Sigmatropic Rearrangement-Based Synthesis of 4-Alkenyl-1,3-dithiol-2-ones

Article abstract of DOI:10.1021/acs.orglett.9b01157

A series of conjugated 4-alkenyl-1,3-dithiol-2-ones have been prepared by microwave-assisted rearrangement of S-(4-acyloxy-2-alkynyl)-O-ethyl xanthates in moderate to good yields. The synthetic approach is based on a combination of [3,3] and [1,5] sigmatropic rearrangements as well as the intermediacy of a reactive betaine that induces the ionic elimination of the acyloxy group. The [1,5] sigmatropic rearrangement was confirmed by a deuterium-labeling experiment.

Full text of DOI:10.1021/acs.orglett.9b01157

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sigmatropic Rearrangement-Based Synthesis of 4‑Alkenyl-1,3-
dithiol-2-ones
Pavels Ostrovskis,† Andrey A. Mikhaylov, and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, Ecole Polytechnique, CNRS UMR 7652, Palaiseau 91128 Cedex, France
S
* Supporting Information
ABSTRACT: A series of conjugated 4-alkenyl-1,3-dithiol-2-
ones have been prepared by microwave-assisted rearrange-
ment of S-(4-acyloxy-2-alkynyl)-O-ethyl xanthates in moderate
to good yields. The synthetic approach is based on a
combination of [3,3] and [1,5] sigmatropic rearrangements
as well as the intermediacy of a reactive betaine that induces
the ionic elimination of the acyloxy group. The [1,5] sigmatropic rearrangement was confirmed by a deuterium-labeling
experiment.
1,3-Dithiol-2-ones are 5-membered sulfur heterocycles with
notable aromatic character. They are generally recognized as
universal precursors to tetrathiafulvalenes upon phosphite-
mediated reductive coupling with the analogous 1,3-dithiol-2-
thiones.1 The charge-transfer properties of tetrathiafulvalenes
have found widespread applications in nonlinear optics and in
photovoltaics.2 Another mainstream utilization of 1,3-dithiol-2-
ones consists of their base-induced cleavage into 1,2-dithiols,
which are valuable bidentate ligands in molybdenum and
tungsten complexes, such as in the molybdopterin cofactor.3
Other transition-metal derivatives are found as redox switches
and near-IR dyes.4 We report herein a novel general approach
for synthesis of 1,3-dithiol-2-ones conjugated with a double
bond, thus opening up an unusual and straightforward route to
tetrathiafulvalenes and dithiolene complexes with possibly
improved electronic properties.
sigmatropic rearrangement of xanthate 1 into allenyl xanthate
2, which we found to be in equilibrium with betaine 3. This
equilibrium strongly favors the former. Betaine 3 can be viewed
as a slightly stabilized allylic anion, with perhaps some aromatic
character, since the ring in canonical resonance structure 3b
contains six electrons. The build-up of electron density on the
carbon adjacent to the benzoate group causes β-elimination to
give intermediate 4, which rapidly collapses into bis-
(methylidene)-1,3-dithiolan-2-one 5 and methyl benzoate.
Rigid, cisoid diene 5 is highly reactive and rapidly dimerizes
through a Diels−Alder cycloaddition to give compound 6.
However, it can be readily captured by a powerful dienophile
such as maleimide 7 to give the corresponding Diels−Alder
product 8 in high yield. The intramolecular variant of this
transformation proceeds equally efficiently and allows access to
highly complex polycyclic structures.5d
In an attempt to expand the scope of the process to more
substituted bis(alkylidene)-1,3-dithiolan-2-ones 10, we exam-
ined the behavior of S-propargyl xanthates of general structure
9 (Scheme 2). In the event, we were surprised to find that
The approach is based on the thermally induced isomer-
ization of S-propargyl xanthates equipped with a leaving group
such as 1, which we serendipitously discovered some years ago
(Scheme 1).5−7 This isomerization starts with the [3,3]-
Scheme 2. Sequential Thermal Sigmatropic Rearrangements
Scheme 1. Example of Diene Formation from an S-
Propargyl Xanthate
dienes 10 underwent a rapid [1,5] sigmatropic rearrangement
to give the much less reactive isomeric dienes 11, which could
be isolated.
For this study, we prepared a series propargyl xanthates 9
using the two routes outlined in Scheme 3 (see the Supporting
Information). Route A was used for the majority of the
Received: April 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Propargyl Xanthates
Scheme 4. Synthesis of 4-Alkenyl-1,3-dithiol-2-ones
examples, giving precursors with an acetate leaving group (R3 =
H and R4 = Me). The acetylation of the somewhat fragile
tertiary chloromethyl propargylic alcohols 12 proved to be
unexpectedly challenging, and numerous methods had to be
screened. Ultimately, the most effective procedure was the
acid-catalyzed acetyl exchange with 2-propenyl acetate.8 Route
B could be applied for the case where R3 ≠ H through reaction
of lithium acetylide derived from pivalate 13 with the
appropriate aldehyde (Piv = pivalate). The use of a pivalate
obviates possible complications caused by direct attack of BuLi
on the ester group or by deprotonation of acidic hydrogens
next to the carbonyl group, since none are present.
We examined initially the behavior of cyclohexanone derived
xanthate 9a in order to establish the best experimental
conditions. We started by heating this compound in
chlorobenzene at reflux, a procedure that had worked well
for the less substituted S-propargyl xanthates (such as 1) we
had studied previously.5 In this case, however, the reaction
required a long time to reach completion, and significant
amounts of tarry material were formed. After some
experimentation, we found that heating a chlorobenzene or
toluene solution in a microwave oven at 180 °C furnished 4-
cycloxehenyl-5-methyl-1,3-dithiol-3-one 11a in 80% in just 30
