 2001, 57,
7185.
(8) Fehe´r, F.; Langer, M. Tetrahedron Lett. 1971, 2125.
(9) Typical Experimental Procedure. A solution of triphenylphosphine
(4 mmol) in dichloromethane (3 mL) was added dropwise to a stirred
solution of appropriate pentathiepin (1 mmol) and appropriate alkyne (3
mmol) in dichloromethane (10 mL) at room temperature. The reaction
mixture was stirred for 1 h, solvent was evaporated under reduced pressure,
and the corresponding dithiin was separated by column chromatography
(silica gel Merck 60).
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Org. Lett., Vol. 8, No. 20, 2006

Scheme 6
The much less reactive phenylacetylene did not react with
Ph3P and pentathiepins 3, 7a, or 9 to give dithiins; the
pentathiepins were decomposed in the same way (TLC) as
by Ph3P alone.
To gain some insight into the mechanism for the formation
of 1,4-dithiins from the pentathiepins (see Scheme 7), we
Figure 1. Dibenzoyldithiins 16-19 obtained.
Alkynes with only one electron-withdrawing group are of
particular interest because, with unsymmetrical pentathiepins,
they could lead to a pair of regioisomers. We therefore
examined the above reactions but with DMAD replaced by
methyl propiolate. This reacted under the same conditions
with pentathiepinopyrrole 3 and triphenylphosphine to give
dithiin 20, accompanied by baseline material from 3 and
triphenylphosphine also observed (TLC) in the absence of
methyl propiolate. No evidence for regioisomer 20a was
Scheme 7
1
observed in the H and 13C NMR spectra (Scheme 5).
Scheme 5
investigated the reaction of N-methylindolopentathiepin 9,
which is less reactive than other pentathiepins toward Ph3P
and DMAD. When Ph3P (1 equiv) was added to 9 (1 equiv),
the reaction mixture still contains a substantial amount of 9;
another 1 equiv of Ph3P caused the complete disappearance
of 9. If DMAD is added to this mixture, there is no reaction.
Possibly the sequential removal of sulfur atoms from the
pentathiepin does not stop at the tetrathiin (e.g., 24) but
proceeds to the trithiole (e.g., 25); Ph3PdS is formed
immediately after the addition of Ph3P. Addition of a third
equivalent of Ph3P led to complete removal of the pentathi-
epin, but no products were isolated from it; however, if
DMAD was added to the reaction mixture before adding the
third equivalent of Ph3P, or immediately after, dithiin 10 was
formed in high yields (80-90%). No products were observed
from the breaking of any carbon-sulfur bonds by Ph3P. The
preliminary observations above with methyl propiolate
suggest that unsymmetrical pentathiepinopyrroles react with
this alkyne regioselectively. This can also be accommodated
by a proposed mechanism (Scheme 7) shown for the reaction
of the pentathiepinopyrrole 3.
The molecular formula of 20 was based on elemental
1
analysis and mass spectra. According to H and 13C NMR
spectra, only one isomer is formed in this reaction. The exact
structure of 20 was determined by an HMBC experiment10
elucidating long-range hydrogen-carbon correlations (see
Supporting Information). There are two strong correlations
between pyrrole C(2) atom (δ ) 115.0 ppm) and 1,4-dithiin
C-H proton (δ ) 7.4 ppm) and protons of the N-methyl
group (δ ) 3.5 ppm) through three bonds, confirming the
structure 20; these interactions would not be observed with
20a (Scheme 5).
A similar result was obtained in the reaction of pyrrolo-
pentathiepin 21 with the same mixture of methyl propiolate
and triphenylphosphine. Again one dithiin 22 was isolated,
and its structure was proved, as for 20, by spectra and an
HMBC experiment (Scheme 6).
The symmetrical pyrrolopentathiepin 7a gave 1,4-dithiin
23 (40%); indolopentathiepin 9 did not react with methyl
propiolate but was decomposed by the action of triph-
enylphosphine.
It is likely that in the 1,2-dithione intermediate 26a the
thioamide electronic contribution 26c will be greater than
(10) Bax, A.; Summers, M. F. J. Am. Chem. Soc. 1986, 108, 2093.
Org. Lett., Vol. 8, No. 20, 2006
4531

26b; thus S-2 will be more nucleophilic than S-3 and addition
to methyl propiolate would occur as shown to give the
observed regioisomer 20. It is also possible, in a slightly
more complex mechanism, that once the polysulfur rings are
opened by Ph3P to give dipolar intermediates, their terminal
sulfide anions could add to the triple bond before loss of
Ph3PS, but the same overall electronic considerations should
apply.
Basic Research (grant no. 05-03-32032), and an RSC
Research Fund Grant to O. A. R. We thank Dr. P. A.
Belyakov for his expert help in NMR experiments.
Supporting Information Available: Experimental pro-
cedure and full characterization for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We gratefully acknowledge financial
support from the Royal Society, the Russian Foundation for
OL0617042
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Org. Lett., Vol. 8, No. 20, 2006