C-O Bond Activation as a Strategy in Palladium-Catalyzed Cross-Coupling

Article abstract of DOI:10.1055/a-1306-3228

The activation of strong C-O bonds in cross-coupling catalysis can open up new oxygenate-based feedstocks and building blocks for complex-molecule synthesis. Although Ni catalysis has been the major focus for cross-coupling of carboxylate-based electrophiles, we recently demonstrated that palladium catalyzes not only difficult C-O oxidative additions but also Suzuki-Type cross-couplings of alkenyl carboxylates under mild conditions. We propose that, depending on the reaction conditions, either a typical Pd(0)/(II) mechanism or a redox-neutral Pd(II)-only mechanism can operate. In the latter pathway, C-C bond formation occurs through carbopalladation of the alkene, and C-O cleavage by β-carboxyl elimination. 1 Introduction 2 A Mechanistic Challenge: Activating Strong C-O Bonds 3 Exploiting Vinylogy for C-Cl and C-O Oxidative Additions 4 An Alternative Mechanism for Efficient Cross-Coupling Catalysis 5 Conclusions and Outlook.

Full text of DOI:10.1055/a-1306-3228

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–F
synpacts
A
en
J. Becica, D. C. Leitch
Synpacts
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C–O Bond Activation as a Strategy in Palladium-Catalyzed Cross-
Coupling
Ph
R
Alkenyl
carboxylates
Pd(0)
catalysis
O
Joseph Becica
MeO2S
David C. Leitch*
0
0
0
0
-
0
0
0
2
-
8
7
2
6
-3
3
1
8
Piv/AcO
O
Department of Chemistry, University of Victoria,
3800 Finnerty Rd., Victoria, BC, V8P 5C2, Canada
dcleitch@uvic.ca
O
F
Pd
Boronic
acids
Pd(II)
catalysis
NC
B(OH)2
Ar
N
DeMeavpaiaidClrotdCmrc.rlLeeeensiitpttcocohhnf@dCuihnvegimcA.ciuastrhyo,rUniversity of Victoria, 3800 Finnerty Rd., Victoria, BC, V8P 5C2, Canada
Boc
• C–O activation at Pd(0) and Pd(II)
• Catalysis at rt, air/water tolerant
• Cross-coupling with arylboronic acids
• New pool of electrophiles for Pd catalysis
Received: 31.10.2020
Accepted: 09.11.2020
Published online: 09.11.2020
DOI: 10.1055/a-1306-3228; Art ID: st-2020-p0577-sp
Abstract The activation of strong C–O bonds in cross-coupling catal-
ysis can open up new oxygenate-based feedstocks and building blocks
for complex-molecule synthesis. Although Ni catalysis has been the ma-
jor focus for cross-coupling of carboxylate-based electrophiles, we re-
cently demonstrated that palladium catalyzes not only difficult C–O ox-
idative additions but also Suzuki-type cross-couplings of alkenyl
carboxylates under mild conditions. We propose that, depending on the
reaction conditions, either a typical Pd(0)/(II) mechanism or a redox-
neutral Pd(II)-only mechanism can operate. In the latter pathway, C–C
bond formation occurs through carbopalladation of the alkene, and C–
O cleavage by -carboxyl elimination.
Joseph Becica (left) is a native of New Jersey, USA. He obtained his
Ph.D. in organometallic chemistry in 2019 from Temple University
(Philadelphia, USA) in the group of Professor Graham Dobereiner, devel-
oping methods for organic reactions catalyzed by palladium and molyb-
denum. During this time, he was also a visiting researcher at
GlaxoSmithKline, where he first worked with Dave Leitch on a collabora-
tive project on challenging C–N couplings. Previously, he studied or-
ganometallic chemistry in the groups of Nathan West at the University
of the Sciences (Philadelphia, USA) and Professor Ola Wendt at Lund
University (Lund, Sweden). He joined the Leitch group at the University
of Victoria in 2019 as a New Frontiers Postdoctoral Fellow.
1
2
3
4
5
Introduction
A Mechanistic Challenge: Activating Strong C–O Bonds
Exploiting Vinylogy for C–Cl and C–O Oxidative Additions
An Alternative Mechanism for Efficient Cross-Coupling Catalysis
Conclusions and Outlook
Key words cross-coupling, C–O activation, palladium catalysis, vinyl-
ogy, oxidative addition, carbopalladation
David C. Leitch (right) grew up on Vancouver Island, BC, and obtained
both his B.Sc. (2004) and Ph.D. (2010) at the University of British Co-
lumbia, Vancouver (Canada). There, he worked with Professor Laurel
Schafer on organozirconium chemistry and hydroamination catalysis.
