Scalable synthesis of oxazolones from propargylic alcohols through multistep palladium(II) catalysis: β-selective oxidative heck coupling of cyclic sulfonyl enamides and aryl boroxines

Article abstract of DOI:10.1002/anie.201307471

A whale of a scale: The title oxidative Heck coupling proceeded with unusual β selectivity to generate a variety of branched substituted oxazolones (see scheme; Ts=p-toluenesulfonyl). The three-step synthesis from readily available starting materials with a simple palladium catalyst and inexpensive reagents could be carried out in a single reaction vessel or scaled up for the preparation of large amounts of these amino acid precursors. Copyright

Full text of DOI:10.1002/anie.201307471

Angewandte
Chemie
DOI: 10.1002/anie.201307471
Heterocycle Synthesis
Hot Paper
Scalable Synthesis of Oxazolones from Propargylic Alcohols through
Multistep Palladium(II) Catalysis: b-Selective Oxidative Heck
Coupling of Cyclic Sulfonyl Enamides and Aryl Boroxines**
Santosh Kumar Alamsetti, Andreas K. ꢀ. Persson, Tuo Jiang, and Jan-E. Bꢁckvall*
Palladium-catalyzed cross-coupling reactions are among the
most widely used and versatile reactions for carbon–carbon
bond formation in organic synthesis.[1] Of particular impor-
tance is the palladium(0)-catalyzed Mizoroki–Heck reaction,
discovered in the 1970s,[2] which has since then been
developed successfully. The outcome of the Mizoroki–Heck
reaction is the rapid formation of new carbon–carbon bonds
and overall stability together with their commercial avail-
ability.
Our long-standing interest in palladium(II)-catalyzed
oxidative carbon–carbon bond-forming reactions,[14] and
more recently in the oxidative Heck reaction,[15] has led us
to search for robust synthetic procedures that enable smooth
carbon–carbon bond formation under oxidative conditions.
We have been particularly interested in broadening the scope
of the oxidative Heck reaction with respect to the alkene
component to enable the synthesis of more complex mole-
cules. Herein we disclose a novel and selective palladium(II)-
catalyzed oxidative coupling between cyclic enamides A and
aryl boroxines that provides access to useful aryl-substituted
amino acid precursors C and/or D (Scheme 1). The target b-
À
between alkenes and aryl halides or pseudohalides (e.g. Ar
OTf, Tf = trifluoromethanesulfonyl). Interestingly, prior to
the reaction of aryl halides, Heck disclosed a catalytic
reaction yielding the same type of products that proceeded
in an oxidative manifold and relied on PdCl2 and CuCl2 in
combination with an aryl mercury species and an olefin.[3]
A
modified variant in which a vinylboronic acid was used
instead of the mercury reagent as the coupling partner was
reported by Dieck and Heck in 1975.[4] However, in the latter
reaction, Pd(OAc)2 was used in stoichiometric amounts. To
circumvent the use of stoichiometric quantities of a PdII
catalyst, Cho and Uemura reported a catalytic version of
the oxidative Heck coupling of arylboronic acids in 1994.[5]
The oxidative Heck coupling has since been studied in detail
by several research groups, including those of Larhed,[6]
Mori,[7]and Jung.[8] Heck-type coupling reactions are often
limited to a narrow range of alkene coupling partners, thus
hampering the use of this methodology in complex organic
synthesis. The latter issue has recently been addressed (in
part), and much effort has been devoted to broadening the
synthetic utility of this transformation as well as gaining
a more detailed understanding of its mechanism.[9]
Scheme 1. Envisioned palladium(II)-catalyzed oxidative Heck arylation
of cyclic enamides.
Heck-type coupling reactions have been investigated
extensively with various transmetalation partners, including
arylbismuth reagents,[10] arylantimony reagents,[11] aryl-
silanes,[12] arylstannanes,[8a] and arylphosphonic acids;[13] how-
ever, arylboronic acids remain the most widely used coupling
partners owing primarily to their relatively nontoxic nature
arylated cyclic carbamate D contains a prevalent structural
backbone suitable for the synthesis of a wide range of natural
products, chiral ligands, and pharmaceuticals[16] (Scheme 2).
