Sulfur-directed olefin oxidations: Observation of divergent reaction mechanisms in the palladium-mediated acetoxylation of unsaturated thioacetals

Article abstract of DOI:10.1021/om2000585

The Pd-mediated oxidation of unsaturated thioacetals gives either allyl or vinyl esters, depending on the substrate structure. We report the characterization of a range of sulfur-stabilized palladium intermediates via a combined computational and experime

Full text of DOI:10.1021/om2000585

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Sulfur-Directed Olefin Oxidations: Observation of Divergent Reaction
Mechanisms in the Palladium-Mediated Acetoxylation of Unsaturated
Thioacetals
Sam E. Mann,† Abil E. Aliev,† Graham J. Tizzard,‡ and Tom D. Sheppard*,†
†Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, U.K.
‡UK National Crystallography Service, School of Chemistry, University of Southampton, Southampton SO17 1BJ, U.K.
S Supporting Information
b
ABSTRACT: The Pd-mediated oxidation of unsaturated thioa-
cetals gives either allyl or vinyl esters, depending on the
substrate structure. We report the characterization of a range
of sulfur-stabilized palladium intermediates via a combined
computational and experimental NMR approach, demonstrat-
ing that the oxidation proceeds via two divergent reaction
mechanisms. We were also able to synthesize an unusual σ-
bound Pd complex, via acetoxypalladation of an unsaturated
dithiane, which was characterized by X-ray crystallography.
alladium-mediated oxidation reactions play an important role
in synthetic chemistry, providing methods for the conversion
the reaction mixture was allowed to stand overnight at room
temperature, the allylic acetate 2 was observed as the major
product and was isolated in 78% yield. No trace of the correspond-
ing branched acetate was observed in the crude NMR spectrum.7
The parent ketone 3 was not oxidized under similar reaction
conditions to any significant extent, although after prolonged
reaction times (ca. 48 h) a complex mixture of products was
observed by NMR. Inorder to determine how the thioacetal group
was directing the oxidation reaction, we carefully monitored the
reaction by NMR in order to study any intermediate complexes.
Upon treatment of 1 with Pd(OAc)2 in CDCl3, we observed
immediate formation of an approximately 1:1 mixture of the two
isomeric complexes 4 and 5 (Figure 1). Over the course of around
15 min at room temperature, this mixture of complexes was
converted into the single new species 6.
P
of alkenes to methyl ketones or aldehydes (Wacker process)1,2
and of ketones to enones (Saegusa oxidation).3 More recently,
there has been considerable interest in the Pd-mediated oxida-
tion of alkenes to allylic esters4-9 and in oxidative alkene
functionalization reactions.10 Typically these processes require
a co-oxidant (e.g., benzoquinone/BQ, MnO2, Cu salts, O2) and
these co-oxidants often play a complex role in the catalytic cycle.
As a consequence, mechanistic studies using stoichiometric
quantities of Pd salts are not always consistent with the results
obtained from catalytic reactions.5,6,8 A good understanding of
the reaction mechanism can be extremely valuable for optimizing
reaction procedures and developing new transformations. In
recent reports sulfur ligands have been employed for controlling
the outcome of the Pd-catalyzed oxidation of alkenes, to give
either linear or branched allylic esters selectively.7,8 Even in very
early reports, the important effect of DMSO as a solvent in
stoichiometric palladium oxidations was noted.9 The oxidation of
alkenes to give allyl acetates is thought to proceed via a Pd π-allyl
complex, although mechanistic studies have often given conflict-
ing results.5,8,11 In this communication we report a study of the
oxidation of unsaturated thioacetals with Pd(OAc)2. The reac-
tion can proceed via two divergent mechanisms to give either
allylic or vinylic ester products, and these oxidation processes are
operative under both stoichiometric and catalytic reaction condi-
tions. In addition, the intermediate palladium complexes are stabi-
lized by the thioacetal unit and can be observed and characterized by
NMR, providing a detailed understanding of the reaction pathways.