He then held a postdoctoral position at McGill University (2010–2012),
working with Professor Bruce Arndtsen on a multicomponent approach
to building conjugated organic materials. In 2012, Dave obtained an
NSERC Postdoctoral Fellowship to work with Professor John Bercaw and
Dr. Jay Labinger at the California Institute of Technology (USA) (2012–
2014) on tandem catalysis for alkane functionalization. In 2014, he
joined GlaxoSmithKline’s Catalysis Center of Excellence at Research Tri-
angle Park, NC (USA), and then moved with the group to Pennsylvania
in 2015. There he became group leader of the rechristened Chemical
Catalysis group (2016–2018), as well as the Continuous Primary group
(2017–2018). In 2019, Dave returned home as an assistant professor at
the University of Victoria (Canada). His research group is focused on
mapping chemical reaction space by using high-throughput experi-
mentation, and developing new catalysts and catalytic reactions for
complex-molecule synthesis.
1 Introduction
Engaging a wider array of electrophiles in metal-cata-
lyzed cross-coupling reactions continues to be an import-
ant goal in synthetic methods development.1 Whereas the
nature of the nucleophile (be it organometallic or other-
wise) often defines the reaction class,2–5 the nature of the
electrophile is equally important in determining reactivity
and mechanism. Typical electrophiles used in cross-cou-
pling reactions are the ubiquitous organo(pseudo)halides
(–I, –Br, –Cl, –OSO2R), which undergo (relatively) well-under-
stood oxidative addition6 reactions with transition-metal
catalysts, such as those based on Pd7–14 or Ni.15–21 Expand-
ing the scope of suitable electrophiles beyond (pseudo)ha-
lides to those with oxygen-based leaving groups offers op-
portunities to improve reaction mass efficiency, remove
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Becica, D. C. Leitch
Synpacts
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hazardous upstream halogenation processes, and open up
new feedstocks (Scheme 1a);22–27 however, there are signifi-
cant unmet challenges and knowledge gaps with respect to
reaction and catalyst design. In this account, we describe
our initial efforts in pursuing a C–O bond-activation strate-
gy for developing new Pd-catalyzed transformations, spe-
cifically by enabling Suzuki-type cross-couplings of alkenyl
carboxylates, an attractive yet challenging class of electro-
philes, under surprisingly mild conditions.28,29
simple hydrolysis or transesterification. From the perspec-
tive of oxidative addition, there is some hope: breaking the
stronger C–O bond should be thermodynamically favored,
as a stronger M–O bond results. Notably, there is evidence
to support this assertion for Ni systems.30,42,46–48 Even with
thermodynamics on our side, the kinetic accessibility of
C(acyl)–O activation could potentially divert the course of
catalysis.
Finally, we would like to address the question ‘why Pd?’,
especially in light of the general view that the field should
be moving away from precious metals toward Earth-abun-
dant metals,49 and the specific view that Ni should be supe-
rior to Pd for C–O bond activation. The synthesis of complex
molecules as low-volume high-value products (such as
pharmaceuticals, agrochemicals, or advanced materials) re-
quires robust, efficient, and economical chemical processes
that work for highly functionalized substrates. Despite the
high cost and low natural abundance of Pd, organopalladi-
um catalysis offers many distinct advantages, including ex-
cellent functional-group tolerance,50,51 relatively high cata-
lytic efficiency (i.e., low catalyst loadings), and the ability to
act in the presence of water or even air. To us, discovering
and exploiting complementary reactivity with both pre-
cious- and abundant-metal catalysts is an important goal.
Process economics and sustainability are case-dependent,
and we in the academic community should do our best to
provide our industry-based colleagues with as many op-
tions as possible.
