Base catalyzed [2,3]-sigmatropic rearrangements of propargylic sulfonium and selenonium salts

Article abstract of DOI:10.1016/S0040-4039(01)00322-7

The synthesis and reactivity of bis-γ-substituted and unsubstituted propargylic sulfonium and selenonium salts under various basic conditions have been investigated. While the former compounds reacted only by [2,3]-sigmatropic rearrangement of the corresponding sulfur ylides, the latter salts exhibited a wider range of reactivity and showed potent DNA-cleaving properties.

Full text of DOI:10.1016/S0040-4039(01)00322-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2911–2914
Base catalyzed [2,3]-sigmatropic rearrangements of propargylic
sulfonium and selenonium salts
Samuel Braverman,a,* Yossi Zafrania and Shai Rahimipourb
aDepartment of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
bDepartment of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel
Received 25 January 2001; accepted 21 February 2001
Abstract—The synthesis and reactivity of bis-g-substituted and unsubstituted propargylic sulfonium and selenonium salts under
various basic conditions have been investigated. While the former compounds reacted only by [2,3]-sigmatropic rearrangement of
the corresponding sulfur ylides, the latter salts exhibited a wider range of reactivity and showed potent DNA-cleaving properties.
© 2001 Published by Elsevier Science Ltd.
The chemistry of sulfonium1 and selenonium2 salts is
well documented and reviewed. The well-known stabi-
lized carbanion adjacent to the cationic sulfur/selenium
atom is a common intermediate in many reactions
involving such species. However, to our knowledge
bis-allenic sulfonium salts have not been studied and
relatively little attention has been given to the bis-
propargylic sulfonium salts.3,4 Furthermore, as far as
we are aware, no bridged propargylic nor allenic
selenonium analogues, have been investigated to date.
In addition, while [2,3]-sigmatropic rearrangement of
allyl sulfonium ylides is well known, the rearrangement
of the corresponding selenonium salts has been studied
to a smaller extent.5
Recently, we became interested in the behaviour of
some novel p-conjugated bis-propargylic sulfides, sulf-
oxides and sulfones. These compounds have been found
to undergo facile isomerization to the corresponding
diallenes, followed by a tandem cyclization and aroma-
tization via a diradical intermediate, in the presence of
various bases at room temperature.6 Surprisingly, we
have found that the rate of the cyclization step was
independent of the nature of the bridging functionality
(Scheme 1). Interestingly, such a diradical cyclization
of bis-g,g-dimethylallenyl sulfone, discovered by us in
the past,7 was subsequently used by Nicolaou as a
model for the design of a new class of DNA-
cleaving molecules that could mimic the activity of
Scheme 1. Tandem isomerization, cyclization and aromatization of bridged dipropargylic systems.
Keywords: sulfur and selenium compounds; allenes; acetylenes; sigmatropic rearrangements.
* Corresponding author. Tel.: +972-3-5318322; fax: +972-5351250; e-mail: bravers@mail.biu.ac.il
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00322-7

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the naturally occurring enediynes.8 However, subse-
quent mechanistic studies by Nicolaou9 and others10 led
to the conclusion that an alternative mechanism, the
Maxam–Gilbert mechanism,11 involving nucleophilic
addition of DNA to the diallenic sulfone was responsi-
ble for its biological activity.
gate the behaviour of the bis-propargylic sulfonium
4a–c and selenonium 4d,e analogues. One may expect
that these analogues may at least partly cyclize to the
corresponding thiophenium and selenophenium salts.
Recently, thiophenium salts have received considerable
attention.12 The structural similarities between S-
alkylthiophenium salts and thiophen-S-oxides have
prompted the suggestion that these classes are antiaro-
matic. In addition, and in contrast to the related
Prompted by the high reactivity of p-conjugated bis-
allenyl sulfones and sulfoxides,6 we decided to investi-
Scheme 2. Base catalyzed [2,3]-sigmatropic rearrangement of bis-g-substituted bridged propargylic systems.
Scheme 3. Rearrangements of unsubstituted bridged propargylic systems 7a,b.