Inspired by the studies of Larhed and co-workers on the
oxidative Heck arylation of acyclic enamides,[6g] we aimed to
[*] Dr. S. K. Alamsetti, Dr. A. K. ꢀ. Persson, T. Jiang,
Prof. Dr. J.-E. Bꢁckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
10691 Stockholm (Sweden)
E-mail: jeb@organ.su.se
[**] Financial support from the European Research Council (ERC AdG
247014), the Swedish Research Council, and the Berzelii Centre
EXSELENT is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307471.
Scheme 2. Examples of pharmaceuticals with structural elements of
the products obtained in this study.
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develop a catalytic multistep protocol that could provide
access to arylated cyclic carbamates from propargylic alcohols
and isocyanates through palladium(II)-mediated hydroami-
nation. Subsequent palladium(II)-catalyzed oxidative cou-
pling of the cyclic carbamate with an appropriate trans-
metalation partner would then produce the desired oxazo-
lone.
The desired propargylic carbamates were obtained by the
condensation of a propargylic alcohol with an equimolar
amount of tosylisocyanate (TsNCO) in 1,2-dichloroethane
(DCE). The subsequent cyclization, which formally consti-
tutes a hydroamination of tosylcarbamates 1, was then
investigated.[17,18] The best conditions for this transformation
were found to be treatment with Pd(OAc)2 (2.5 mol%) along
with Bu4NOAc (2.5 mol%) in DCE at room temperature.
Under these reaction conditions, the desired tosyl-protected
enamides 2 and 4–6 resulting from a 5-exo cyclization were
obtained with Z selectivity in excellent yields (Scheme 3).
Scheme 4. Initial conditions for the oxidative Heck arylation of 2 and
X-ray crystal structure of the product 7a (right). DMSO=dimethyl
sulfoxide.
consumed both the aryl boroxine and the oxidant. The choice
of catalyst turned out to be less crucial: at a catalyst loading of
5 mol%, Pd(OAc)2, Pd(OCOCF3)2, Pd(OPiv)2, and Pd(acac)2
(acac = acetylacetonate, Piv = pivaloyl) all catalyzed the
reaction at 558C to some extent, albeit with some minor
variations.
During our initial studies of this reaction, it quickly
became apparent that the addition of a cosolvent in the form
of dry DMSO is required. In a 2:1 mixture of a chosen solvent
and DMSO, the reaction proved effective at 558C with many
common solvents, such as THF, DCE, EtOAc, toluene, and
acetone. We finally chose DCE, as both carbamate formation
Scheme 3. Palladium(II)-catalyzed cycloisomerization (hydroamination)
of propargylic tosylcarbamates. Ts=p-toluenesulfonyl.
