Unusual sulfur chemistry in the thermal reaction of sultene and thiophene endoperoxide sulfur donors with cyclic alkynes: Reversible formation of a persistent thiirenium ion and trapping of a thiirene by [4 + 2] cycloaddition

Article abstract of DOI:10.1021/ja025934x

The highly reactive cyclooctyne 2b serves as sulfur acceptor for both sulfur donors, namely the sultene 1A and thiophene endoperoxide 1B to afford sulfur-transfer products. With the acid-activated sultene 1A, the persistent thiirenium ion 3Ab is formed, which has allowed the direct observation of the initial sulfur-transfer adduct. On treatment with base, the thiirenium ion 3Ab reverts quantitatively to the cyclooctyne and sultene, whereas in neutral media it rearranges to the diene 6Ab. The rearrangement to the diene 6Ab, as well as the formation of spirocyclic adduct 6Ac in the reaction with dithiocyclononyne 2c, is proposed to proceed through a carbene mechanism. In the reaction of the cyclooctyne 2b with thiophene endoperoxide 1B, a thiirene is formed through sulfur transfer by an intermediary oxathiirane derived from the thiophene endoperoxide; as final product, the episulfide (R*,R*,R*)-3Bb is produced diastereoselectively by immediate [4 + 2] cycloaddition of the thiirene with the heterodiene 4B.

Full text of DOI:10.1021/ja025934x

Published on Web 06/20/2002
Unusual Sulfur Chemistry in the Thermal Reaction of Sultene
and Thiophene Endoperoxide Sulfur Donors with Cyclic
Alkynes: Reversible Formation of a Persistent Thiirenium Ion
and Trapping of a Thiirene by [4 + 2] Cycloaddition
Waldemar Adam,*,† Sara G. Bosio, Bettina Fr o¨ hling, Dirk Leusser, and
†
†
‡
‡
Dietmar Stalke
Contribution from the Institut f u¨ r Organische Chemie and Institut f u¨ r Anorganische Chemie der
UniVersit a¨ t,
Am Hubland, D-97074 W u¨ rzburg, Germany
Received February 14, 2002
Abstract: The highly reactive cyclooctyne 2b serves as sulfur acceptor for both sulfur donors, namely the
sultene 1A and thiophene endoperoxide 1B to afford sulfur-transfer products. With the acid-activated sultene
1A, the persistent thiirenium ion 3Ab is formed, which has allowed the direct observation of the initial
sulfur-transfer adduct. On treatment with base, the thiirenium ion 3Ab reverts quantitatively to the cyclooctyne
and sultene, whereas in neutral media it rearranges to the diene 6Ab. The rearrangement to the diene
6
Ab, as well as the formation of spirocyclic adduct 6Ac in the reaction with dithiocyclononyne 2c, is proposed
to proceed through a carbene mechanism. In the reaction of the cyclooctyne 2b with thiophene endoperoxide
B, a thiirene is formed through sulfur transfer by an intermediary oxathiirane derived from the thiophene
endoperoxide; as final product, the episulfide (R*,R*,R*)-3Bb is produced diastereoselectively by immediate
1
[
4 + 2] cycloaddition of the thiirene with the heterodiene 4B.
Introduction
Scheme 1
Recent work from our group showed that a persistent cyclic
sulfenate, the sultene 1A and the in situ generated thiophene
endoperoxide 1B effect sulfur-atom transfer to strained cyclic
olefins in very good yields, especially cyclooctene trans-2a
(
Scheme 1).1 Such sulfur transfer to a triplebond would
correspondingly lead to a thiirene, a highly reactive substance
in view of its expected antiaromatic character. Indeed, our work
on the sulfur transfer from fluorenethione S-oxide (1C) to
cyclooctyne 2b showed that the thiirene does not persist and
2
dimerizes to the 1,4-dithiin 3b. It was, therefore, of mechanistic
interest to investigate the sulfur-transfer chemistry of strained
cyclic alkynes, namely cyclooctyne 2b and 1,5-dithiacyclonon-
7-yne (2c), with the sulfur donors sultene 1A and endoperoxide
1
B. Our present results disclose some unusual and hardly
predictable transformations in the sulfurization of strained
acetylenes.