2 A Mechanistic Challenge: Activating
Strong C–O Bonds
In moving from breaking C–X bonds to C–O bonds
during cross-coupling catalysis, there are several linked
challenges. From a kinetic standpoint, the C–O bonds in
question are generally quite strong (~100–110 kcal/mol),
making oxidative addition to a low-valent organometallic
species difficult.22 There is a prevailing view in the field that
Pd catalysts are less able (or unable) to achieve the required
C–O oxidative additions;26 as a result, the community has
focused on Ni catalysis, as low-valent Ni generally under-
goes oxidative addition reactions more readily than does
Pd.6,15,16,24,30 Seminal work on Ni-catalyzed cross-coupling
with O-based electrophiles by Snieckus and co-workers
(using Grignard reagents)31 and later by the Garg32 and
Shi33,34 groups (using boronic acids or zinc reagents) led to
an explosion of research on Ni-based systems.1,15,16,22–25,35
Oxygenates as building blocks
3 Exploiting Vinylogy for C–Cl and C–O Oxi-
dative Additions
R
E
R
R
O
R
O
N
HO
O
H
The inspiration for our initial foray into Pd-catalyzed
cross-coupling through C–O activation came from an indus-
trial project carried out at GlaxoSmithKline. The seemingly
simple problem of how to prepare ,-unsaturated--keto
esters in a redox-neutral manner alerted us to the potential
of exploiting vinylogy52 in reaction and substrate design. To
access the target keto esters, we developed a Pd-catalyzed
carbonylative esterification of -chloroenone derivatives,
i.e. vinylogous acyl chlorides.53 Although carbonylation of
typical aryl and vinyl chlorides is challenging54,55 due to
turnover-limiting oxidative addition,56 through high-
throughput experimentation we discovered many effective
catalyst systems for carbonylating -chloroenones.57,58
These reactions proceed with low Pd loadings (down to 0.5
mol%), use simple trialkylphosphines [PCy3, P(t-Bu)3, or
PMe(t-Bu)2], and work on ≥1 g scales to produce many syn-
thetically versatile -keto esters (Scheme 2). Subsequent
mechanistic studies revealed rapid oxidative addition of the
-chloroenones to Pd(0), which we attribute to both preco-
ordination of the C=C bond and the increased electrophilici-
ty at C due to the vinylogous ketone.
Acylation
• Mild conditions
• Less-toxic reagents
• More mass efficent
Metal-catalyzed Cacyl–O activation
e.g. acyl-Suzuki coupling
This work:
O
Ar-[M]
R
R
O
R'
R'
Ar
Ni & Pd:
known
Ar-[M]
R'
Ar
O
O
Ni: known
Pd: rare
Nuc
Pd-catalyzed
C–O activation
cross-coupling
Nuc
Bond strength: Bond strength:
BDE ~80 kcal mol–1 BDE ~100 kcal mol–1
Direct acyl
substitution
(e.g. hydrolysis)
Scheme 1 Metal-catalyzed cross-coupling with carboxylate-based
electrophiles: opportunities and challenges
A second significant challenge specific to the use of car-
boxylate-based electrophiles is achieving chemoselectivity.
Whereas the C–O bond that requires activation is strong,
C(acyl)–O bonds are significantly weaker (~80 kcal/mol),
and there are many kinetically accessible pathways for acyl
substitution (Scheme 1). These include metal-catalyzed re-
actions (e.g., the acyl-Suzuki reaction36–41 or decarbonyla-
tive cross-couplings42–45) and substrate decomposition by
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
J. Becica, D. C. Leitch
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PdCl2(MeCN)2 (0.5–2 mol%)
PR3 (1–4 mol%)
sible with this Pd(0) complex, but also that both C(acyl)–O
(undesired) and C(alkenyl)–O (desired) bonds undergo ad-
dition to Pd. With the pyrone acetate 1a and the coumarin
acetate 2, C(acyl)–O cleavage occurs rapidly at room tem-
perature to give the corresponding Pd(II) acyl complexes;
however, upon heating, these complexes are transformed
into the Pd(II) alkenyl species. In other words, oxidative
addition of the weaker C–O bond is kinetically favored,
whereas oxidative addition of the stronger, desired C–O
bond is thermodynamically favored. This is entirely con-
sistent with previous observations with Ni,30,42,46–48 but is
the first time such behavior has been observed with Pd.
This promising reactivity is nevertheless complicated by
the kinetic accessibility of C(acyl)–O cleavage. In contrast,
oxidative addition experiments with the pyrone pivalate
1b and the cyclohexenyl acetate 3 revealed no C(acyl)–O
cleavage at room temperature, and only C(alkenyl)–O oxi-
dative addition at elevated temperature. Thus, both the
steric nature and the electronic nature of the carboxylate
group influence the accessibility of these two oxidative
addition pathways.
