Differences in the Performance of Allyl Based Palladium Precatalysts for Suzuki-Miyaura Reactions

Article abstract of DOI:10.1002/adsc.202000987

Palladium(II) precatalysts are used extensively to facilitate cross-coupling reactions because they are bench stable and give high activity. As a result, precatalysts such as Buchwald's palladacycles, Organ's PEPPSI species, Nolan's allyl-based complexes, and Yale's 1-tert-butylindenyl containing complexes, are all commercially available. Comparing the performance of the different classes of precatalysts is challenging because they are typically used under different conditions, in part because they are reduced to the active species via different pathways. However, within a particular class of precatalyst, it is easier to compare performance because they activate via similar pathways and are used under the same conditions. Here, we evaluate the activity of different allyl-based precatalysts, such as (η³-allyl)PdCl(L), (η³-crotyl)PdCl(L), (η³-cinnamyl)PdCl(L), and (η³-1-tert-butylindenyl)PdCl(L) in Suzuki-Miyaura reactions. Specifically, we evaluate precatalyst performance as the ancillary ligand (NHC or phosphine), reaction conditions, and substrates are varied. In some cases, we connect relative activity to both the mechanism of activation and the prevalence of the formation of inactive palladium(I) dimers. Additionally, we compare the performance of in situ generated precatalysts with commonly used palladium sources such as tris(dibenzylideneacetone)dipalladium(0) (Pd₂dba₃), bis(acetonitrile)dichloropalladium(II) (Pd(CH₃CN)₂Cl₂), and palladium acetate. Our results provide information about which precatalyst to use under different conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202000987

Title: Differences in the Performance of Allyl Based Palladium
Precatalysts for Suzuki-Miyaura Reactions
Authors: Matthew Espinosa, Angelino Doppiu, and Nilay Hazari
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000987
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Differences in the Performance of Allyl Based Palladium
Precatalysts for Suzuki-Miyaura Reactions
a
b
a,
Matthew R. Espinosa , Angelino Doppiu , and Nilay Hazari *
aDepartment of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut, 06520, USA. E-mail:
nilay.hazari@yale.edu.
bPrecious Metals Chemistry, Umicore AG & Co. KG, Rodenbacher Chaussee 4, Hanau-Wolfgang, Germany.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.202######
Abstract. Palladium(II) precatalysts are used extensively to reactions. Specifically, we evaluate precatalyst performance
facilitate cross-coupling reactions because they are bench as the ancillary ligand (NHC or phosphine), reaction
stable and give high activity. As a result, precatalysts such as conditions, and substrates are varied. In some cases, we
Buchwald’s palladacycles, Organ’s PEPPSI species, Nolan’s connect relative activity to both the mechanism of activation
allyl-based complexes, and Yale’s 1-tert-butylindenyl and the prevalence of the formation of inactive palladium(I)
containing complexes, are all commercially available. dimers. Additionally, we compare the performance of in situ
Comparing the performance of the different classes of generated precatalysts with commonly used palladium
precatalysts is challenging because they are typically used sources such as tris(dibenzylideneacetone)dipalladium(0)
under different conditions, in part because they are reduced to (Pd
the active species via different pathways. However, within a (Pd(CH
2
dba
3
),
CN)
bis(acetonitrile)dichloropalladium(II)
), and palladium acetate. Our results
3
Cl
2 2
particular class of precatalyst, it is easier to compare provide information about which precatalyst to use under
performance because they activate via similar pathways and different conditions.
are used under the same conditions. Here, we evaluate the
3
activity of different allyl-based precatalysts, such as ( - Keywords:
Cross-Coupling,
Precatalyst, Suzuki-Miyaura, Precatalyst comparison
Catalysis,
Palladium,
3
3
allyl)PdCl(L), ( -crotyl)PdCl(L), ( -cinnamyl)PdCl(L),
3
and ( -1-tert-butylindenyl)PdCl(L) in Suzuki-Miyaura
Introduction
Palladium-catalyzed cross-coupling reactions are
widely used in both industry and academia due to their
reliability and versatility.[ One of the major reasons
that cross-coupling reactions are so effective is that
there are a variety of specialized phosphine and N-
heterocyclic carbene (NHC) ligands that can promote
1]
Figure 1. Selected examples of commercially available
palladium(II) precatalysts for cross-coupling reactions.