and
the
palladium(II)-catalyzed
cycloisomerization
(Scheme 3) proceeded well in this solvent. The ratio of
DCE to DMSO was also investigated. It was found that the
amount of DMSO is crucial; when too much DMSO was used,
it had a strong inhibitory effect (Figure 1). The best results
were obtained with a 70:30 mixture of DCE and DMSO,
which corresponds to approximately 15 equivalents of DMSO
relative to the starting enamide 2. With this set of reaction
conditions, we were able obtain 7a in 84% yield (as based on
Having found efficient catalytic conditions for the palla-
dium(II)-catalyzed cycloisomerization, we turned our atten-
tion toward the oxidative arylation. Treatment of the cyclic
enamide 2 with Pd(OAc)2 (5 mol%), commercially available
PhB(OH)2 (1 equiv), and 1,4-benzoquinone (BQ; 1.5 equiv)
in a mixture of DCE and DMSO provided 7a as a single
regioisomer.[19] We were surprised to find that the oxidative
arylation occurred exclusively at the b carbon atom and with
selective b-hydride elimination to give oxazolone 7a. This
finding clearly demonstrates that cyclic enamides show
completely different reactivity toward palladium(II)-cata-
lyzed oxidative arylation than the acyclic enamides studied by
Larhed and co-workers, when arylation preferentially oc-
curred at the a carbon atom.[6g] Furthermore, the most
efficient source of aryl groups proved to be triarylboroxines[20]
(Ar3(BO)3); all other related reagents, such as arylboronic
acids (ArB(OH)2), N-methyliminodiacetic acid (MIDA)
boronates, potassium aryltrifluoroborates, and arylboronic
esters, provided the desired oxazolones in only moderate
yields. For complete consumption of the starting material, an
excess of both Ar3(BO)3 (0.50–0.67 equiv, which corresponds
to 1.5–2.0 equiv of the “aryl group”) and BQ (1.5 equiv) was
required (Scheme 4). A closer inspection of the crude
reaction mixture revealed that the homocoupled product
(Ar–Ar) was formed in varying amounts; this side reaction
Figure 1. Conversion observed in the oxidative Heck arylation of cyclic
enamide 2 with varying amounts of DMSO. The yield was determined
by 1H NMR spectroscopy (CDCl3) with methyl methoxyacetate
(1 equiv) as the internal standard.
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1H NMR spectroscopic measurements with an internal stan-
dard). We reinvestigated the use of THF as a solvent with
DMSO as a cosolvent and found that THF performed
similarly to DCE as a solvent, with the difference that the
optimum amount of DMSO in the solvent mixture was 40%
(Figure 1).
After some further alterations of the reaction parameters,
which mainly involved the introduction of HOAc (0.8 equiv)
and some further tweaking of the stoichiometry between
Ar3(BO)3 and BQ, we were confident that we had a working
reaction protocol. Under these conditions, we investigated the
scope of the transformation with a range of Ar3(BO)3 and the
two structurally different cyclic enamides 2 and 5 (Scheme 5).
Gratifyingly the reaction proceeded consistently well with
a range of electronically different Ar3(BO)3, including those
with alkyl, Cl, Br, F, NO2, TMS, keto, CF3, and MeO
substituents. Electron-rich Ar3(BO)3 produced the desired
products 7a–c and 7e–g in good to excellent yield. However,
ines underwent the oxidative Heck reaction to give 7i–m in
around 75% yield in most cases. We were positively surprised
to see that the reaction is compatible with p-trifluoromethyl
groups (product 7k, 65%) as well as simple p- and m-fluoro
substituents (products 7l, 75% and 7m, 77%). However, one
electron-deficient boroxine, namely, p-nitrophenylboroxine,
displayed considerably lower activity, and product 7j was
formed in lower yield.
Two structurally different cyclic enamides, 2 and 5, were
investigated in this oxidative Heck reaction. When the size of
the substituent on the cyclic enamide was increased from
a methyl to a propyl group, the reaction performed well with
the phenyl-substituted boroxine to give the expected product
8, which was isolated in 72% yield (Scheme 5). With the six-
À
as the electron density of the C B bond increases, the yield
drops, as indicated by the quite modest yield of 58% observed
with p-methoxyphenylboroxine (product 7 f) as opposed to
75% for m-methoxyphenylboroxine (product 7g). Surpris-
ingly, 2-furylboroxine completely failed to produce the
desired arylated product 7h. Electron-deficient aryl borox-
Scheme 6. Palladium(II)-catalyzed oxidative Heck reaction between the
six-membered cyclic enamide 6 and phenylboroxine.
membered cyclic enamide 6,
the yield dropped to 51% for
the Heck coupling product 9
(Scheme 6).
As this study progressed,
one major limitation became
evident. Aryl boroxines with
an ortho substituent were inef-
ficient as coupling partners
(products
7d
and
7o,
Scheme 5). This behavior was
surprising, and the rationale
behind it is still not known.
Our current explanation is that
transmetalation becomes more
difficult as a result of steric
factors, especially if the aryl
boroxine is the actual trans-
metalation
species
(Scheme 10).