Results
Sulfur Transfer from the Sultene 1A to Cyclooctyne 2b.
With catalytic amounts of Brønsted and Lewis acids, the sultene
1
A did not react at all with cyclooctyne 2b even at elevated
*
To whom correspondence should be addressed. E-mail:
temperature (up to 80 °C). However, when this cycloalkyne was
treated with 1 equiv of TFA, the sultene 1A was quantitatively
converted to the unprecedented thiirenium ion 3Ab in only 1
min at ca. 20 °C (Scheme 2, path a). The assigned structure is
supported by the two C NMR signals at δ 112.9 and 113.2
ppm for the ring carbons of the thiirenium functionality. These
adam@chemie.uni-wuerzburg.de. FAX: Int +49-931-8884756.
†
Institut f u¨ r Organische Chemie.
Institut f u¨ r Anorganische Chemie.
‡
(
1) (a) Adam, W.; Weink o¨ tz, S. J. Am. Chem. Soc. 1998, 120, 4861-4862.
(
b) Adam, W.; Weink o¨ tz, S. Chem. Commun. 1996, 177-178. (c) Adam,
W.; Fr o¨ hling, B.; Peters, K.; Weink o¨ tz, S. J. Am. Chem. Soc. 1998, 120,
914-8919.
2) Adam, W.; Fr o¨ hling, B.; Weink o¨ tz, S. J. Org. Chem. 1998, 63, 9154-
155.
1
3
8
(
3
9
resonances are in good agreement with those reported for the
8316
9
J. AM. CHEM. SOC. 2002, 124, 8316-8320
10.1021/ja025934x CCC: $22.00 © 2002 American Chemical Society

Sulfur-Transfer in Cycloalkynes and Cycloalkenes
A R T I C L E S
Scheme 2
Scheme 3
Since the Lewis acid Sn(tpp)(ClO4)2 (Scheme 2, path b) has
two free coordination sites, only 0.5 equiv was necessary to
generate the thiirenium ion 3Ab, although the latter was formed
more slowly. After 10 min at ca. 20 °C, only 75% of 3Ab was
obtained.
On silica gel chromatography of the persistent thiirenium ion
3
Ab, ca. 25% of the sultene 1A was recovered. When solid
potassium carbonate was added to the solution of 3Ab to
neutralize excess acid, NMR analysis disclosed quantitative
reversal to the starting materials 1A and 2b (Scheme 2, path
a). When TFA was added again, the thiirenium ion 3Ab was
regenerated quantitatively, and this reversible process may be
repeated several times. In the case of the Lewis acid Sn(tpp)-
(ClO4)2 (path b), no regeneration of the starting materials 1A
and 2b from the thiirenium ion was observed on addition of
solid K2CO3.
On addition of TFA to a mixture of the sultene 1A and
cyclooctyne 2b in petroleum ether (PE) and methylene chloride
(20:1), immediately a colorless solid precipitated (Scheme 2,
path c). On attempted isolation of this colorless powder, fast
deterioration was observed even under the rigorous exclusion
of air and moisture. The NMR spectrum of this powder shows
that it consists of ca. 50% each of the thiirenium ion 3Ab and
the diene 6Ab. The structure of this diene was elucidated by
1
13
various spectroscopic methods ( H and C NMR, INAD-
EQUATE, H,H- and C,H-COSY, MS) and by the fact that with
N-phenyl-1,2,4-triazoline-3,5-dione (PTAD) it afforded the [4
+ 2] cycloadduct 7Ab (Scheme 2, path c).