As part of an ongoing project on the development of new
transformations of acetals, we examined the reaction of unsatu-
rated dithiane 1 with 1 equiv of Pd(OAc)2 (Scheme 1).2,12 When
Scheme 1. Reaction of Unsaturated Dithianes with
Pd(OAc)2
Intermediate 6 has an NMR spectrum consistent with a π-allyl
species, showing 13C resonances at 61.9, 115.2, and 77.5 ppm for
Received: January 21, 2011
Published: March 09, 2011
r
2011 American Chemical Society
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Scheme 2. Reaction of Unsaturated Dithiane 7 with
Pd(OAc)2
Scheme 3. Proposed Mechanism of the Pd-Mediated
Oxidation Reactions
give the vinyl acetate 9 as the major oxidation product in 23%
yield.14 There was no evidence for the formation of allylic acetate
products or the internal vinyl acetate, which might be expected to
form via a Wacker-type oxidation.1,2 Dithiane complex 8 had an
NMR spectrum similar to 5, with a high chemical shift for the
axial proton at C-7 (4.53 ppm). This complex was formed as a
single stereoisomer with the palladium complexed to the same face
as the carbon chain (Scheme 2). Over time 8 did not react to
form a π-allyl complex but was instead slowly converted into the
vinyl acetate 9 as the major oxidation product. The formation of
terminal vinyl acetates in this type of oxidation reaction is highly
unusual.15
On the basis of these observations it seems that two divergent
reaction mechanisms can operate during the oxidation of these
unsaturated dithianes (Scheme 3). Initial formation of the
palladium dithiane complexes 10 and/or 11 occurs prior to
oxidation. Reaction can then occur via abstraction of an allylic
hydrogen atom to give the π-allyl complex 6, followed by attack
of acetate to give the allyl acetate product 2. The π-allyl complex
6 has the palladium coordinated to an equatorial lone pair on the
sulfur, with the tether occupying an axial position. Alternatively,
direct acetoxypalladation to give the σ-complex 12 can occur,
followed by β-hydride elimination to give the vinyl acetate
product 9. This latter process presumably becomes more favor-
able with a bulkier chain (R = Me) for two reasons: (i)
abstraction of the allylic hydrogen atom to form a π-allyl complex
is more difficult; (ii) complex 10, with the bulky chain occupying
an equatorial position, becomes favored over 11. This latter effect
may prevent access to the intermediate conformer necessary for
the formation of a π-allyl complex similar to 6, which contains the
unsaturated chain in an axial position.
Figure 1. Structures of complexes 4-6. Observed chemical shifts for
selected atoms are shown, with calculated values from DFT in
parentheses.13
carbons 1-3 (Figure 1). Deshielding of the protons on C-6 but
not C-8 suggested that the Pd atom was only coordinated to one
of the sulfur atoms. The NMR spectrum of the mixture of com-
plexes 4 and 5 suggested coordination of the Pd to both sulfur
atoms, however, with the protons at C-6 and C-8 shifted down-
field. An unusually high chemical shift of around 4.5 ppm was
seen for the axial proton at C-7 on the dithiane ring in both
isomers of this complex. The structures of 4-6 were established
using a combined application of NMR, semiempirical (PM6),
and quantum-mechanical (QM) methods.13 Initially, molecular
structures were built satisfying the experimentally measured
nuclear Overhauser effects (NOEs) and vicinal J couplings.
The geometries of these structures were optimized subsequently
using PM6 calculations, followed by QM DFT (density func-
tional theory) calculations. The final structures elucidated in this
manner are shown in Figure 1. The observed NOEs suggest a
chair conformation of the six-membered ring, the presence of
which is further supported by the large values of 3J couplings for
trans-diaxial protons. The equatorial/axial orientations of the 5-Me
groupin4and 5are further supported by their 1Hand13C chemical
shifts. Significant high-frequency shifts of the 7-Hax proton in 4 and
5 can be attributed to its spatial proximity to the oxygen atoms of
the nearby acetates (around 3.4 Å in the structures shown). The 1H
and 13C NMR shifts for the proposed structures of 4-6 were
calculated using DFT, and these values showed good agreement
with those observed experimentally, including the unusual high-
frequency shifts for the 7-Hax proton in 4 and 5 (Figure 1).
The oxidation of closely related dithiane 7 proceeded very
differently from the reaction of dithiane 1 (Scheme 2). Initial
formation of complex 8 was observed, which over time evolved to
We then sought to determine whether these mechanisms were
also operative under catalytic conditions (Scheme 4). With
MnO2 benzoquinone (BQ) as co-oxidants,4b and we found that
unsaturated thioacetals 1 and 7 could be oxidized to give the
corresponding acetates 2 and 9. The R1 group (H or Me) did not
appear to affect the reaction outcome, with dithianes 13 and 17
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Scheme 4. Catalytic Oxidation Reactions of Unsaturated
Dithianes
Scheme 6. Oxidation of an Unsaturated Dithiolane
Scheme 7. Formation of Stable Pd σ-Complexes
Scheme 5. Chemoselective Oxidation of an Unsaturated
Dithiane in the Presence of Another Alkene
structure of this σ complex was subsequently confirmed for the
naphthalene-substituted analogue 32 via single-crystal X-ray
diffraction (Figure 2).17 Interestingly, these complexes are
formed as single diastereisomers (on the basis of the NMR
spectrum), despite the fact that three stereogenic centers are
generated during the reaction.The complex is dimeric, with two
bridging acetate ligands linking the Pd atoms with an interme-
tallic distance of only 2.959 Å. Each Pd atom is coordinated to a
single sulfur atom via the axial lone pair and adopts a square-
planar geometry. This dimeric structure appears to be main-
tained in solution, as an NOE was observed between the protons
at C-2 and C-60 (Figure 2). This highly rigid structure presum-
ably accounts for the fact that the complexes do not readily
undergo β-hydride elimination. In fact, treatment of 29 with 1
equiv of pyridine only led to β-acetoxyelimination and regenera-
tion of the starting dithiane 27 (Scheme 7).