min (Scheme 4). Toluene is easier to eliminate and was chosen
as the preferred solvent for the remainder of the study.
Other examples are displayed in Scheme 4. The first five
involve substrates derived from symmetrical ketones so as to
avoid complications due to isomeric intermediates (examples
11a−e). The yield in these cases is generally good for both
acetate and pivalate derivatives, and no difficulties were
observed in the case of the N-Cbz-protected piperidine
propargyl xanthate 9c, which gave the expected dithiolone
11c in good yield. In the case of substrates derived from
unsymmetrical ketones, such as 9f and 9g, prepared,
respectively, from methyl isopropyl ketone and menthone,
the reaction produced essentially equimolar amounts of the
inseparable isomeric pairs 11f /11f′ and 11g /11g′ in reduced
yield. This observation indicates that the formation of diene 10
is irreversible under these conditions and that the process is
under kinetic control with little selectivity.
Scheme 5. Rearrangement of Propargyl Xanthates Derived
from Aldehydes
These factors appeared to be also operating in the case of
propargyl xanthates derived from aldehydes, as shown by the
two examples in Scheme 5. Heating compound 9h, prepared
from dihydrocinnamaldehyde, under the usual conditions
furnished dithiolone 11h as the only isolable product.
However, the reaction was not very clean, and the yield of
11h was modest (45%). In all probability, the first rearrange-
ment produces irreversibly isomeric dienes 10h and 10h′, but
only the former can undergo the subsequent [1,5] sigmatropic
rearrangement to give the observed dithiolone 11h as only the
E isomer. In contrast, the cyclododecyl derivatives 9i and 9i′
can only rearrange into the same intermediate diene 10i, which
is ideally disposed for the [1,5] sigmatropic rearrangement
leading to product 11i in high yield in both cases. The nature
of the “leaving” group, an acetate or a benzoate, hardly makes a
difference.
A similar behavior presumably underlies another set of
propargylic xanthates derived from ketones, where only one of
B
DOI: 10.1021/acs.orglett.9b01157
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the corresponding isomeric dienes of general structure 10 is
able to undergo the [1,5] sigmatropic rearrangement. Two
examples are pictured in Scheme 6. In the first, 9j, prepared
Upon vigorous heating, the tertiary allylic acetate can
undergo elimination of acetic acid to give diene 15, which then
evolves into various products, including oxidation of the labile
cyclohexadienyl system, or undergo a [3,3] sigmatropic
rearrangement to furnish isomeric allylic acetate 16. This
compound can undergo a second [3,3] sigmatropic rearrange-
ment involving this time the propagylic xanthate motif to give
isomeric allene 17, which is in equilibrium with betaine 18.
Protonation of the latter with acetic acid and concomitant loss
of ethyl acetate finally generates the observed dithiolone 14.
In summary, we have described an unusual yet inexpensive
and versatile route to 4-alkenyl-1,3-dithiol-2-ones. These are
rare structures. Indeed, only three synthetic routes have been
described in the open literature. The first is based on a Wittig
reagent prepared from 4-bromomethyl-1,3-dithiol-2-one.10
The second is the radical addition of bis(O-isopropylxanthate)
to enynes.11 The last is the acid-catalyzed closure of O-ethyl-S-
(4-hydroxybut-2-yn-1-yl)-xanthate.3a The last approach was
applied to only one example but could in principle be
generalized. The present procedure complements the earlier
routes and provides in many instances structures that are not
otherwise easily accessible.
Scheme 6. Rearrangement of Propargyl Xanthates Derived
from Unsymmetrical Ketones
ASSOCIATED CONTENT
* Supporting Information
■
S
from norbornanone, the rearrangement afforded dithiolanone
11j in 56% yield. This compound can only arise from
intermediate 10j. The isomeric alkene 10j′ follows other
pathways leading to unidentified side products. By starting
with deuterated analogue 9j-d,1 we observed an apparent 2:1
preference for migration of the exo hydrogen atom. However,
taking into account the primary kinetic isotope effect, which
for thermal sigmatropic hydrogen migrations is estimated to be
in the range of 5−8,9 the actual preference for migration of the
exo hydrogen must be much higher, of the order of 10−15:1.
Incidentally, this deuteration experiment confirms the
sigmatropic rearrangement proposed in Scheme 2. The second
example is estrone-derived propargylic xanthate 9k, which
furnished diene 11k in 50% yield upon heating under the usual
conditions.
We studied one case of a propargyl xanthate derived from an
unsaturated ketone, namely compound 9l obtained from 2-
cyclohexenone. Microwave heating of a toluene solution did
not result in a clean reaction, but a major product was isolated
in 33% yield. Spectroscopic analysis indicated it to have
structure 14, where the acetate group has been retained but
not in the same position (Scheme 7).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01157.
Experimental procedures, full spectroscopic data, and
1
copies of H and 13C NMR for all new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: samir.zard@polytechnique.edu.
ORCID
Samir Z. Zard: 0000-0002-5456-910X
Notes
The authors declare no competing financial interest.
†Deceased September 5, 2014.
ACKNOWLEDGMENTS
We thank the ANR for financial support to two of us (P.O. and
A.A.M.).
■
Scheme 7. Rearrangement of a Propargyl Xanthate Derived
from Cyclohexenone
DEDICATION
■
This article is respectfully dedicated to the memory of Pavels
Ostrovskis (1985−2014).
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Org. Lett. XXXX, XXX, XXX−XXX