Palladium-Catalyzed Cross-Coupling of Alkenyl Carboxylates

Article abstract of DOI:10.1002/anie.202006586

Carboxylate esters have many desirable features as electrophiles for catalytic cross-coupling: they are easy to access, robust during multistep synthesis, and mass-efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non-aromatic electrophiles, remain difficult to functionalize through cross-coupling. We demonstrate that Pd catalysis is effective for coupling electron-deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C?O bond activation. A Pd^0/II catalytic cycle is viable when using a Pd⁰ precatalyst, with turnover-limiting C?O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β-carboxyl elimination is proposed for Pd^II precatalysts. This work provides a clear path toward engaging myriad oxygen-based electrophiles in Pd-catalyzed cross-coupling.

Full text of DOI:10.1002/anie.202006586

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Accepted Article
Title: Palladium-Catalyzed Cross-Coupling of Alkenyl Carboxylates
Authors: Joseph Becica, Oliver Heath, Cameron Zheng, and David C
Leitch
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Palladium-Catalyzed Cross-Coupling of Alkenyl Carboxylates
Joseph Becica, Oliver R. J. Heath, Cameron H. M. Zheng, and David C. Leitch*
[*]
Dr. J. Becica, O. R. J. Heath, C. H. M. Zheng, Prof. Dr. D. C. Leitch
Department of Chemistry
University of Victoria
3800 Finnerty Rd., Victoria, BC V8P 5C2, Canada
E-mail: dcleitch@uvic.ca
Supporting information for this article is given via a link at the end of the document.
Abstract: Carboxylate esters have many desirable features as elec-
trophiles for catalytic cross-coupling: they are easy to access, robust
during multistep synthesis, and mass efficient in coupling reactions.
Alkenyl carboxylates, a class of readily prepared non-aromatic elec-
trophiles, remain difficult to functionalize via cross-coupling. We
demonstrate that Pd catalysis is effective for coupling electron-defi-
cient alkenyl carboxylates with arylboronic acids in the absence of
base or oxidants. Furthermore, these reactions can proceed by two
distinct mechanisms for C–O bond activation. A Pd(0)/(II) catalytic cy-
cle is viable when using a Pd(0) precatalyst, with turnover-limiting C–
O oxidative addition; however, an alternative pathway that involves
alkene carbopalladation and β-carboxyl elimination is proposed for
Pd(II) precatalysts. This work provides a clear path toward engaging
myriad oxygen-based electrophiles in Pd-catalyzed cross-coupling.
Metal-catalyzed cross-coupling is among the most important C–C
bond forming strategies in organic chemistry.[1] For practical ap-
plications in synthesis,[2–5] the most prevalent approach is to cou-
ple an organometallic nucleophile with a (pseudo)halide electro-
phile.[6–9] A major focus of new reaction development is to expand
the scope of suitable electrophiles beyond aryl halides.[10–19]
Alkenyl carboxylates,[20–22] and acetates in particular, are an at-
tractive alternative: they are a convenient source of non-aromatic
functionality, are easily prepared by O-acylation of ketones, and
impart high reaction mass efficiency relative to other leaving
groups. Unfortunately, using alkenyl acetates in cross-coupling
remains challenging. The most general catalysts currently re-
ported require sensitive organometallic nucleophiles or bases
(Scheme 1a).[23–26] While powerful, these protocols can be proce-
durally complex, especially for generating highly-functionalized
substrates. An alternative strategy is to couple alkenyl carbox-
ylates with boron-based reactants. There are few successful ex-
amples of this approach, with Ni,[27] Pd[28] or Rh[29,30] catalysts;
however, these systems have limited scope and/or require high
temperatures.
We report an operationally simple Pd-catalyzed method to
couple substituted electron-deficient alkenyl carboxylates with
readily available arylboronic acids (Scheme 1b). Many of these
reactions occur at room temperature with no need for inert atmos-
phere, use water as a co-solvent, and do not require exogenous
base. This process takes advantage of the broad functional group
tolerance common to many Pd catalyzed reactions[31,32] to func-
tionalize multiple pharmaceutically-relevant heterocycles. The
success of this method is in stark contrast to the general percep-
tion that Pd catalysts are less reactive or inert toward many
C(sp2)–O electrophiles.[18,19]
Scheme 1. Cross-Coupling of Alkenyl Carboxylates.