[2]
the elementary steps in catalysis. These ligands also
stabilize monoligated palladium(0), which is proposed
to be the active species in many cross-coupling
reactions, but they often have comparable expense to
developed and are now commercially available.[3]
Common examples of palladium(II) precatalysts
[4]
include Buchwald palladacycles, Organ’s PEPPSI
[3]
the palladium source. Thus, the traditional route for
forming the active species, the addition of excess
ligand to a palladium(0) complex, is no longer
attractive. Instead, several well-defined palladium(II)
precatalysts with a 1:1 palladium to ligand ratio that
are reduced in situ to palladium(0) have been
[5]
[2d,6]
precatalysts, Nolan’s allyl-based systems,
and
the related 1-tert-butylindenyl-based precatalyst
[7]
developed at Yale (Figure 1). although it would be
valuble for researchers to understand the relative
performance of the different types of precatalysts,
comparing catalytic activity across different
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
precatalyst classes is challenging because they are
typically used under different reaction conditions and
have different pathways for activation. In contrast,
comparing the activity of precatalysts within a
particular class should be more straightforward, as in
this case, they are normally used under the same
conditions.
through a solvent assisted pathway, but information on
the relative rates of activation of the different allyl-
[10]
based systems is limited. In fact, more generally,
there is a lack of knowledge about the relative catalytic
activity of the different types of allyl-based
precatalysts, especially when supported by different
ancillary ligands.
Allyl-based precatalysts, which were developed by
3
3
Nolan, can feature either an unsubstituted  -allyl,  -
3
crotyl, or  -cinnamyl ligand and are used to facilitate
[2d]
a plethora of cross-coupling reactions.
Although
these systems were initially developed for use with
NHC ligands, the Colacot and Shaughnessy groups
established that phosphine ligands are also compatible
with allyl-type systems.[
6e,8]
However, when supported
by certain phosphine or NHC ligands, allyl-type
precatalysts can form palladium(I) dimers during
activation, via a comproportionation reaction between
the unreacted palladium(II) precatalyst and the
monoligated palladium(0) active species (Figure
Figure 3. The three main pathways of precatalyst activation
proposed for allyl-type precatalysts: (A) solvent assisted
activation, (B) nucleophilic attack, and (C) transmetallation.
[6e,8-9]
2).
The formation of palladium(I) dimers
Here, we examine the catalytic performance of a
number of different allyl-type precatalysts for Suzuki-
Miyaura reactions as the ancillary ligand (NHC or
phosphine), reaction conditions, and substrates are
varied. We use the results of these studies to make
general comments about the types of reactions and
conditions where there may be advantages to using a
particular precatalyst and interpret our results in terms
of the mechanism of activation. Additionally, we
compare precatalysts to in situ systems generated from
sequesters the active catalyst in a less reactive form
and is proposed to lower catalytic activity. To prevent
dimer formation, the bulkier Yale precatalyst, which
3
features
a
 -1-tert-butylindenyl ligand, was
developed and showed improved activity, although it
was only directly compared to allyl-based precatalysts
[7,9]
in a limited number of cross-coupling reactions.
common palladium precursors, such as Pd(OAc)
2
or
Pd dba , and free ligand. Our results may assist
2
3
researchers in selecting a precatalyst when they are
performing Suzuki-Miyaura reactions.
Figure 2. Comproportionation of palladium(0) active
catalyst and palladium(II) precatalyst to form inactive
palladium(I) dimers.
