Synthesis of 1,3-dithiin dithioortho esters from the reaction of Fischer carbenes and 3H-1,2-dithiole-3-thiones

Article abstract of DOI:10.1021/jo052168e

Tricyclic 4-ethyl-5-thioxo-3H,5H-bis[1,2]dithiolo[3,4-d][4,3-b]pyrrol-3-one and monocyclic 3H-1,2-dithiole-3-thione derivatives reacted with Fischer carbene complexes, giving 1,3-dithiin dithioortho esters through insertion of the carbenic carbon into the S-S bond next to the thiocarbonyl function of the substrate.

Full text of DOI:10.1021/jo052168e

Synthesis of 1,3-Dithiin Dithioortho Esters from
the Reaction of Fischer Carbenes and
3H-1,2-Dithiole-3-thiones
Alejandro M. Granados,*,† Jeronimo Kreiker,†
Rita H. de Rossi,† Pedro Fuertes,‡ and Toma´s Torroba*,‡
Instituto de InVestigaciones en F´ısico Qu´ımica de Co´rdoba
(INFIQC), Departamento de Qu´ımica Orga´nica, Facultad de
Ciencias Qu´ımicas, UniVersidad Nacional de Co´rdoba,
Ciudad UniVersitaria, 5000 Co´rdoba, Argentina, and
Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad de
Burgos, 09001 Burgos, Spain
ale@dqo.fcq.unc.edu.ar; ttorroba@ubu.es
ReceiVed October 18, 2005
FIGURE 1. Single-crystal X-ray diffraction structure of 3a.
SCHEME 1
Tricyclic 4-ethyl-5-thioxo-3H,5H-bis[1,2]dithiolo[3,4-d][4,3-
b]pyrrol-3-one and monocyclic 3H-1,2-dithiole-3-thione
derivatives reacted with Fischer carbene complexes, giving
1,3-dithiin dithioortho esters through insertion of the carbenic
carbon into the S-S bond next to the thiocarbonyl function
of the substrate.
Selected starting materials 1a-c, 4, and 6a,b were subjected
to reaction with pentacarbonyl[(methoxy)(aryl)vinylidenechro-
mium(0)] 2a,b in dioxane at 40 °C. The reaction of 1a with 2a
gave, after column chromatography, the insertion product 3a
(55%) as blue crystals (Scheme 1). Surprisingly, single-crystal
X-ray diffraction afforded the unexpected structure 6-butylthio-
2-methoxy-2-(4-methoxyphenyl)-S-[pentacarbonylchromium(0)]-
[1,3]dithiin-4-thione 3a coming from the insertion of the carbene
moiety into the S-S bond (Figure 1).3
Under similar conditions, 1b was completely unreactive with
2b, and therefore the presence of the thiocarbonyl group is
necessary to get a reaction product (Scheme 1). We then
subjected compound 1c,4 having an additional chromium
complex, to reaction with 2b, and after column chromatography
we only separated the product 3b (34%), which showed exactly
Fischer carbene complexes have been shown to be very
efficient and versatile starting materials for carrying out a wide
variety of organic transformations.1
In a previous article about the reactivity of a series of
5-alkylthio-3H-1,2-dithiole-3-thione derivatives with Fischer
carbene complexes, we reported the insertion of the carbene
ligand into the C3-C4 bond of 5-alkylthio-3H-1,2-dithiole-3-
thione to give mainly the complexes 6-alkylthio[pentacarbon-
ylchromium{or tungsten}(0)]- 4H-1,2-dithiin-3-thione.2 After-
ward, we worked on this reaction with the aim of establishing
the role of the alkylthio and thiocarbonyl groups present in the
1,2-dithiole-3-thione derivatives, as well as the 4-substituent,
in the insertion reaction, and the results are reported in this Note.
In addition, the new results clearly show that the assignment of
structures reported in previous work2 was not correct.
(3) X-ray measurements were made using a Bruker SMART CCD area-
detector diffractometer with Mo KR radiation (λ ) 0.71073 Å). Crystal
data for 3a: C21H20CrO7S4, M ) 564.61, monoclinic, P2(1)/n, a ) 11.3847-
(13) Å, b ) 12.0263(13) Å, c ) 19.227(2) Å, R ) 90°, â ) 97.452(2)°,
γ ) 90°; V ) 2610.2(5) Å3, Z ) 4, Dcalcd ) 1.437 g cm-1, µ(Mo KR) )
0.795 mm-1. Brown prism, (0.20 × 0.20 × 0.20) mm3. 24 994 measured
reflections, 4588 independent (Rint ) 0.0449), 3617 observed (I > 2σ(I)).