We were also able to generate the analogous σ complex 33 by
carbopalladation of dithiane 27 using phenyltributylstannane in
the presence of a Pd(II) salt (Scheme 8).10 The NMR of complex
33 was somewhat broad, possibly due to monomer-dimer
exchange. However, 33 could readily be converted to the
monomeric complex 34, which was more easily characterized
by NMR. Oxidation of the carbon-palladium bond in dimer 33
giving allyl and vinyl acetate products 14 and 18, respectively.
Other esters could readily be introduced by addition of 2 equiv of
the carboxylic acid to the reaction mixture (15, 16, and 19).
Although the vinyl acetate products were only obtained in
moderate yields, it is notable that the isolated yield of 9 is
significantly higher than that obtained in the stoichiometric
reaction. This is likely to be a consequence of the instability of
these vinyl acetates in the presence of excess Pd salts.14
We also found that the dithiane-directed oxidation reaction
could be carried out chemoselectively in the presence of another
oxidizable alkene, allyl anisole 20 (Scheme 5). In the absence of
dithiane 1, 20 was oxidized to give the corresponding allylic
acetate 21 in 93% yield.8 However, only the unsaturated dithiane
was oxidized to any significant extent, when a mixture of 1 and 20
was treated under the same conditions, with 20 being recovered
in 86% yield together with a trace of the corresponding oxidation
product 21.
Given that the oxidation pathway seems to be significantly
affected by the conformation of the dithiane ring, we also
examined the reaction of dithiolane 22. This gave a mixture of
the allyl and vinyl acetate products 23 and 24 in 93% overall yield
(Scheme 6). The two isolated products 23 and 24 were shown
not to interconvert under the reaction conditions, although vinyl
acetate 24 was slowly oxidized to give geminal diacetate 25 after
prolonged reaction times. These experiments provide further
evidence that the two types of oxidation products are produced
via divergent reaction pathways and not via Pd-mediated isomeriza-
tion processes. A stoichiometric reaction of 22 with Pd(OAc)2 in
CDCl3 led to the formation of small quantities of 24, together with
the π-allyl complex 26, which gradually reacted to give 23.
Although the formation of the vinyl acetate products 9 (and
24) appears to proceed via an intermediate Pd σ-complex such as
12, we were unable to observe this intermediate by NMR. However,
we found that treatment of dithiane 27 with Pd(OAc)2 (Scheme 7)
gave the stable Pd σ-complex 29 via the initial short-lived
dithiane complex 28.16 The σ-complex complex 29 has a
distinctive signal for the proton at C2 (3.26 ppm, dddd). The
Figure 2. X-ray crystal structure of 32.
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Scheme 8. Carbopalladation of Dithiane 27
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In summary, we have demonstrated that two divergent reac-
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unsaturated thioacetals, leading to allyl and vinyl acetates. The
reaction intermediates can be characterized via NMR due to the
useful stabilizing effect of the thioacetal group, and the two
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could be charactized via NMR studies and, in one case, single-
crystal X-ray diffraction. We anticipate that thioacetals can be
used to control many other transition-metal-catalyzed reactions
and to facilitate the direct observation of a variety of reaction
intermediates. Further work is underway to extend the scope of
these sulfur-directed organometallic reactions, and the results
will be reported in due course.
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’ ASSOCIATED CONTENT
S
Supporting Information. Full experimental procedures
b
and details of the NMR shift calculations for complexes 4-6,
spectroscopic data for all new compounds, and X-ray crystal-
lographic data for complex 32 (CIF file). This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tom.sheppard@ucl.ac.uk.
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’ ACKNOWLEDGMENT
This work was supported by the EPSRC (EP/E052789/1:
Advanced Research Fellowship to T.D.S.) and University Col-
lege London (studentship to S.E.M.). We thank the EPSRC
national crystallography service at Southampton and the EPSRC
national mass spectroscopy service at Swansea for analytical
support and Dr. Stephen Goldup (QMUL) for helpful discussions.
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