The primary challenge to engaging carboxylates in Pd-cat-
alyzed coupling is achieving selective C–O oxidative addition to
Pd(0).[33,34] Rather than being inert, many aryl carboxylates un-
dergo Pd-catalyzed acyl-Suzuki reactions via acyl–O oxidative
addition (Scheme 1c).[35–40] The accessibility of this pathway com-
plicates selective arylation of the alkene.[41–44] We recently re-
ported that pyrone and coumarin esters undergo acyl–O and aryl–
O oxidative addition to Pd(0), with the outcome depending on the
conditions and substrate structure.[45] As an alternative to the tra-
ditional Pd(0)/(II) mechanism, we hypothesized that alkenyl car-
boxylates may access a Pd(II)-only pathway (Scheme 1d). A
Pd(II) aryl could react with the C=C bond of an alkenyl carboxylate
via carbopalladation, followed by β-carboxyl elimination[46–48] to
generate the coupling product. A related mechanism was pro-
posed by Larhed and co-workers for Pd-catalyzed styrene syn-
thesis using vinyl acetate.[28] Notably, both approaches proceed
via direct transmetalation[49] between a Pd(II) acetate complex
and the boronic acid, bypassing the need for exogenous base.
1
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catalyst can achieve selective C–O activation over C–Cl (3o, 3q)
and even C–Br (3p, 3q) activation.
Heterocyclic alkenyl carboxylates based on unsaturated lac-
tone or lactam structures do not appear to react under the opti-
mized conditions at room temperature, likely due to their reduced
electrophilicity.[52] By increasing the reaction temperature to
100 °C we are able to arylate coumarin (3r, 3s) and tetronic acid
(3t) pivalate derivatives using Pd(OAc)2/L6. Using Pd(PCy3)2 as
the catalyst, pyrone (3u)[45] and quinolinone (3v) pivalates are
successfully arylated, as are 5-membered lactam (3w) and lac-
tone (3x, 3y) acetates. Finally, rofecoxib (Vioxx, 3y),[53] a COX-2
inhibitor with a storied history[54] and resurgent interest as a po-
tential treatment for hemophilic arthropathy,[55] is synthesized in
only three steps from commercially-available materials.[50]
Several observations from our synthetic work are mechanis-
tically relevant. First, reactions involving β-acetoxyenone sub-
strates (giving products 3a-3q) all proceed at room temperature;
therefore, if these operate via a Pd(0)/(II) mechanism, oxidative
addition of the C(sp2)–OAc bond must also readily occur at room
temperature. Second, for 3o-3p to be formed by a Pd(0)/(II) mech-
anism, the C(sp2)–OAc oxidative addition also needs to be much
faster than activation of Ar–Cl and Ar–Br bonds. Finally, less elec-
trophilic lactone and lactam substrates (resulting in products 3r-
3y) require much higher reaction temperatures, use of pivalate in
place of acetate (3r-3v), and a Pd(0) precatalyst (3u-3y). This di-
chotomy suggests a mechanistic divergence based on substrate
structure. To better understand the implications of this divergence,
we have carried out an initial mechanistic analysis into the feasi-
bility of both proposals from Scheme 1.[56]
We first evaluated a Pd(0)/(II) mechanism, proceeding
through a Pd(0) resting state (I) and Pd(II) intermediates II and III
(Scheme 2a). We previously demonstrated that pyrone pivalate
1h (the substrate for producing 3u) adds to Pd(PCy3)2 to generate
a Pd(II)(alkenyl)(pivalate) complex.[45] Similarly, oxidative addition
of 1b to Pd(PCy3)2 (I) occurs to give the Pd(II)(alkenyl)(acetate)
complex 4 (II) (Scheme 2b); notably, this reaction is slow even at
60 °C (24-72 h reaction time).[50] Complex 4 was isolated in 59%
yield, and its structure confirmed by NMR spectroscopy and