Results and Discussion
3
To understand the activity of the different types of  -
Apart from the prevalence of palladium(I) dimer
formation during catalysis, the other key factor in the
performance of allyl-based precatalysts is proposed to
be their rate of activation from palladium(II) to
palladium(0).[ To date, three main pathways have
been proposed for activation of allyl-type
precatalysts[ (Figure 3): (A) a process in which a
solvent alcohol with a -hydrogen coordinates to the
metal, is deprotonated by base, and then transfers a
hydrogen to the allyl-type ligand[ ; (B) a process in
allyl-based precatalysts, we selected systems with a
chloride ancillary ligand as these are commercially
available for the  -allyl,  -crotyl,  -cinnamyl, and
 -1-tert-butylindenyl scaffolds (Figure 1). We note
that Colacot et al. have reported  -allyl-type
precatalysts with a triflate ligand instead of a chloride
ligand, but these systems are not as widely available
and have not been synthesized for the Yale type
3
3
3
7,9]
3
3
10]
11]
[6e]
system.
Precatalysts
supported
by
both
-
t
-
which a nucleophile such as OH or O Bu directly
attacks the allyl-type ligand[6b,12]; or (C) a process
which involves transmetallation of the halide with a
boronic acid followed by reductive elimination of the
allyl-type ligand.[ Preliminary activation studies
indicate that the Yale precatalyst activates faster than
other allyl-based systems when the reaction proceeds
monodentate phosphine and NHC ligands were
evaluated as these ligands are the most commonly used
in cross-coupling reactions and comparing results with
both types of ligand would enable us to understand the
generality of our conclusions. The Suzuki-Miyaura
reaction was used as the model reaction as it is by far
the most prevalent cross-coupling reaction in synthetic
13]
[3]
[14]
chemistry. Reactions were performed using a range
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
of substrates, including heteroaryl chlorides, sterically
bulky aryl chlorides, and non-traditional electrophiles,
such as aryl esters, all of which require slightly
different conditions. In most cases, our method for
comparing precatalysts was to obtain kinetic data
showing the yield of product versus time under
conditions that had been previously reported in the
literature. Kinetic data provides a higher quality
assessment of relative performance than only
comparing yield at a single time. Nevertheless, in
some select cases, we compared precatalysts by
measuring performance at a single time as it is
operationally simpler. In all cases the errors in our
yields are ±5%, a level of uncertainity at which it is
often possible to make significant conclusions about
precatalyst performance.
previously,[7] the same trend is observed under both
tBuInd
sets of conditions. Specifically,
Pd(IPr)Cl
displays the highest activity and is the only precatalyst
that gives yields of greater than 80% after 6 hours. We
propose that the lower yields found with
Cinnamyl
Crotyl
Allyl
Pd(IPr)Cl,
Pd(IPr)Cl, and
Pd(IPr)Cl are
caused by their tendency to comproportionate and
form off-cycle palladium(I) dimers with the IPr ligand
[9] Cinnamyl
(Figure 2).
Pd(IPr)Cl is slightly more active
than the other allyl precatalysts because it is less likely
to form palladium(I) dimers due to its increased steric
[9]
tBuInd
bulk. In contrast, the steric bulk of
Pd(IPr)Cl
means that it does not form palladium(I) dimers, which
is why it has the highest activity. Further, under these
conditions, activation to palladium(0) likely occurs via
[10]
a solvent-mediated pathway (Figure 3),
which is
most efficient for the Yale precatalyst and is likely
another reason for the observed higher activity. The
same trends in precatalyst performance were observed
when the catalyst loading was reduced from 0.5 mol%
to 0.1 mol% (see SI). Finally, to verify that these
results were not an artifact of the chosen conditions,
Coupling Reactions with Well-Defined Allyl-Type
Precatalysts
NHC supported systems
Mondentate NHC ligands are widely used as ancillary
ligands in Suzuki-Miyaura reactions.[
2d,6c,6d,15]
This
i
section explores the performance of NHC ligated allyl-
type precatalysts for a variety of different reactions.
Simple aryl substrates: Our starting point was to
perform a Suzuki-Miyaura coupling between 4-
chlorotoluene and phenyl boronic acid with
precatalysts ligated with IPr, one of the most common
NHC ligands used in cross-coupling. The reaction
was performed under two sets of conditions; one was
we also compared precatalyst activity in neat PrOH,
as these conditions have previously been used in the
[6d]
literature.