A competition experiment between cyclooctyne 2b and trans-
cyclooctene (trans-2a) (Scheme 2, path d) manifested almost
exclusive formation of the thiirenium ion 3Ab. No sulfur transfer
to the usually highly reactive trans-2a was observed, since only
traces of the desulfurized product of 1A, the aldehyde 5A, were
detected.
di-tert-butyl-substituted thiirenium ions (δ 114.98 and 115.86
ppm). Additionally, the mass spectrum of the crude reaction
mixture contains a m/z peak at 431 amu for the elemental
composition of the thiirenium cation.
The persistence of the thiirenium ion 3Ab depends on the
amount of TFA added: With exactly 1 equiv or a slight excess
(1.2 equiv) of acid, 3Ab survived only up to 1 h; subsequently
the diene 6Ab (cf. Scheme 2, path c) slowly appeared. When a
large excess (3 to 5 equiv) of acid was used, 3Ab remained
unchanged for about 24 h and then slowly decomposed to a
complex mixture. With other strong Brønsted acids such as
picric acid, perchloric acid, and tetrafluoroboric acid, the
thiirenium ion 3Ab was also formed, but with aqueous acids
Sulfur Transfer from the Sultene 1A to 1,5-Dithiacy-
clonon-7-yne (2c). Treatment of the readily accessible dithia-
4
cyclononyne 2c and sultene 1A (Scheme 3) with 3 mol % of
the Lewis acid Sn(tpp)(ClO ) gave the adduct 6Ac as main
4
2
product in 46% yield. Its spirocyclic structure was elucidated
by NMR and mass spectroscopy; the (R*,S*,S*) diastereomer
was formed predominantly (dr ) 91:9). With stoichiometric
amounts of TFA, full conversion of the sultene 1A occurred
within 5 min at ca. 20 °C; however, the spirocyclic 6Ac did
not persist under these strongly acidic conditions and decom-
posed into a complex product mixture on prolonged standing
(60 h). A control experiment confirmed that the authentic adduct
6Ac deteriorated on exposure to TFA into a complex mixture.
Sulfur Transfer from the Thiophene Endoperoxide 1B to
Cyclooctyne 2b. For these sulfur-transfer experiments, the
(70% HClO4 and 50% HBF4), vigorous shaking of the hetero-
geneous system was necessary to ensure full conversion of 1A
into 3Ab. In the case of the aqueous acid HCl (37%), the
thiirenium ion 3Ab persisted only ca. 7 min in CDCl3 solution
to decompose subsequently to a mixture of unidentified products.
With concentrated (98%) H2SO4, additionally a second, uni-
dentified product appeared right from the beginning, as moni-
1
tored by H NMR spectroscopy; similar results were obtained
in d3-acetonitrile and d4-methanol as solvent.
(
3) Fachini, M.; Lucchini, V.; Modena, G.; Pasi, M.; Pasquato, L. J. Am. Chem.
(4) Kerton, F. M.; Mohmand, G. F.; Tersteegen, A.; Thiel, M.; Went, M. J. J.
Organomet. Chem. 1996, 519, 177-184.
Soc. 1999, 121, 3944-3950.
J. AM. CHEM. SOC.
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VOL. 124, NO. 28, 2002 8317

A R T I C L E S
Adam et al.
Scheme 5
proposed as the logical intermediate in the reaction of sultene
A with cis- or trans-cyclooctene, except that the thiirenium
1
ion 3Ab has been directly observed. The following experimental
facts establish unequivocally the existence of the thiirenium ion
3
Ab: First, the reaction is reversible upon base treatment (K2-
CO3) when a Brønsted acid (TFA) is used for generating 3Ab;
second, the diene 6Ab is formed in slightly acidic or neutral
media. Expectedly, the reversal of the reaction, that is, the
quantitative recovery of the starting materials 1A and 2b, is
not possible on base treatment when the Lewis acid Sn(tpp)-
Figure 1. X-ray structure of episulfide 3Bb.