R1 ) 0.0566, wR2 ) 0.1322 (all data). CCDC 290963.
† Universidad Nacional de Co´rdoba.
‡ Universidad de Burgos.
(1) (a) Do¨tz, K. H. Metal Carbenes in Organic Synthesis; Springer: New
York, 2004. (b) Barluenga, J.; Santamaria, J.; Tomas, M. Chem. ReV. 2004,
104, 2259.
(2) Granados, A. M.; Kreiker, J.; de Rossi, R. H. Tetrahedron Lett. 2002,
43, 8037.
10.1021/jo052168e CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/20/2005
808
J. Org. Chem. 2006, 71, 808-810

SCHEME 2
FIGURE 2. Single-crystal X-ray diffraction structure of 7.
SCHEME 3
the same spectral and physical data of the product that we
previously described from the reaction of 1a with 2b,2 although
this time it was obtained in slightly lower yield. Therefore,
complexation of the starting material has little influence on the
reaction pathway.
Under the light of structure 3a and, after careful comparison
of all spectral data, we assigned the 1,3-dithiin-4-thione structure
3b to the product of the reaction of 1c with 2b (Scheme 1).
The coordination site of the pentacarbonylchromium[0] moiety
in 3b will be discussed later in this Note.
We then performed the reaction of a simpler starting material
4 with 2b under similar conditions, from which we obtained
the crystalline brown product 5 (43%) (Scheme 2), which was
characterized spectroscopically. The crystals were not good
enough to get a refined structure by single-crystal X-ray
diffraction. However, it was clear from the crystallographic data
that the Cr(CO)5 moiety was close to the thiocarbonyl group.5
Therefore, it is also evident that the presence of an alkylthio
group in the starting material is not necessary for the reaction.
On the other side, the reaction of the tricyclic bisdithiolopyrrole
6a with 2b gave the orange crystalline [1,2]dithiolo [1,3]-
dithiinopyrrole 7 (25%), a new heterocyclic system, which was
fully characterized by spectroscopy (Scheme 2).
13C NMR showed a downfield shift of 4.3 ppm in the N-CH2
signal of 7 with respect to 6a, probably due to shielding of the
CH2 by the nonplanar thiocarbonyl group and a downfield shift
of 2.2 ppm of the CdS signal of 7 with respect to 6a, in
agreement with the insertion of the carbene in the cycle. The
structure 7 was confirmed by single-crystal X-ray diffraction
(Figure 2).6 It is interesting to note that 7 was not complexed
with Cr(CO)5 and that the insertion of the carbene occurred only
into the S-S bond near the thiocarbonyl group. Additionally,
the reaction of the diketone 6b with 2b gave no product,
showing that the presence of the dithiolethione moiety is
necessary to get reaction products with Fischer carbene com-
plexes.
To confirm the structures and get the free heterocycle in the
cases where the products were obtained as metal complexes
such as 3a,b, 5, and 9,7 the compounds were exposed to ligand
exchange using MeOH as competitor ligand. Under these
conditions complexes 3b and 9 were demetalated quite easily,
giving 8 (78%) and 10 (54%), respectively.8 On the other hand,
complexes 3a and 5 gave only decomposition products (Scheme
3).
The dissimilar reactivity of these complexes suggested the
existence of structural differences that could be evidenced by a
careful examination of the IR spectra of 3a,b and 9 compared
with those of 8 and 10. The IR spectrum of 8 and 10 showed
the absence of bands corresponding to the chromium pentacar-
bonyl moiety in the region between 1900 and 2100 cm-1
(observed in the IR spectrum of 3a,b and 9) and the presence
of signals at 1600-1750 cm-1, corresponding to the vibration
of the CdC double bond in the heterocyclic ring. It is
noteworthy that these signals are absent in the spectra of 3b
and 9, but there is a signal at 1604 cm-1 in the spectrum of 3a.
These data indicate that the CdC double bond is involved in
the coordination with the metal in compounds 3b and 9 but not
(4) This compound was obtained as follows: In a quartz tube, we added
5-butylthio-3H-1,2-dithiole-3-thione (222 mg, 1 mmol), Cr(CO)6 (264 mg,
1.2 mmol), and benzene (15 mL). The mixture was irradiated at 254 nm
with a UV lamp as N2 was bubbled through the solution.
(5) We thank Prof. Ricardo Baggio, Dpto. de F´ısica, Comisio´n Nacional
de Energ´ıa Ato´mica, Buenos Aires, Argentina, for this study.