S. Bra6erman et al. / Tetrahedron Letters 42 (2001) 2911–2914
2913
and selenonium salts (7a,b), which might have a better
chance of propargyl–allene isomerization. We have thus
found that sulfonium salt 7a underwent a series of
reactions which depend on the nature of the base.
These reactions involved prototropic and sigmatropic
rearrangements as well as nucleophilic addition and
displacement (Scheme 3). For instance, treatment of
sulfonium salt 7a with sodium methoxide in methanol
at room temperature afforded sulfides 9a and 10a,
which mechanistically can be explained by [2,3]-sigma-
tropic rearrangements of the corresponding ylide.3 Con-
versely, the same reaction with t-BuOK as base in 85%
t-BuOH–acetone yielded sulfide 9a as a single product.
On the other hand, when sulfonium salt 7a reacts with
tertiary amine bases such as DABCO or Et3N, the
nucleophilic addition–displacement of the base to allene
8a is exclusive. The stable crystalline ammonium
product 11a was thus formed in quantitative yield.
However, using the secondary base morpholine, sulfo-
nium salt 7a initially gives the expected eneamine 12a,
which easily hydrolyzed to the corresponding keto-
sulfide 13a, followed by slow isomerization to diene
14a. Finally, the conjugated bis-allene 15a and diyne
10a were obtained by the use of DBU as base in the
ratio of 7:3, respectively. The formation of 15a is easily
explained by a prototropic isomerization of 9a in the
presence of a strong base. In contrary to these various
reactions of sulfonium salt 7a, the selenonium salt
analogue 7b has been found to undergo only [2,3]-sig-
matropic rearrangements to the corresponding selenides
9b and 10b in the presence of either DBU or CH3ONa.
Using weaker bases like DABCO leads to mixtures of
SN2 products. This result indicates the relatively high
sensitivity of selenonium salts to nucleophilic displace-
ment as compared to sulfonium salts, which may be
explained by the relatively higher polarizability of the
selenium atom as well as the weaker SeꢀC bond.17
Figure 1. DNA cleavage by sulfonium 7a and selenonium 7b
salts. FX 174 form I DNA (50 mM per base pair) was
incubated for 23 h at 37°C with compounds 7a,b in various
concentrations in 10% DMSO in tris-HCl buffer (pH 8.5, 50
mM) and analyzed by electrophoresis (1% agarose gel, ethid-
ium bromide stain). Lanes 1–3 correspond to DNA and
selenonium salt 7b at 1000, 500 and 100 mM, respectively;
lanes 4–6 correspond to DNA and sulfonium salt 7a at 1000,
500 and 100 mM, respectively, and lane 7 to DNA alone.
Forms I, II and III correspond to supercoiled, relaxed and
linear DNA, respectively.
bridged sulfur bis-propargylic systems 1a–c, these
onium salts have some water solubility, which in gen-
eral is necessary for biological activity.
All starting materials were prepared by standard proce-
dures.13 Despite our expectation for competition
between tandem cyclization and aromatization (path a,
Scheme 2) and [2,3]-sigmatropic rearrangement (path
b), we were surprised to find that these bis-g-substituted
sulfonium/selenonium salts reacted by the latter process
exclusively. For example, reaction of ethyl bis-g-cyclo-
hexenylpropargyl sulfonium tetrafluoroborate (4c) with
DBU in CHCl3 at room temperature resulted in practi-
cally spontaneous and quantitative [2,3]-sigmatropic
rearrangement, affording the sulfide derivative 5c.
These results may be partly explained by the steric
hindrance introduced by the bulky g-substituent for
isomerization of the propargyl to the allenyl system. It
may also be consistent with thermodynamic data which
indicate that a nonterminal acetylene is more stable
than an isomeric nonterminal allene by 1.0 kcal/mol.14
In contrast to the stability of sulfides 5a–c, selenides
5d,e underwent a subsequent [1,3]-shift to the appropri-
ate ynedienes 6d,e in CDCl3 at room temperature after
24 h. This result is not surprising in view of the fact
that selenoallylic rearrangements15 occur more readily
than their thioallylic analogues.16 However, whereas the
known selenoallylic rearrangements occur at a relatively
high temperature, in the case of allenes 5d,e it takes
place at room temperature.
Sulfonium 7a and selenonium 7b salts have been found
to cleave DNA. Thus, incubation of onium salts 7a,b
with FX 174 form I DNA aerobically at 37°C led to
form II and form III DNA, as shown by gel elec-
trophoresis analysis (Fig. 1). According to the above-
mentioned results and in view of our previous work,6
one may expect two modes of action in the biological
activity of sulfur bridged bis-propargyl systems, which
depends on the nature of both the bridge and the
g-substituent. The predictable DNA-cleavage by water-
soluble onium salts 7a,b may occur by the Maxam–
Gilbert mechanism, whereas the bis-g-phenylpropargyl
sulfone 1c may cleave DNA by the diradical mechanism
(Scheme 4).
In view of the above results, we became interested in
investigating the unsubstituted bis-propargyl sulfonium
Scheme 4. Two modes of action for DNA-cleavage by onium salts 7a,b and sulfone 1c.

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S. Bra6erman et al. / Tetrahedron Letters 42 (2001) 2911–2914
K.; Ohtsuka, A.; Matsumura, S.; Nakata, M. J. Chem.
Acknowledgements
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Financial support of this work by the Israel Science
Foundation is gratefully acknowledged.
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1
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