Abnormally mild synthesis of bis(dithiolo)pyrroles from 2,5-dimethylpyrroles

Article abstract of DOI:10.1021/ol052557v

(Chemical Equation Presented) Treatment of N-subslituted 2,5-dimethylpyrroles 2 with an equilibrated mixture of disulfur dichloride and DABCO in chloroform at 0°C gives pentathiepinopyrroles 3 in moderate yields; further reaction of 3 with the same mixtur

Full text of DOI:10.1021/ol052557v

ORGANIC
LETTERS
2
005
Vol. 7, No. 25
725-5727
Abnormally Mild Synthesis of
Bis(dithiolo)pyrroles from
5
2,5-Dimethylpyrroles
†
†
†
Stanislav A. Amelichev, Rinat R. Aysin, 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 of Science, Technology and Medicine, London SW7 2AZ, U.K.
orakitin@ioc.ac.ru; c.rees@imperial.ac.uk
Received October 21, 2005
ABSTRACT
Treatment of N-substituted 2,5-dimethylpyrroles 2 with an equilibrated mixture of disulfur dichloride and DABCO in chloroform at 0 °C gives
pentathiepinopyrroles 3 in moderate yields; further reaction of 3 with the same mixture at room temperature leads, in an extensive reaction
cascade, to bis(dithiolo)pyrroles 4 in high yield; 2 can be converted into 4 in a one-pot operation under unusually mild conditions.
3
The relatively well-known benzopentathiepins display a
varied chemistry and have important biological activity.
epinopyrroles 3 (Cl for Me) in high yield. We have now
1
investigated (Scheme 2) the synthesis of pentathiepino[6,7-
Similar pentathiepins fused to heterocyclic rings are rarer
and much less well investigated. Recently, we have shown
that equilibrated equimolecular mixtures of disulfur dichlo-
ride and 1,4-diazabicyclo[2.2.2]octane (DABCO) in chlo-
roform converted N-alkylpyrroles into N-alkylpentathiepi-
Scheme 2
2 2
nopyrroles; the S Cl -DABCO complex 1 was assumed to
2
be the major reactive intermediate (Scheme 1).
Scheme 1
c]pyrroles 3 from 2,5-dimethylpyrroles, which are very
readily available from acetonylacetone and amines.4
The reaction of N-benzyl-2,5-dimethylpyrrole 2a with an
excess of S
2 2
Cl and DABCO (not preequilibrated) led
unexpectedly to N-benzylbis(dithiolo)pyrrole 4a (Scheme 3)
If the pyrrole R-positions are chlorinated, the pentathiepin
ring is fused across the 3,4-pyrrole bond to give pentathi-
(2) Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W.; Amelichev, S. A.
MendeleeV Commun. 2004, 91.
†
Russian Academy of Sciences.
Imperial College of Science, Technology and Medicine.
(3) Amelichev, S. A.; Konstantinova, L. S.; Lyssenko, K. A.; Rakitin,
O. A.; Rees, C. W. Org. Biomol. Chem. 2005, 3, 3496.
(4) Leonard, N. J.; Curry J. W.; Sagura, J. J. J. Am. Chem. Soc. 1953,
75, 6249.
‡
(
1) Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W. Chem. ReV. 2004,
1
04, 2617.
1
0.1021/ol052557v CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/17/2005