(6) Crystal data for 7: C16H13NO2S5, M ) 411.57, triclinic, P1h, a )
10.1366(7) Å, b ) 13.4877(9) Å, c ) 13.6520(10) Å, R ) 104.6560(10)°,
â ) 90.4560(10)°, γ ) 102.9130(10)°; V ) 1756.0(2) Å3, Z ) 4, Dcalcd
)
1.557 g cm-1, µ(Mo KR) ) 0.669 mm-1. Red plate, (0.40 × 0.30 × 0.05)
mm3. 19 207 measured reflections, 7188 independent (Rint ) 0.0292), 5948
observed (I > 2σ(I)). R1 ) 0.0531, wR2 ) 0.1271 (all data). CCDC 290964.
(7) Complex 9 was obtained as described in ref 2.
(8) See Supporting Information for details of experimental procedures.
J. Org. Chem, Vol. 71, No. 2, 2006 809

SCHEME 4
ogy for the preparation of the scarcely known 1,3-dithiin
derivatives12 or the extremely rare compounds having a
dithioortho ester group.13 The in vitro cytotoxicity toward cancer
cell lines of 2-vinyl-4H-1,3-dithiin from extracts of Allium
Victorialis has been reported.14 Therefore, the synthesis of 1,3-
dithiin derivatives can be considered as an important tool in
the search of new therapeutic agents.
Experimental Section
in 3a. On the other hand, the signal corresponding to the
thiocarbonyl group at 1045 cm-1 in the spectra of 3b and 9
shows only small changes compared with that of 8 and 10.
Additionally, a noticeable increase in the intensity and complex-
ity of the thiocarbonyl absortion band of 3a in comparison with
the corresponding one for 3b was also observed.9 We conclude
that the CdC double bond in the heterocyclic ring of 3b and 9
is involved in the coordination with the metal while the
coordination site involves the CdS bond in compounds 3a and
5. This difference in structure is responsible for their behavior
in the demetalation reactions mentioned above. Aumann and
co-workers previously reported the impossibility of displacing
the metal from a complex between pentacarbonyltungsten(0)
and a cyclic thioketone.10
To confirm the structure of the products, we studied the
hydrolysis of 3a,b and 8 with HgCl2. This method was selected
by considering the similarity between the structure of the
obtained 1,3-dithiins and the 1,3-dithianes, very well-known as
protecting groups for carbonyl compounds.11 Therefore, reaction
of either 1,3-dithiin complexes or free heterocycles with
mercuric chloride should give methyl benzoates that could not
be formed from 1,2-dithiins such as the ones proposed in
previous work.2 We effectively obtained methyl p-methoxy-
benzoate 11a as the hydrolysis product from 3a and methyl
benzoate 11b from 3b and 8 that were identified in all cases by
GC-MS from the crude reaction mixture (Scheme 4). The same
procedure was applied to the compounds reported in ref 2 and
in all the cases methyl benzoate was formed.
Representative Insertion Reaction. Synthesis of Compound
3a. 5-Butylthio-3H-1,2-dithiole-3-thione 1a (250 mg, 1.12 mmol)
and pentacarbonyl[(methoxy)(p-methoxyphenyl)vinylidenechromium-
(0)] 2a (600 mg, 1.75 mmol) were added to 40 mL of dry dioxane
contained in a Schlenk tube under a nitrogen atmosphere, and the
mixture was warmed to 45 °C with continuous stirring. After 3 h,
no substrate was observed by TLC. Then the solvent was removed
at reduced pressure at a temperature below 40 °C. The crude
material was purified by column chromatography using a mixture
of petroleum ether/diethyl ether 80/20 v/v as eluent. Yield of 3a:
355 mg (54.5%), blue crystals mp 71.4-71.9 °C. 1H NMR (CDCl3,
200 MHz): δ 0.97 (t, 3H); 1.53 (m, 2H); 1.73 (m, 2H); 3.11 (m,
2H); 3.27 (s, 3H); 3.86 (s, 3H); 7.00 (d, 2H); 7.59(d, 2H); 7.67 (s,
1H). 13C NMR (CDCl3, 50 MHz): δ 13.48; 21.83; 30.66; 33.68;
54.06; 55.48; 96.85; 114.60; 127.56; 128.67; 131.02; 149.11;
161.24; 206.33; 215.06; 223.96. HRMS calculated for C21H20-
CrO7S4: 563.94969; found 563.94978.