HRMS. We have also confirmed the viability of 4 as an intermedi-
ate in catalysis (II) by treating the isolated complex with 10 equiv-
alents of PhB(OH)2. Within minutes at room temperature we ob-
serve complete consumption of 4 to regenerate Pd(PCy3)2 (I) and
produce cross-coupled product 3j. Finally, we have established
that the regenerated Pd(PCy3)2 remains catalytically active by
adding excess 1b and heating to 60 °C, resulting in a 78% solution
yield of 3j after 18 hours (Scheme 2b). These studies confirm that
a variation of the standard Suzuki-Miyaura coupling mechanism
is possible with Pd(PCy3)2, wherein oxidative addition is turnover-
limiting, and transmetalation occurs without the intervention of an
exogenous base (Scheme 2a). We propose that this mechanism
operates when using Pd(PCy3)2 as the precatalyst (i.e. to form
products 3u-3y in Figure 2). However, the observed oxidative ad-
dition rates[45] are not consistent with the room temperature reac-
tivity observed with Pd(OAc)2/ PCy3 (L2) in our screening experi-
ments (Figure 2), nor the activity of Pd(OAc)2/L6 for the formation
of 3a-3q (Figures 1 and 2). This kinetic inconsistency, combined
with the selective functionalization of C–OAc over C–Cl and C–Br,
requires an alternative mechanistic explanation.
Figure 1. Effect of phosphines on coupling of 1a and 2a. Conv. and yield by 1H
NMR spectroscopy versus internal standard.
Considering these features, we evaluated twelve phos-
phines (L1-L12) with Pd(OAc)2 for the coupling of dimedone ace-
tate (1a) with phenylboronic acid (2a) (Figure 1). Remarkably,
many of these ligands enable this arylation with good solution
yields (39-63%) and mass-balance, even at room temperature.
We also identified P(o-MeOPh)3 (L6) as a superior ligand, which
promotes the cross-coupling with 97% yield. Iterative optimization
[50] revealed robust and practical reaction conditions: an L6/Pd ra-
tio of 1.5:1; 10:1 (v/v) acetone/H2O (0.5 M in alkenyl carboxylate)
as solvent; and an excess of arylboronic acid (1.5-2 equiv). This
protocol provides 3a in 98% isolated yield with only 1 mol% Pd.
We further discovered that these reactions can be performed un-
der air at room temperature, and that all components can be used
without purification.[51] The use of acetone/water is to ensure full
hydration and solubility of the arylboronic acid.[12]
Using this protocol with 4 mol% Pd, we have tested eleven
alkenyl carboxylates and eleven boronic acids for cross-coupling
on 1 mmol scale (Figure 2). Using alkenyl acetate 1a, boronic ac-
ids with a variety of steric/electronic features and functional
groups are successfully coupled, with 40-98% isolated yields (3a-
3i). The ability to run the reaction without base enables incorpo-
ration of base-sensitive functionality, including a methyl ester (3b,
96%), acetamide (3h, 40%), 3-fluoro-4-cyanophenyl (3g, 41%),
as well as the ortho-fluorinated arylboronic acid precursor to 3d
(67%). Other cyclic alkenyl acetates are also successfully ary-
lated under these conditions, including 5- and 6-membered sub-
strates that are prone to hydrolysis (3k, 3l), as well as an N-Boc-
piperidine derivative that yields functionalized heterocyclic scaf-
folds (3m-3o). Remarkably, selective arylation of the alkenyl ace-
tate occurs in the presence of aryl halides; in other words, this
2
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10.1002/anie.202006586
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Figure 2. Scope of the Pd-catalyzed cross-coupling of alkenyl carboxylate electrophiles with arylboronic acids. aPivalate ester substrate. bSolution yield by 1H NMR
spectroscopy versus internal standard.