O
O
O
CO (60–70 psi)
NEt3 (1.5 equiv)
(COCl)2
DMF
R
R
R
O
R'OH (1.2–2 equiv)
toluene and/or MeCN
80 °C, 1–18 h
OR'
OH
Cl
n
n
n
1–60 g
Selected examples:
O
69%
O
O
71%
O
47%
90%
(60 g scale)
N
O
OMe
O
O
OBn
O
O
O
Cl
O
O
O
45%
O
69%
O
44%
O
NHCBz
Ph
OH
OH
O
O
CF3
88%
O
O
O
Rapid oxidative addition to Pd(0)
O
O
O
PCy3
Pd
Pd(PCy3)2
PCy3
Pd
Cl
PCy3
Cy3P
Cl
Cl
Scheme 2 Pd-catalyzed carbonylation of -chloroenones enabled by
rapid oxidative addition of vinylogous substrates to Pd(0)
O
O
R
O
+
60–100 °C
rt
O
PCy3
O
Cy3P
O
Given all the aforementioned challenges associated with
C–O oxidative addition for aryl and alkenyl carboxylate
cross-couplings, we reasoned that exploiting vinylogy in
substrate design might provide new C–O activation and
functionalization chemistry with Pd (Scheme 3). By analo-
gy to the earlier carbonylation chemistry, we targeted viny-
logous anhydrides, formed by O-acylation of -keto esters
and diketones, as a reactive class of alkenyl carboxylates. In
contrast to alkenyl halides, which are generated by using
toxic and/or high-energy reagents [SOCl2, (COCl)2, PX3 or
POX3, PPh3/Br2], alkenyl carboxylates are readily prepared
under relatively mild conditions by using acyl chlorides
and/or anhydrides (basic conditions) or isopropenyl acetate
(acid-catalyzed).
R
Pd
Pd
R
Cy3P
PCy3
Pd(PCy3)2
C(acyl)–O cleavage:
• kinetically favored, reversible
• observed with 1a, 2
C(alkenyl)–O cleavage:
• thermodynamically favored
• only product observed with 1b, 3
O
O
O
O
O
O
O
O
R
O
O
O
R = Me (1a), tBu (1b)
2
3
Scheme 4 Oxidative addition of C–O bonds to Pd(0): kinetic versus
thermodynamic selectivity is dependent on temperature and structure.
Encouraged by these results, we sought a proof-of-con-
cept for cross-coupling with these substrates by using Pd(0)
catalysis.29 Because of their many potential advantages,
alkenyl carboxylates have been previously explored as
cross-coupling partners by several groups, including those
of Shi,34,59 Ackermann,60 von Wangelin,61 and Knochel.62,63
These reactions generally rely on Earth-abundant metal
catalysts, including systems based on Ni, Co, Cr, or Fe, along
with hard organometallic nucleophiles, such as Mg or Zn
reagents. With our stated goal of developing complementa-
ry catalytic methods in mind, we recognized the need for
systems capable of coupling less sensitive nucleophiles. Or-
ganoboronic acids are extremely versatile in cross-coupling,
with myriad building blocks commercially available. Al-
though there are a few examples of successful couplings be-
tween alkenyl carboxylates and boronic acids (using Ni,64
Rh,65,66 or Pd67), these systems tend to have a relatively lim-
ited scope. For example, the single previous example using
exclusive Pd catalysis operates with vinyl acetate itself.67
vinylogous
acyl chlorides
vinylogous acids
as building blocks
vinylogous
anhydrides
O
O
O
R
R
R
O
Cl
OH
O
R'
• rapid oxidative addition
• accessed via chlorination
using toxic/high-energy reagents
• easily accessed via acylation
• C–O cleavage at Pd(0) via
oxidative addition?
Scheme 3 Vinylogy in substrate design to permit C–O oxidative addi-
tion
To assess the possibility of C–O oxidative addition with
these vinylogous substrates, we tested several carboxylates
derived from a pyrone (1), a coumarin (2), or a cyclohex-2-
en-1-one (3) scaffold in combination with Pd(PCy3)2 as a
reactive Pd(0) source (Scheme 4).28 From this initial work,
we determined not only that C–O oxidative addition is fea-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
J. Becica, D. C. Leitch
Synpacts
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O
O
O
Pd(OAc)2 (5 mol%)
O
L1–L12 (10 mol%)
R
R
(HO)2B
Pd(PCy3)2 (10 mol%)
Ph B(OH)2
+
+
Ar
toluene-d8 (0.5 M)
rt, under N2, 17 h
toluene (0.5 M)
100 °C, 18 h
OAc/Piv
OAc
Ph
Ar
97% solution yield using L6
Selected examples:
O
L1: PPh3
L2: PCy3
L3: P(tBu)3
L4: P(Me)(tBu)2
L5: P(o-tol)3
L6: P(o-MeOC6H4)3
L7: P(2-furyl)3
L8: AmPhos
L9: CataCXium A
L10: XPhos
L11: SPhos
L12: tBuXPhos
O
O
MeN
88% (solution)
48% (isolated)
O
O
Ph
O
BnN
Ph
Ph
SO2Me
46% (solution)
68% (isolated)
rofecoxib
91% (solution)
R
X
R
Ar
LnPd0
X = Cl, Br,
OTs, etc.