Scheme 3
Scheme 4
electrophilic reagent, either at the pentathiepin ring or at a
7
methyl group. When N-methyl-2,5-diphenylpyrrole 5 was
treated with complex 1 under the same conditions the yellow
pentathiepinopyrrole 6 was obtained in good yield (62%),
but treatment of this with complex 1 gave no further reaction
even on heating for 3 h, the pentathiepin ring remaining intact
in low yield (10%). Compound 4a was identical with that
2 2
prepared from N-benzyldiisopropylamine, S Cl , and DAB-
5
CO in refluxing chlorobenzene (see Scheme 6 below).
This formation of bis(dithiolo)pyrrole 4 provides a new
and surprisingly mild route to the 1,2-dithiolo-3-thione ring
system; the C-methyl carbons have become incorporated into
thiocarbonyl groups in the course of an extensive reaction
cascade. Attempts to increase the yield of 4a by changing
the quantity and ratio of the reagents, and the reaction
temperature, were unrewarding. However, the reaction of
pyrrole 2a with preformed complex 1 gave a different
product, the pentathiepin 3a, whose yield did vary with the
(Scheme 5). Thus, it is likely that attack of the pentathiepi-
Scheme 5
2 2
reaction conditions; an excess of S Cl or increase in reaction
temperature led to the decomposition of pentathiepin 3a, with
partial transformation to 4a. When 2a (5 mmol) in chloro-
form (50 mL) at 0 °C was treated with complex 1 for 48 h
the best yield (60%) of 3a was obtained with 2.5 equiv of
the complex. Lower yields were obtained with less (2 equiv
gave 22%) and with more complex (3 equiv gave 35%; 4
equiv gave 23%); at 20 °C, 2.5 equiv gave 34% of 3a. It
appears from NMR spectroscopy that the methyl groups in
nopyrroles 3 occurs first at the C-methyl groups, which are
activated by electron release from both heterocyclic rings.
A possible mechanism for this reaction is proposed below
(Scheme 7).
2a, which are transformed by the reagents, are also involved
Scheme 6
in intermolecular reactions to give (unstable) oligomeric
products.
We then extended these reactions to other N-substituted
2
,5-dimethylpyrroles 2. The bis(dithiolo)thiones 4 were
obtained directly in all reactions with a (nonequilibrated)
mixture of S Cl and DABCO, but in low yields (R ) Me,
%, R ) Et, 9%, R ) Pr, 12%, R ) Pr, 17%). The best
2
2
n
i
8
We have previously prepared N-benzyl- 4a and N-ethylbis-
dithiolo)pyrrole 4c from N-benzyl- and N-ethyldiisopropyl-
amine by treatment with S Cl -DABCO to give the corre-
2 2
conditions for the formation of 3a (2.5 equiv of complex 1)
were also best for the analogous pentathiepins 3, formed in
(
n
better yield; R ) Me, 36%, R ) Et, 40%, R ) Pr, 38%,
i
R ) Pr, 37%.
(6) General Procedure for the Preparation of 3 and 6. Disulfur
Surprisingly the isolated and purified pentathiepins 3 were
found to react further with complex 1 quite rapidly at a
slightly higher temperature (20 °C) to give the bis(dithiolo)-
dichloride (12.5 mmol) was added dropwise at -25 to -35 °C to a stirred
solution of DABCO (12.5 mmol) in chloroform (40 mL) under argon. The
mixture was stirred at rt for 1 h. The corresponding substituted 2,5-
dimethylpyrrole (5 mmol) in chloroform (10 mL) was added, the mixture
was stirred at 0 °C for 48 h under argon and filtered, and solvents were
evaporated. The residue was separated by column chromatography (silica
gel, Merck 60, light petroleum and then light petroleum-CH2Cl2 mixtures).
Yields are given in the text. General Procedure for the Preparation of 4
from 3. Disulfur dichloride (3.6 mmol) was added dropwise at -25 to -35
6
pyrroles 4 in high yield (Scheme 4). The reactions are almost
complete after 1 h but heating the mixture briefly under
reflux improved the work up procedure. Although pentathi-
epin rings and methyl groups are normally unreactive toward
S Cl -DABCO at room temperature, the pyrroles 3 react
2 2
in an extensive cascade sequence. Presumably the electron
°
C to a stirred solution of DABCO (3.6 mmol) in chloroform (10 mL) under
argon. The mixture was stirred at rt for 1 h. The corresponding pentathiepin
3 (0.7 mmol) in chloroform (5 mL) was added, the mixture was stirred at
rt for 1 h and then refluxed for 15 min and filtered, and solvents were
evaporated. The residue was separated by column chromatography (silica
gel, Merck 60, light petroleum and then light petroleum-CH2Cl2 mixtures).
Yields are given in Scheme 4.
releasing pyrrole nitrogen activates 3 to attack by the
(5) Konstantinova, L. S.; Obruchnikova, N. V.; Rakitin, O. A.; Rees, C.
W.; Torroba T. J. Chem. Soc., Perkin Trans. 1 2000, 3421.
(7) Duan, X.-G.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1997, 3189.
5726
Org. Lett., Vol. 7, No. 25, 2005