Scheme 4
(ClO4)2 is employed. This implies that the oxygen atom of
thiirenium ion 3Ab is protonated or ligated to the metal, which
makes 3Ab persist for many hours under acidic conditions.
The reversible generation of the persistent thiirenium ion 3Ab
is truly remarkable, since the few thiirenium ions that are known
3
,5
to date are irreversibly formed. In fact, most of the reported
i
thiirenium ions bear sterically demanding alkyl substituents ( -
t
Pr, Bu) and have nonnucleophilic counterions such as SbF6s
or BF4s to persist sufficiently for spectral observation.3 Only
,6
the di-tert-butyl-S-methyl thiirenium ion was persistent enough
5
c
at room temperature for X-ray analysis. The most common
transformations of such thiirenium ions are ring-opening reac-
tions, but Modena and Pasquato have also reported an unusual
t
ring expansion of a Bu-substituted thiirenium ion to its four-
membered thietium ion. Such ring opening of the thiirenium
ion 3Ab by the trifluoroacetic anion does not take place because
endoperoxide 1B was generated by photooxygenation of the
corresponding thiophene at -30 °C.1 Addition of the cyclooc-
tyne 2b to the photooxygenated mixture and warm-up to room
3
c
the nucleophile has to approach the vinyl carbon by backside
1
temperature (ca. 20 °C) revealed by H NMR spectroscopy that
5
f
attack (a SN2-Vin mechanism ) which is encumbered by steric
hindrance of the eight-membered ring. Rearrangement to a
thietium ion is also not feasible, since an unstabilized primary
carbocation would be formed.
after 3 h all of the thiophene endoperoxide 1B was consumed
and the episulfide 3Bb was obtained in 70% yield (Scheme 4).
Its structure was assigned by various NMR-spectral methods
(H,H-COSY, C,H-COSY, INADEQUATE), mass spectrometry,
The mechanism for the formation of the thiirenium ion 3Ab
is analogous to the sulfur transfer from the sultene 1A to the
cis/trans-2a cyclooctenes, in which the saturated thiiranium ion
and X-ray analysis (Figure 1). Addition of cyclooctyne 2b to
the thermolysate of the thiophene endoperoxide 1B did not lead
to the episulfide 3Bb. On treatment with triphenylphosphine at
room temperature (Scheme 4), expectedly this episulfide was
quickly (15 min) and quantitatively desulfurized to the pyran
intervenes as a short-lived intermediate to afford the cis/trans-
1
3
a thiiranes as the final products (Scheme 5). The reaction
entails nucleophilic attack by the strained triple or double bond
of the olefin or alkyne on the acid-activated sultene 1A. Usually,
a double bond is more reactive in its nucleophilicity than a triple
bond; however, a competition experiment revealed that the
reaction of sultene 1A with trans-cyclooctene (trans-2a) is
6
Bb. Also, heating of this episulfide in CDCl3 at 70 °C for 17
h caused 70% sulfur extrusion. When the thermolysis was
carried out in the presence of trans-cyclooctene (trans-2a), no
sulfur transfer was observed to afford the episulfide trans-3a.
The thiophene endoperoxide 1B did not effect sulfuration of
the dithiacyclononyne 2c. On thermolysis, only the desulfurized
products 4B and 5B of the endoperoxide 1B were detected,
along with elemental sulfur and unreacted alkyne 2c.
(
5) (a) Lucchini, V.; Modena, G.; Valle, G.; Capozzi, G. J. Org. Chem. 1981,
46, 4720-4724. (b) Capozzi, G.; DaCol, L.; Lucchini, V.; Modena, G.;
Valle, G. J. Chem. Soc., Perkin Trans. 2 1980, 68-73. (c) Capozzi, G.;
Lucchini, V.; Modena, G.; Scrimin, P. Tetrahedron Lett. 1977, 911-912.
(
d) Benati, L.; Montevecchi, P. C.; Spagnolo, P. Gazz. Chim. Ital. 1991,
Discussion
121, 387-391. (e) Destro, R.; Lucchini, V.; Modena, G.; Pasquato, L. J.
