Synthesis of thienothiopyranthiones by a new molecular rearrangement

Article abstract of DOI:10.1021/ol0476669

(Chemical Equation Presented) On heating with alkynes, the readily prepared 1,3-dithioles 3 undergo a new cycloaddition reaction and an unprecedented molecular rearrangement with loss of chlorine to give the first 7H-thieno[2,3-c]thiopyran-7-thiones 4 and

Full text of DOI:10.1021/ol0476669

ORGANIC
LETTERS
2005
Vol. 7, No. 5
791-794
Synthesis of Thienothiopyranthiones by
a New Molecular Rearrangement
Vladimir A. Ogurtsov,† Oleg A. Rakitin,*,† Charles W. Rees,*,‡
Alexey A. Smolentsev,† Pavel A. Belyakov,† Denis G. Golovanov,§ and
Konstantin A. Lyssenko§
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky Prospect, 47, 119991 Moscow, Russia, Department of Chemistry,
Imperial College of Science, Technology and Medicine, London, UK SW7 2AZ, and
A. N. NesmeyanoV Institute of Organoelement Compounds, Russian Academy of
Sciences, VaViloV Str., 28, 119991 Moscow, Russia
orakitin@ioc.ac.ru
Received November 12, 2004
ABSTRACT
On heating with alkynes, the readily prepared 1,3-dithioles 3 undergo a new cycloaddition reaction and an unprecedented molecular rearrangement
with loss of chlorine to give the first 7H-thieno[2,3-c]thiopyran-7-thiones 4 and 4H-thieno[3,2-c]thiopyran-4-thiones 5 whose structures were
confirmed by X-ray diffraction. Unexpectedly, the different alkynes used to form 3 and to convert it into 4 and 5 were incorporated regiospecifically
into the thiophene and thiopyran rings, respectively.
There is much current interest in the use and mode of action
of 1,2-dithiole-3-thiones as cancer chemopreventive agents.
4-Methyl-5-pyrazinyl-1,2-dithiole-3-thione, oltipraz 1, is one
of the most promising agents against environmentally
induced hepatocellular carcinoma1 and other cancers.2 1,2-
Dithiole-3-thione itself also protects against neoplasia.3
We wished therefore to extend the range of 1,2-dithiole-
3-thiones available and to explore their chemistry further.
One of their most interesting properties is to act as masked
dipoles in 1,3-cycloaddition to electron-deficient alkynes.4
The first cycloaddition is accompanied by heterocyclic ring
opening to give a 1:1 adduct (as in Scheme 1), which under
more vigorous conditions adds a second alkyne in a Diels-
Alder reaction to give a 1,4-dihydrothiopyran.5
† N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences.
We have recently shown6 that 4,5-dichloro-1,2-dithiole-
3-thione 2, readily prepared from 3,4,5-trichloro-1,2-dithio-
‡ Imperial College of Science, Technology and Medicine.
§ A. N. Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences.
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J. C. J. Org. Chem. 2002, 67, 9406 and refs cited therein. Barriga, S.;
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3, Chapter 3.11, p 593.
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10.1021/ol0476669 CCC: $30.25
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(r) ) 1.56 e Å-5) for S(2)‚‚‚S(3) contact (2.945 Å), which
according to Bader’s “Atoms in Molecule” theory9 serves
as criteria of the chemical bond formation.
Scheme 1
Treatment of 4,5-dichloro-1,2-dithiole-3-thione 2 with
DMAD (3 equiv) in xylene at room temperature, followed
by heating under reflux for 30 h, or heating the adduct 3a
with DMAD (2.5 equiv) in xylene for 30 h did not give the
expected Diels-Alder adduct. The reaction took an entirely
different course not observed in the absence of the chlorine
substituents. It gave an approximately equimolecular mixture
(1H NMR spectroscopy) of 7H-thieno[2,3-c]thiopyran-7-
thione 4aa and 4H-thieno[3,2-c]thiopyran-4-thione 5aa in
lium chloride,7 undergoes the same initial 1,3-cycloaddition
to DMAD to give the adduct 3 almost quantitatively at room
temperature. For an aliphatic thioacyl chloride, 3 is unusually
stable but still highly reactive toward nucleophiles such as
ortho-substituted anilines to give benzimidazole, benzox-
azole, and benzothiazole derivatives of 1,3-dithioles.6 Thioa-
cyl chloride 3 and all the other thioacyl chlorides prepared
(see below) are stable, deep red solids. Their stability was
attributed to a significant interaction between the thiocarbonyl
and a heterocyclic sulfur atom, which could reduce the
electrophilicity of the thiocarbonyl group.6 This is now
supported by an X-ray crystal structure determination of 3a,
which shows the planarity of the quasibicyclic portion of
the molecule, with a partial S‚‚‚S bond length of 2.91 Å about
midway between a normal S-S bond (2.05 Å) and the sum
of its van der Waals radii (3.68 Å) (Figure 1).8
1
55% yield. The structures were fully supported by H and
13C NMR and mass spectrometry, and that of 4aa was proved
by X-ray crystallography (Figure 2).8
Figure 2. X-ray structure of molecule 4aa.
Thus, overall, 2 equiv of DMAD added to dithiolethione
2 with expulsion of its two chlorine atoms (Scheme 2).
Scheme 2
Figure 1. X-ray structure of molecule 3a.
The presence of the S(2)‚‚‚S(3) interaction is also reflected
in the elongation of the S(2)-C(3) bond (1.749(3) Å) in
comparison to S(1)-C(2) (1.740(3) Å). In addition, topologi-
cal analysis of the electron density function F(r) in 3a
according to B3LYP/6-31G* calculation has revealed the
presence of the critical point (3,-1) (F(r) ) 0.17 e Å-3, 32F-
When DMAD was replaced by diethyl acetylenedicar-
boxylate and by dibenzoylacetylene, equimolecular pairs of
isomers (4bb + 5bb) and (4cc + 5cc) exactly analogous to
4aa and 5aa were formed in 50 and 32% yields, respectively.
(6) Ogurtsov, V. A.; Rakitin, O. A., Rees, C. W.; Smolentsev, A. A.
Mend. Commun. 2003, 50.
(7) Wentrup, G.-J.; Koepke, M.; Boberg, F. Synthesis 1975, 525.
(8) X-ray data for 3a, 4aa, 5bb, 5bc, and 5cb have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 255373-255377 and are also available in Supporting
Information.
(9) Bader, R. F. W. Atoms In Molecules. A Quantum Theory; Clarendron
Press: Oxford, 1990
792
Org. Lett., Vol. 7, No. 5, 2005