R
OC(O)R'
R
R
C–O oxidative
addition
LnPd
LnPd
Ar
X
Scheme 6 Identification of an active Pd(II)-based catalyst system
M
OH
R
LnPd
(HO)2B OR
Ar B(OH)2
Salt metathesis
by base precedes
transmetalation
M
X
OR
for halide substrates
R = H, C(O)R'
By using Pd(PCy3)2 as a Pd(0) precatalyst, we were in-
deed able to cross-couple several alkenyl acetates and piva-
lates with simple arylboronic acids (Scheme 5).29 Although
these reactions required elevated temperatures and high Pd
loadings (10 mol%), we noted that they proceeded in the ab-
sence of exogenous base.68 Standard Suzuki coupling with
halide-based electrophiles generally operate through a salt
metathesis–transmetalation sequence, where the Pd(II) ha-
lide intermediate is converted into a Pd(II) hydroxide before
transmetalation occurs.69 In the present system, C–O oxida-
tive addition at Pd(0) instead produces a Pd(II) carboxylate
intermediate that directly undergoes transmetalation. In
other words, no intervening salt metathesis or boronic acid
activation70 is required, which permits base-free cross-cou-
pling. Carboxylate electrophiles are therefore advantageous
from both a feedstock perspective (as in Scheme 1) and a
reactivity perspective. Our initial conditions, especially the
need for large amounts of a sensitive and expensive Pd(0)
precatalyst, do, however, leave much to be desired from the
standpoint of practicality.
Scheme 5 Proof-of-concept for base-free Suzuki coupling via oxidative
addition of C–O bonds to Pd(0), with mechanistic proposal
During further development of the reaction conditions,
we observed variable reactivity depending on the particular
arylboronic acid used and even on the particular batch of a
specific arylboronic acid. We attribute this to varying quan-
tities of the corresponding boroxine (i.e. boronic acid anhy-
dride) in the commercial materials. By refining the reaction
conditions, we identified a protocol that leads to reproduc-
ible reactivity for a broad scope of substrates. Acetone–H2O
(10:1) is generally an effective solvent system that fully dis-
solves and hydrates the boronic acid. A Pd/(o-MeOC6H4)3P
ratio of 1:1.5 is optimal at catalyst loadings as low as 0.5
mol% Pd, although our typical conditions for scope explora-
tion employed 4 mol% Pd. The reactions are generally per-
formed at room temperature under air and in the absence
of an exogenous base. Using these conditions, we synthe-
sized various substituted cyclic enones through cross-cou-
pling in good to excellent isolated yields (40–99%; Scheme
7). These conditions permit the presence of various func-
tional groups, including potentially base-sensitive ones.
Aryl chlorides and bromides appear to be compatible with
this chemistry, which is noteworthy for a Pd-catalyzed re-
action.
4 An Alternative Mechanism for Efficient
Cross-Coupling Catalysis
During the course of our investigation into oxidative ad-
dition reactivity using Pd(0), we pursued a parallel effort to
identify potential catalyst systems for the aforementioned
user-friendly catalyst system capable of operating at or
near room temperature without the need for an inert atmo-
sphere. Through an iterative screening and optimization
process (Scheme 6 is representative), we identified the
combination of Pd(OAc)2 and (o-MeOC6H4)3P as an effective
catalyst system for a model cross-coupling reaction.29
Given the observed chemoselectivity for substitution at
the alkenyl acetate rather than an aryl halide, and the mild
operating conditions relative to those observed with a Pd(0)
precatalyst (Scheme 5), we considered a Pd(0)/(II)-based
mechanism unlikely. Instead, we proposed a redox-neutral
Pd(II) pathway for the Pd(OAc)2/(o-MeOC6H4)3P catalyst
combination (Scheme 8). Here, transmetalation of ArB(OH)2
to an LnPdII(OAc) species generates a Pd(II)–aryl complex
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
J. Becica, D. C. Leitch
Synpacts
Synlett
O
O
gave a comparable reactivity. Notably, when Pd2(dba)3·CH-
Cl3 was used as the Pd source, no product was observed at
23 °C; however, an 87% yield of the product was obtained at
60 °C, likely through a variation of the catalytic cycle shown
in Scheme 5. As both Pd(0)/(II) and Pd(II)-only mechanisms
appear to operate, depending on the Pd source used, we are
currently exploring both avenues to enable new reaction
and catalyst development toward complex-molecule syn-
thesis.