Acknowledgment. This research was supported in part by
the Consejo Nacional de Investigaciones Cient´ıficas y Te´cnicas
(CONICET), the Agencia Co´rdoba Ciencia, Fundacio´n Antor-
chas, Agencia Nacional de Promocio´n Cient´ıfica y Te´cnica
(FONCYT), and the Universidad Nacional de Co´rdoba, Argen-
tina. We gratefully acknowledge financial support from the
Direccio´n General de Investigacio´n of Spain (Project Ref
BQU2001-0258) and Junta de Castilla y Leo´n, Consejer´ıa de
Educacio´n y Cultura, y Fondo Social Europeo (Project Ref
BU01/03). We thank to SCAI for solving structures 3a and 7
by single-crystal X-ray diffraction.
Supporting Information Available: Detailed experimental data
In conclusion, we have shown that Fischer carbene complexes
reacted with 3H-1,2-dithiole-3-thione derivatives to give 1,3-
dithiin derivatives that result from the insertion of the carbenic
carbon into the S-S bond. This reaction did not take place when
the thiocarbonyl group was replaced by a carbonyl group, which
may indicate that the reaction begins with the attack of the
nucleophilic thiocarbonyl group to the electrophilic carbenic
carbon of the Fischer carbene complex. In addition, the fact
that with all the compounds reported previously2 methyl
benzoate was obtained under the hydrolysis conditions (Scheme
4) allowed us to rectify our previosly published structure for
the products of related reactions.2 The products obtained in the
reactions reported here belong to a novel type of 1,3-dithiin
dithioortho esters that fill a large gap in the synthetic methodol-
for the synthesis of new compounds, physical data, and HRMS,
1
IR, H, and 13C NMR spectra of all new compounds and crystal-
lographic data for compounds 3a and 7. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO052168E
(12) See, for example: (a) Degl’Innocenti, A.; Capperucci, A.; Nocentini,
T.; Biondi, S.; Fratini, V.; Castagnoli, G.; Malesci, I. Synlett 2004, 2159-
2162. (b) Nizovtseva, T. V.; Komarova, T. N.; Nakhmanovich, A. S.; Larina,
L. I.; Lopyrev, V. A. ArkiVoc 2003 (xiii), 191. (c) Li, G. M.; Niu, S.; Segi,
M.; Tanaka, K.; Nakajima, T.; Zingaro, R. A.; Reibenspies, J. H.; Hall, M.
B. J. Org. Chem. 2000, 65, 6601. (d) Fujii, T.; Kusanagi, H.; Takahashi,
O.; Horn, E.; Furukawa, N. Tetrahedron 1999, 55, 5027. (e) Bianchini, C.;
Frediani, P.; Herrera, V.; Jime´nez, M. V.; Meli, A.; Rinco´n, L.; Sa´nchez-
Delgado, R.; Vizzala, F. J. Am. Chem. Soc. 1995, 117, 4333. (f) For a
review, see: Freeman, F. Heterocycles 1990, 31, 701.
(13) See, for example: (a) Kwang-Fu Shen, C.; Duong, H. M.; Sonmez,
G.; Wudl, F. J. Am. Chem. Soc. 2003, 125, 16206. (b) Blagoev, M.; Linden,
A.; Heimgartner, H. HelV. Chim. Acta 2000, 83, 3163. (c) Herrmann, E.;
Gais, H. J.; Rosenstock, B.; Raabe, G.; Lindner, H. J. Eur. J. Org. Chem.
1998, 275. (d) Becher, J.; Simonsen, O.; Saether, H.; Hansen, T. K.;
Jorgensen, T.; Bowadt, S. Heterocycles 1993, 35, 445. (e) Herdewijn, P.
A. M.; Van Aerschot, A.; Jie, L.; Esmans, E.; Feneau-Dupont, J.; Declercq,
J. P. J. Chem. Soc., Perkin Trans. 1 1991, 1729.
(9) See the compared IR spectra in the Supporting Information
(10) Wu, P.; Aumann, R.; Fro¨hlich, R.; Wegelius, E.; Saavenketo, P.
Organometallics 2000, 19, 2373.
(11) The protection of carbonyl groups is routinely achieved by the
formation of dithio acetals and ketals. Due to the resistance of these groups
to conventional acid-catalyzed hydrolytic cleavage, various available
methods for deprotection, by using transition metal-induced hydrolysis, are
widely used. See, for example: Corey, E. J.; Erickson, B. W. J. Org. Chem.
1971, 36, 3553.
(14) Lee, K. T.; Choi, J. H.; Kim, D. H.; Son, K. H.; Kim, W. B.; Kwon,
S. H.; Park, H. J. Arch. Pharm. Res. 2001, 24, 44.
810 J. Org. Chem., Vol. 71, No. 2, 2006