Finally, we used an array of
chlorinated aryl boroxines in
the oxidative coupling to
determine the effect of differ-
ently substituted chlorides.
The boroxine with an ortho-
chloro substituent was incom-
patible with the reaction
(product 10a), whereas the
meta- and para-substituted
counterparts behaved similarly
to nonchlorinated substrates
(products 10b, 60% and 10c,
Scheme 5. Palladium(II)-catalyzed oxidative Heck reaction between cyclic enamides and aryl boroxines. The
reactions were carried out at 558C in a 70:30 mixture of DCE and DMSO. The yields given are for the
isolated product after flash chromatography. TMS=trimethylsilyl.
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Our ultimate goal throughout this study was to develop
a robust and scalable procedure that provides access to useful
building blocks (oxazolones) for the synthesis of biologically
active compounds. The reaction was therefore tested on
a scale of more than 60 mmol. The treatment of alcohol 13
with an equimolar amount of TsNCO provided the prop-
argylic carbamate 1 in quantitative yield (Scheme 9). Carba-
mate 1 was then subjected to the palladium(II)-catalyzed
cycloisomerization to provide the cyclic enamide 2 (16.2 g,
90% yield as based on 13). This quantity of 2 was subjected to
the palladium(II)-catalyzed oxidative Heck reaction with
phenylboroxine to provide 18.6 g (90%) of the desired
phenylated oxazolone 7a.
Having proved that this reaction was scalable, we
embarked on our ultimate goal: to perform this reaction in
a one-pot sequential fashion. The stage was set, as we had
already spent considerable time finding reaction conditions
that (possibly) would be compatible with each individual step
(solvent, base, and catalyst). To our delight, we could use
almost the same conditions as described in Scheme 5 to
directly conduct this reaction in a one-pot sequential manner
(1 mmol scale). The only modification that we made was to
lower the catalytic loading in both palladium(II)-catalyzed
reactions from 5 to 2.5 mol% of Pd(OAc)2. With this
approach, only one extraction and purification step was
required, thus making this reaction attractive from a prepara-
tive perspective. The yield of 7a obtained by the one-pot
procedure on a small scale (82%) was comparable to the
overall yield of the three-step reaction on a large scale (81%).
The mechanism of the oxidative Heck reaction has been
studied both experimentally and computationally in quite
some detail.[21] From these studies it is clear that the reaction
relies on initial transmetalation of some form of [LmPd-
(OAc)n] species to give an arylpalladium species, which
undergoes insertion of a p-coordinated alkene with subse-
quent b-hydride elimination. One interesting aspect of the
present study is that arylboronic acids (ArB(OH)2) perform
poorly; it therefore seems unlikely that ArB(OH)2 is the
actual transmetalation species in the reaction described
herein.
Scheme 7. Trends observed in the oxidative Heck arylation of cyclic
enamides with chloro-substituted aryl boroxines.
63%; Scheme 7). The introduction of two chloro substituents
(3,4-dichlorophenylboroxine) resulted in an approximate
15% loss in yield (product 10d).
The oxidative Heck coupling of substrate 4, the simplest
cyclic enamide formed in the cycloisomerization, was not
included in Scheme 5. This case requires additional comment,
and our attempts to arylate 4 are summarized in Scheme 8.
Scheme 8. Product distribution observed when the simplest cyclic
enamide, 4, was used in the oxidative Heck coupling.
Interestingly, the oxidative Heck arylation of 4 afforded two
products, both of which are derived from arylation of the
b carbon atom: the endo alkene 11 and the exo alkene 12. The
latter was formed exclusively with the Z configuration. The
ratio between these two products depends on the palladium
catalyst used. When [Pd(IMes)(OAc)2] (IMes = bisimidazol-
2-ylidene) was employed as the catalyst, the ratio of 11 to 12
was 38:62. The highest selectivity for 11 was observed with
Pd(OAc)2, which afforded 11 and 12 in a ratio of 80:20. We
have not yet found conditions that show complete selectivity
for 11 or 12. These two isomers originate from the same
organopalladium intermediate, which undergoes b-hydride
elimination through two dif-
We speculate that the aryl boroxine is transmetalated
directly with the palladium acetate catalyst through a pseudo-
intramolecular migration of the acetate anion (M2) to give
a tetrahedral borate intermediate (M3; Scheme 10). On the
basis of the effect of DMSO on the reaction, we suggest that
ferent pathways. In the selec-
tivity-determining step, it
seems that the electronic
nature and perhaps structural
factors of the catalyst play
a role in the selectivity of the
b-hydride elimination. It was
shown that 11 does not isomer-
ize to 12 under the reaction
conditions; thus, any variation
in distribution based on a sub-
sequent isomerization can be
ruled out.