Pd(OAc)2 (4 mol%)
P(o-MeOC6H4)3 (6 mol%)
(HO)2B
+
Ar
acetone/H2O (10:1 v/v)
0.5 M, rt, under air, 18 h
OAc
Ar
Selected examples:
O
O
O
O
OMe
F
O
99%
85%
83%
67%
O
40%
CF3
N
H
CO2Me
O
O
O
5 Conclusions and Outlook
CF3
BocN
54%
67%
65%
CN
Through a combination of fundamental organometallic
chemistry and catalytic reaction design, we have developed
methods to engage alkenyl carboxylates in Pd-catalyzed
cross-couplings. C–O oxidative addition with alkenyl car-
boxylates is feasible at Pd(0), with selectivity for C(acyl)–O
versus C(alkenyl)–O activation, depending on the reaction
conditions and substrate structure. In addition, the catalytic
reactivity that we observe indicates that an alternative
mechanism to the standard Pd(0)/(II) cycle can operate
when using a Pd(II) precursor. Importantly, catalysis in this
regime is robust, mild, base-free, and tolerant of air, water,
and a variety of potentially sensitive functional groups. This
methodology is therefore complementary to other import-
ant cross-coupling reactions that employ first-row transi-
tion metals as catalysts. In-depth synthetic and mechanistic
studies are underway to achieve a more thorough under-
standing of these catalytic systems, particularly the dichot-
omy between the proposed Pd(0)-mediated and Pd(II)-me-
diated pathways. By taking advantage of these two general
reaction pathways, we aim to expand the scope of amena-
ble coupling partners and to deploy this method toward
complex-molecule synthesis.
NMe
CF3
F
Br
Cl
Scheme 7 Catalytic cross-coupling of alkenyl acetates under mild con-
ditions
that can undergo carbopalladation across the C=C double
bond of the alkenyl acetate. For the cyclic substrates that we
investigated, epimerization of the resulting Pd(enolate) via
the O-bound isomer brings the Pd atom and the acetoxy
group into a syn-confirmation, permitting -acetoxy elimi-
nation to release the cross-coupled product and regenerate
LnPdII(OAc). We note that similar mechanisms have been
proposed for the aforementioned Rh65,66 and Pd-catalyzed67
couplings of alkenyl acetates and boronic acids, as well as
for related chemistries including Pd-catalyzed conjugate ad-
dition71–74 and oxidative Heck coupling.75,76
Ar
H
O
Ar B(OH)2
[PdII]
OAc
transmetalation
β-acetoxyl elimination
Ar
AcO
H
[PdII]
O
[PdII]
Ar
Funding Information
carbopalladation
AcO
We thank the Natural Sciences and Engineering Research Council
(NSERC) of Canada, the New Frontiers in Research Fund (NFRF), and
the University of Victoria for general operating funds, as well as the
Canadian Foundation for Innovation (CFI) and British Columbia
H
epimerization via:
Ar
[PdII]
H
Ar
AcO
H
O
[PdII]
AcO
O
O
Knowledge Development Fund (BCKDF) for infrastructure funding.NaturalSciences
a
n
d
E
n
g
inerin
g
Research
C
o
u
nci
l
o
f
Canada()
Scheme 8 Proposed mechanism for cross-coupling of alkenyl acetates
with arylboronic acids by using Pd(II) precatalysts
Acknowledgment
We acknowledge with respect the Lekwungen peoples on whose tra-
ditional territory the University of Victoria stands, and the Songhees,
Esquimalt, and W̱SÁNEĆ peoples whose historical relationships with
the land continue to this day.
As part of a preliminary study of the feasibility of this
alternative mechanism, we evaluated a series of Pd precur-
sors in the model reaction shown in Scheme 6 at both 23 °C
and 60 °C. As a model for the key Pd–aryl intermediate gen-
erated by the initial transmetalation, we employed the
known complex [(o-MeOC6H4)3P]Pd(OAc)(Ph)77 as a precat-
alyst. Use of this complex resulted in excellent reactivity in
the catalytic reaction, giving >99% yield at 23 °C in one
hour. Only the combination of Pd(OAc)2 and (o-MeOC6H4)3P
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