These isomers were separated by chromatography and
recrystallization from methanol; all isomers 4 are red and 5
are yellow (see electronic spectra in Supporting Information).
Products 4 and 5 are examples of relatively rare ring systems
(Scheme 3).10
9812 program was used for calculations. The best match of
experimental and calculated 13C NMR data for compound
4aa has been obtained for the structure confirmed by X-ray
analysis (Figure 2). The results of comparing the experi-
mental and DFT PBE13 13C NMR data, obtained for
compound 5aa with a quite different structure (Scheme 3),
also agreed with X-ray analysis. 13C NMR signals of cyclic
carbons for other isomers of 4 and 5 are similar to 4aa or
5bb, respectively. Additional support for the structures of
the isomeric pairs came from their electronic spectra. All
the red isomers 4 had characteristic bands at λmax 254-268
nm (ꢀ ) 15 000-34 000), 336-348 nm (ꢀ ) 11 000-
17 000), and 420-467 nm (ꢀ ) 4000-6700), and all the
yellow isomers 5 had λmax at 258-269 nm (ꢀ ) 23 000-
36 000) and 373-397 nm (ꢀ ) 9500-16 600).
Scheme 3
To our surprise, however, we found that in every case the
substituents R1 in 3 from the first alkyne to be reacted
appeared in the thiophene ring of the products 4 and 5, and
the second alkyne substituents R2 appeared in the thiopyran
ring, implying an unexpectedly convoluted and unprece-
dented rearrangement that we are now investigating. One
possible pathway is tentatively suggested in Scheme 4.
Consideration of the most direct pathways from the 1,3-
dithiole 3 and the second alkyne to the thienothiopyrans 4
and 5 suggested that the methoxycarbonyl groups would
appear in the six-membered ring and the substituents on the
second alkyne in the five-membered ring. To examine this,
we repeated the reaction of each of the three 1,3-dithioles
3a-c with each of the three alkynes R2-t-R2, R2 ) CO2-
Me, CO2Et, and COPh. These nine reactions each gave a
pair of isomeric thienopyrans in the yields shown in Table
1. Of these isomers, 14 of the 18 were isolated pure, and
Scheme 4 a
Table 1. Yields of 4 and 5 (Schemes 2 and 3)
R1
CO2Me
55%
CO2Et
53%
C(O)Ph
33%
CO2Me
CO2Et
C(O)Ph
4aa
5aa
4ba
5ba
4ca
5ca
1:1
1:1
1:1
57%
50%
4bb
43%
4cb
R2
4ab
5ab
5bb
5cb
1:1
1:1
1:2
49%
30%
32%
4ac
5ac
4bc
5bc
4cc
5cc
1:1
2:3
1:1
the structure of three more of them, 5bb, 5bc, and 5cb, were
proved by X-ray crystallography.8 The structures of the
isolated isomers were based on spectroscopic comparison
of calculated and experimental 13C NMR spectra. 13C NMR
spectra of various isomers of compounds 4aa and 5aa have
been calculated by the method DFT/GIAO/B3LYP/6-31G*11
(structure optimization with B3LYP/6-31G*). The Gaussian
a Typical Experimental Procedure. A mixture of 3 (2 mmol) and
alkyne (5 mmol) was refluxed in xylene (20 mL) until compound
3 disappeared on TLC. The solvent was evaporated, and the residue
was separated by column chromatography (Silica gel Merck 60).
Single isomers were isolated by further column chromatography
(Silica gel Merck 60) and/or crystallization of a mixture of isomers
from methanol and/or from a mixture of hexane-toluene or
hexane-ethyl acetate. Yields are given in Table 1.
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T. E.; Hamel, C. R. J. Org. Chem. 1970, 35, 816 and 821. Schuijl-Laros,
D.; Schuijl, P. J. W.; Brandsma, L. Recl. TraV. Chim. 1972, 91, 785. Alam,
I.; Thyagarajan, G. Tetrahedron 1973, 29, 1829. Grafing, R.; Brandsma,
L. Synthesis 1978, 578. Grafing, R.; Brandsma, L. Recl. TraV. Chim. 1980,
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In the reaction of thioacyl chloride 3 with the second
alkyne, the intramolecular S‚‚‚S interaction may suppress
Org. Lett., Vol. 7, No. 5, 2005
793