Org. Chem. 2000, 65, 3367-3370. (f) Modena, G.; Pasquato, L.; Lucchini,
V. Phosphorus, Silicon Sulfur 1994, 95-96, 265-282. (g) Lucchini, V.;
Modena, G.; Pasquato, L. Gazz. Chim. Ital. 1997, 127, 177-188.
6) Destro, R.; Pilati, T.; Simonetta, M. J. Chem. Soc., Chem. Commun. 1977,
576.
The formation of the thiirenium ion 3Ab in the reaction of
the sultene 1A with cyclooctyne 2b and stoichiometric amounts
of acid (Scheme 5) is analogous to that of the thiiranium ion,
(
8318 J. AM. CHEM. SOC.
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VOL. 124, NO. 28, 2002

Sulfur-Transfer in Cycloalkynes and Cycloalkenes
A R T I C L E S
Scheme 6
Scheme 7
Scheme 8
definitely much slower than with cyclooctyne 2b. Thus, no
episulfide trans-3a was observed; instead, the thiirenium ion
3Ab was formed nearly quantitatively. It should be emphasized
that trans-cyclooctene has thus far been the most reactive sulfur-
atom acceptor. Presumably, the higher reactivity of the cy-
1
release of the Lewis acid. The spirocyclic adduct 6Ac is obtained
preferentially (dr 91:9) as the (R*,S*,S*) diastereomer. This
pronounced diastereoselectivity may be reconciled in terms of
the steric interactions between the exocyclic methylene group
and the cyclooctane ring during the nucleophilic attack by the
oxygen functionality in the precursor of 6Ac (Scheme 7); thus,
the si-face attack that leads to the (R*,S*,S*) diastereomer is
preferred. For better visualization of the steric interactions, the
position of the attacking nucleophile has been maintained in
the same place and the thiocarbonyl moiety has been rotated to
expose either the si-face or the re-face.
Analogous to reactions with the sulfur-substituted cy-
clononyne 2c, for the reaction of the sultene 1A with the
carbocyclic cyclooctyne 2b, the first step is also proposed to
entail carbene formation (Scheme 6). Subsequent hydrogen shift
to the carbene center leads to the endocyclic double bond and
deprotonation to the diene 6Ab.
clooctyne derives from the more extensively deformed triple
bond on account of the greater ring strain. Another significant
difference in the reactivity between trans-cyclooctene and
cyclooctyne is the fact that the resulting thiiranium ion releases
the episulfide as final product, whereas the persistent thiirenium
ion 3Ab eventually rearranges to the diene 6Ab. Evidently,
sulfur transfer in the case of the thiirenium ion 3Ab through
the formation of the aldehyde 5A is less favored than the
rearrangement to the diene 6Ab because the first process would
require CC-bond cleavage. Moreover, an antiaromatic thiirene
would have to be set free, which is energetically unfavorable.
The mechanism of diene 6Ab formation may be understood,
when a closer look is taken at the similar reaction of sultene
1
A with the heterocyclic dithiacyclononyne 2c and Sn(tpp)-
(ClO4)2 as Lewis acid (Scheme 3). In this case, neither thiirene
liberation nor diene formation occurs, but instead the spirocyclic
product 6Ac is generated. The formation of this unexpected
adduct may be rationalized in terms of ring opening of the
In the reaction of thiophene endoperoxide 1B with cyclooc-
tyne 2b, still another reactivity was observed; namely, the sulfur
transfer to the unexpected episulfide 3Bb occurred (Scheme 4).