Scheme 7
sponding bis[1,2]dithiolo[5,4-b][4′,5′-e][1,4]thiazine-3,5-
4 which further illustrates the manifold oxidizing, chlorinat-
7
,11
dithiones 7, followed by thermal extrusion of the [1,4]thiazine
sulfur (Scheme 6).5 However, this procedure does not give
the analogous dithiolopyrroles 4b, 4d and 4e from the
corresponding diisopropylamines, and it appears to be less
general than the present route (Scheme 4). The latter is
equally simple and can be performed in one pot from the
dimethylpyrroles 2 by adding complex 1 (2.5 equiv) in
chloroform and stirring the mixture for 48 h at 0 °C and
then heating under reflux with more complex 1 (5 equiv)
without isolation of the pentathiepin 3.
ing, and sulfurating properties of S
2
Cl
2
,
and involves the
,8
breaking and making of at least eight old and eight new
bonds in high overall yield (74-85%). A reasonable
sequence could be as follows: (i) oxidation and sulfuration
of the activated C-methyl group; (ii) ipso-cyclization of the
CH SSX group onto the pyrrole â-position; (iii) oxidation
2
and sulfuration of the activated methyl group to the thio-
carbonyl group of the dithiolthione; (iv) opening and
fragmentation of the pentathiepin ring, and cyclization onto
the second methyl group; and (v) conversion of the second
methylene group to thiocarbonyl.
The actual sequence of these steps is not known, and there
may be some equilibration/disproportionation of the polysul-
fur chain.
This reaction cascade (Scheme 3) provides a new and
unusual route from 2,5-dimethylpyrroles to bis(dithiolo)-
pyrroles, some of which have marked activity against various
9
cancer lines. The procedure is better yielding and very much
milder than the classical, high temperature (ca. 200 °C)
reactions between sulfur and a variety of three-carbon
components such as arylalkanes, arylalkenes, alkynes, and
their chloro derivatives, largely used hitherto to form the
This unusual reaction cascade is under further investigation
and extension, but it is already clear that it provides a very
short and unusually mild route to potentially antitumor 1,2-
dithiole-3-thiones.
1
,2-dithiolo-3-thione ring system.10
Acknowledgment. We gratefully acknowledge financial
support from the Royal Society, the Russian Foundation for
Basic Research (Grant No. 05-03-32032), and the Wolfson
Foundation for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College.
The conversion of pentathiepinopyrroles 3 into dithiolo-
pyrroles 4 (Scheme 4) is reminiscent of the similar conver-
sion of diisopropylamines into dithiolothiazines 7 (Scheme
6) and is probably mechanistically related. We now propose
(Scheme 7) a working hypothesis for the cascade of 3 into
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
8) Rees, C. W.; White, A. J. P.; Williams, D. J.; Rakitin, O. A.; Marcos,
C. F.; Polo, C.; Torroba, T. J. Org. Chem. 1998, 63, 2189.
9) Curphey, T. J. J. Org. Chem. 2002, 67, 6461. Barriga, S.; Fuertes,
P.; Marcos C. F.; Torroba, T. J. Org. Chem. 2004, 69, 3672.
(
(
10) McKinnon, D. M. In ComprehensiVe Heterocyclic Chemistry I;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 6,
Chapter 4.31. McKinnon, D. M. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
OL052557V
(11) Konstantinova, L. S.; Rakitin, O. A.; Rees, C. W. MendeleeV
Commun. 2001, 165, 167.
1
996; Vol. 3, Chapter 3.11; Pedersen, C. Th. Sulfur Rep. 1995, 16, 173.
Org. Lett., Vol. 7, No. 25, 2005
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