the Diels-Alder cycloaddition referred to above in favor of
a sequence of heterocyclic ring-opening and -closing reac-
tions. This could give initially the isomeric thioacyl chloride
6, possibly in a concerted rearrangement; 6 could then
collapse to the bicyclic systems 7 and 8, the latter undergoing
ring opening to give 9, which could react with the second
alkyne to give 10. Aromatization of 10 by dechlorination
would give the observed product 5. Alternatively, 9 could
rearrange via 11 to give the regioisomer (12) of 8, which
would react with the second alkyne in the same way via 13
to give the other observed product 4.
by adding the appropriate alkyne (3 equiv) at room temper-
ature, followed by heating under reflux, to give 4aa/5aa
(57%), 4bb/5bb (52%), and 4cc/5cc (35%).
As expected, dithiole-thione 2 reacted similarly but much
more slowly with monosubstituted alkynes R-t-H (R )
CO2Me, Ph) (Scheme 5). Methyl propiolate required reflux-
Scheme 5
The formation of the heteroaromatic products 4 and 5 from
3 plus an alkyne by the loss of Cl2 suggested the formation
and subsequent dechlorination of dichloro adducts of the
aromatic systems such as 10 and 13. In keeping with this,
we found that treatment of o-xylene with Cl2 gas gave
4-chloro-1,2-xylene and 3,3′,4,4′-tetramethylbiphenyl as the
major products, and treatment of 3a with DMAD in boiling
o-xylene gave 4aa and 5aa, as before, together with exactly
the same chlorination byproducts.
ing in toluene for 3 h, and phenylacetylene required refluxing
in toluene for 32 h. Both gave inseparable mixtures of two
red thioacyl chlorides 14a and 15a (ratio 1:3) and 14b and
15b (ratio 2:3).
When R1 ) R2 ) CO2Me, CO2Et, or COPh, this new
synthesis of thienothiopyrans 4 and 5 can be readily
performed in one pot from the dithiole-thione 2 in xylene
Acknowledgment. We gratefully acknowledge financial
support from the Royal Society, MDL Information Systems
(UK), Ltd., and an RSC Journals Grant to O.A.R. We thank
Dr. V. P. Anannikov for calculations and the Wolfson
Foundation for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College.
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Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
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Supporting Information Available: Experimental pro-
cedure and full characterization for compounds 3-5 and
theoretical calculations for 4 and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
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