To explain this transformation, we recall that in our previous
work on the thermal sulfur transfer from thiophene endoperoxide
thiirenium ion 3Ac to an R-thiono carbene, in analogy to the
ring opening of oxirenes7 (Scheme 6). Subsequently, the
neighboring thioether functionality of the nine-membered ring
attacks the carbene to result in the ylide, which by ring opening
leads to the exocyclic methylene group. Such intramolecular
rearrangements of â-thioalkyl carbenes through ylide-like
1
c
1
B to strained cyclic alkenes, as well as in earlier work by
9
Matturro, oxathiiranes or carbonyl O-sulfides or both have been
(
8) (a) Robson, J. H.; Shechter, H. J. Am. Chem. Soc. 1967, 89, 7112-7114.
(b) Bissolino, P.; Alpegiani, M.; Borghi, D.; Perrone, E.; Franceschi, G.
Heterocycles 1993, 36, 1529-1539. (c) Tamura, Y.; Ikeda, H.; Chisato,
M.; Bayomi, S. M. M.; Ikeda, M. Chem. Pharm. Bull. 1980, 28, 3430-
3433.
8
intermediates have been documented. Finally, the spirocyclic
adduct 6Ac is obtained by nucleophilic attack of the juxtaposed
oxygen atom on the thiono carbon atom with simultaneous
(
9) (a) Matturro, M. G.; Reynolds, R. P.; Kastrup, R. V.; Pictroski, C. F. J.
Am. Chem. Soc. 1986, 108, 2775-276. (b) Matturro, M. G.; Reynolds, R.
P. Tetrahedron Lett. 1987, 28, 4981-4984.
(7) Lewars, E. G. Chem. ReV. 1983, 83, 519-534.
J. AM. CHEM. SOC.
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A R T I C L E S
Adam et al.
postulated as transients. In the present case with cyclooctyne
the thiiranium ion releases the thiirane as sulfur-transfer product,
under appropriate conditions, the thiirenium ion either reverts
to the starting materials or rearranges to more complex sulfur-
functionalized products. The antiaromatic thiirene is only
reluctantly released as sulfur-transfer product in view of its
higher energy, but if it is set free, it either dimerizes or is
trapped. This distinctive chemical reactivity between cy-
cloalkynes and cycloalkenes toward the sulfur donors 1A and
1B has provided valuable mechanistic insight into the sulfur-
transfer process through the direct observation of a persistent
and reversible thiirenium ion.
2b, carbonyl O-sulfides may be excluded as sulfur-transferring
intermediates because such dipolar structures would hardly lead
to the observed product, the episulfide (R*,R*,R*)-3Bb (cf.
Scheme 4). Instead, it is more likely that the oxathiiranes I and
II (Scheme 8) serve as sulfur-transfer agents to the cyclooctyne
2
b.
Since the oxathiirane I is cross-conjugated and oxathiirane
II extendedly conjugated, we stipulate that the latter is
preferentially formed and serves as sulfur-transferring interme-
diate to the triple bond. A very reactive thiirene is set free, as
previously demonstrated in the reaction of fluorenethione
2
Acknowledgment. We thank the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie for generous
financial support. This work is dedicated to Professor P. Welzel
S-oxide (1C) with cyclooctyne, in which the released thiirene
dimerized to the dithiin 3b. In view of proximity, the thiirene
cycloadds immediately to the simultaneously generated trienone
(Leipzig) on the occasion of his 65th birthday in appreciation
4
B and affords the observed (R*,R*,R*)-episulfide 3Bb.
of his important scientific contributions.
Conclusions
Supporting Information Available: Experimental procedures
and full characterization for products 6Ab, 7Ab, 6Ac, 3Bb with
the pertinent NMR spectral data and X-ray crystallographic data
for 3Bb (PDF). This material is available free of charge in the
Internet at http://pubs.acs.org.
The present work demonstrates that the sulfur donors sultene
A and thiophene endoperoxide 1B exhibit a totally different
reactivity with strained cycloalkynes compared to that with
cycloalkenes. For both substrates, three-membered-ring cy-
cloadducts are formed, namely the thiirenium ions from the
cycloalkynes and thiiranium ions from the cycloalkenes. Whereas
1
JA025934X
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