One possible Pd(II)-mediated catalytic cycle that bypasses
the relatively slow oxidative addition to Pd(0) is shown in Scheme
2c. Starting from a Pd(II) acetate species (IV), transmetalation
with arylboronic acid would form a Pd(II) aryl (V). This complex
would undergo turnover-limiting syn-carbopalladation to the
alkenyl carboxylate to form a C-bound Pd-enolate, with the aryl
geminal to the OAc group (VI). Epimerization can occur via suc-
cessive 1,3-palladatropic shifts through the O-bound Pd-enolate,
bringing Pd and the OAc group into a syn arrangement (VI’). Elim-
ination[46–48] of Pd–OAc would liberate the coupling product and
23% yield, possibly due to inefficient reduction of
Pd(PCy3)2(OAc)2 to Pd(PCy3)2.[64] Notably, using a 1:1 ratio of
PCy3 to Pd(OAc)2 generates a system active at 23 °C, albeit with
modest reactivity (8%). In stark contrast, we observe 97-98% yield
under these conditions using Pd(OAc)2/L6 (1-1.5 equiv L6 per Pd).
To evaluate the intermediacy of a Pd(II) aryl species (V), we also
tested Pd(Ph)(OAc)(L6)[65] as a precatalyst. It exhibits similarly
high reactivity, achieving quantitative yield in ≤60 minutes at room
temperature. While the poor reactivity of Pd2dba3/L6 relative to
both Pd(OAc)2/L6 and Pd(Ph)(OAc)(L6) is not definitive, the bal-
regenerate intermediate IV, closing a redox-neutral catalytic cycle. ance of current evidence supports a Pd(II)-mediated mechanism
All of the individual steps in this proposed mechanism have ample
precedent in other Pd(II)-catalyzed transformations. Key among
these are Pd-catalyzed oxidative Heck coupling,[57,58] which pro-
ceeds via a related alkene arylation with boronic acids, and Pd-
catalyzed conjugate addition.[59–63] This latter process shares
many of the same steps as the present transformation; however,
the two reactions diverge at the Pd-enolate intermediate. For con-
jugate addition, the Pd-enolate is protonated to give the saturated
ketone, whereas here β-acetoxyl elimination gives the unsatu-
rated product.
To assess this Pd(II)-only mechanism, we evaluated the ki-
netic competency of various Pd(0) and Pd(II) precatalysts
(Scheme 2d).[50] As expected from our study of oxidative addition,
Pd(PCy3)2 is unable to catalyze this reaction at 23 °C, but does
produce 3a in 60% solution yield at 60 °C. Using L6 and
Pd2dba3•CHCl3 as a Pd(0) source leads to a similar outcome: <1%
yield at 23 °C, but 87% at 60 °C. For Pd(II) precatalysts, a mixture
of Pd(OAc)2 and PCy3 (2 equiv PCy3 per Pd) is inactive after 60
minutes at 23 °C. At elevated temperature, this system gives only
when using L6 rather than one involving Pd(0)/(II). Further work
is underway to fully explore the role of L6 in promoting catalysis,
including the potential for supporting cationic Pd(II) intermedi-
ates.[66–68]
In summary, we have demonstrated that Pd catalysis is ef-
fective for the cross-coupling of alkenyl carboxylates. This obser-
vation, contrary to the often observed and generally accepted re-
activity patterns for Pd-catalyzed cross-coupling, opens the door
to discovery of new methods complementary to those involving
other transition metals. Many of the reactions reported here occur
under mild conditions, providing access to versatile cyclic enones
and heterocycles. Preliminary mechanistic studies indicate C–O
bond activation can occur through oxidative addition to Pd(0), or
via β-carboxyl elimination to Pd(II). Understanding both of these
mechanisms should enable a wide array of carboxylate electro-
philes to be functionalized with Pd, and work is ongoing to use
these insights to expand the scope of coupling partners in pursuit
of complex molecular targets.
3
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Scheme 2. Mechanistic hypotheses and evidence for Pd(0)/(II) and Pd(II)-mediated catalysis.
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Keywords: alkenylation • cross-coupling • palladium catalysis •
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5
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Entry for the Table of Contents
Carboxylate, activate! Pd catalysis is generally assumed to be ineffective for cross-coupling with most oxygen-based electrophiles.
Here, we show that not only are alkenyl carboxylates able couple with boronic acids under extremely mild conditions, but that there
are two distinct pathways for C–O activation. The result is an operationally simple arylation of many pharmaceutically-relevant (het-
ero)cyclic cores with excellent functional group tolerance.
Institute and/or researcher Twitter usernames: @LeitchLab, @chemistryatuvic
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