Scheme 9. Scale-up and one-pot sequential oxidative Heck reaction starting from the propargylic alcohol
13.
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2004,
b) R. F.
pp. 619 – 670;
Heck, Acc.
Chem. Res. 1979, 12,
146; c) M. Larhed, A.
Hallberg in Handbook
of
Organopalladium
Chemistry for Organic
Synthesis, Vol. 1 (Ed.:
E.-I. Negishi), Wiley-
Interscience, New York,
2002, p. 1133; d) A. B.
Dounay, L. E. Overman,
Scheme 10. Schematic description of one possible DMSO-aided transmetalation pathway.
the process is facilitated by DMSO or possibly by BQ (as the
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ligand L). We have no direct experimental evidence for this
mechanism, but similar mechanisms have been suggested
previously, for example, in the “boron-to-zinc” transmetala-
tion between Et2Zn and aryl boroxines.[22] Another plausible
pathway is that the small amount of water present slowly
releases small quantities of ArB(OH)2 through hydrolysis of
the boroxine, and the ArB(OH)2 in turn undergoes trans-
metalation with the Pd catalyst in a more conventional
fashion. The latter process seems less likely simply on account
of the observation that the addition of a large excess of the
“free arylboronic acid” inhibits the reaction.
In summary, we have developed a catalytic procedure for
the formation of cyclic tosylenamides that relies on a simple
catalyst (Pd(OAc)2), a simple base (Bu4NOAc), and cheap
and commercially available substrates (propargylic alcohols
and tosylisocyanate). The main feature of this method is the
b-selective Pd-catalyzed oxidative Heck reaction, which
enables selective arylation of the cyclic enamide to give
valuable oxazolones with high efficiency. In this process, b-
hydride elimination occurs selectively at the position adjacent
to the carbamate oxygen atom to provide the oxazolone with
one new tertiary stereogenic center in good to excellent yield.
The oxidative Heck reaction requires a cheap catalyst (Pd-
(OAc)2) and oxidant (BQ) together with commercially
available aryl sources (aryl boroxines). The showcased
protocol is very robust and proved readily scalable to
> 66 mmol. Finally, and most importantly, the three-step
reaction was successfully conducted in a one-pot sequential
fashion, thus minimizing the work needed for workup and
purification. We are confident that the oxazolones will be
useful in the synthesis of ligands, pharmaceuticals, and other
biologically active substances. Further studies on the reaction
scope with more structurally diverse enamides and propagylic
alcohols/amines are under way. We also intend to study the
chemistry of the acquired oxazolones to determine what
reactivity this moiety displays in classical reactions, such as
hydrogenation, hydrolysis, and transition-metal-catalyzed
reactions.
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Received: August 25, 2013
Published online: October 31, 2013
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Keywords: arylation · boroxines · oxazolones ·
oxidative Heck coupling · palladium
.
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[18] Further details regarding this transformation will be disclosed
elsewhere. Additional details regarding the depicted reaction
can be found in the Supporting Information.
[19] At this point of the investigation, we used commercially
available phenylboronic acid as the source of the aryl group.
However, we quickly realized that most of the boronic acids that
we acquired from commercial suppliers contained the cyclic aryl
boroxine and in fact very small amounts of the ArB(OH)2.
[20] The aryl boroxines were prepared by the removal of water with
a Dean–Stark apparatus. See the Supporting Information for
more details.
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