No major differences in relative
i
precatalyst activity were observed between PrOH and
a THF/MeOH mixture (see SI). To assess if our results
were relevant to other NHC ligands, we explored the
catalytic activity of our library of precatalysts with the
ligands IMes, IPr*OMe, and SIPr in the coupling of 4-
chlorotoluene and phenyl boronic acid under the
optimized conditions for allyl-type precatalysts (see
SI). Overall, IPr supported precatalysts are far more
compatible with the weak base K
the other with the strong base KO Bu (Figure 4B). In
a similar fashion to what we have observed
2
t
CO (Figure 4A) and
3
[7]
Figure 4. Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using a
t
weak base (K
2 3
CO ) (A) or a strong base (KO Bu) (B) with different precatalysts. Reaction conditions: [ArCl] =
0
.5 M, [Boronic Acid] = 0.55 M, [Base] = 0.55 M, [Precatalyst] = 0.0025 M, 0.66 mL MeOH, and 0.33 mL THF.
Product yield was determined through comparison of product signal with an internal naphthalene standard on a
gas chromatogram with an FID detector and is the average of two trials.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
active than SIPr, IMes, or IPr*OMe ligated
precatalysts, which is not unexpected as the nature of
the ancillary ligand modifies the rates of the
elementary steps in catalysis and IPr is known to
promote Suzuki-Miyaura reactions.[6d] However, the
Yale precatalyst is typically the most active when all
precatalysts are supported by the same ligand. The
trends for the other precatalysts vary because some
ancillary ligands require elevated temperatures to
promote the catalytic reaction, and at these
these conditions, tBuIndPd(IPr)Cl achieved full
conversion in 3 hours, whereas the other precatalysts
displayed significantly lower activity at this time.
Consistent with our results in Figure 4,
Cinnamyl
Pd(IPr)Cl displayed higher activity than either
Allyl
Crotyl
Pd(IPr)Cl or
Pd(IPr)Cl, which is again likely
due to the reduced formation of palladium(I) dimers
with the more sterically bulky system. Further, in
coupling reactions with heteroaryl substrates, the exact
identity of the heteroatoms can have a significant
impact on the reaction because it alters the ability of a
substrate to coordinate to the metal center. Therefore,
we performed a coupling reaction with different
heteroaryl substrates. Namely, we coupled 2-
chlorothiophene and 3-furan boronic acid and
observed the same trends as for the coupling of 2-
chloro-4,6-dimethoxypyrimidine and benzo[b]furan-
temperatures, palladium(I) dimer formation is
reversible.[
9,16]
In these cases, catalyst performance is
presumably primarily related to the rate of initial
solvent assisted activation, which with some NHC
3
3
ligands follows the trend  -1-tert-butylindenyl >  -
3
3
allyl >  -crotyl ~  -cinnamyl ligand under these
[10]
reaction conditions (vide supra). Nevertheless, at
this stage activation rates have not been investigated
with a large enough range of NHC ligands to explain
all of our catalytic results.
2-boronic acid (Figure 5B).
Sterically demanding substrates: Tetra-ortho
substituted biaryls have historically been difficult to
[5d]
form through cross-coupling reactions.
As the
Heteroaryl substrates: Active pharmaceutical
ingredients often contain heteroaromatic groups, but
heteroaryl substrates can be challenging to couple due
sterically bulky IPr*OMe ligand is known to facilitate
the formation of these products, we chose to compare
IPr*OMe ligated precatalysts for the coupling of 2,6-
dimethyl-1-chlorobenzene with 2,4,6-trimethylphenyl
to
heteroatom
coordination
We evaluated the performance
and/or
[
2f,17]
protodeborylation.
[18]
boronic acid (Figure 6). For this transformation, all
of the systems examined give comparable activity,
of different IPr-supported precatalysts in the Suzuki-
Miyaura coupling of 2-chloro-4,6-
3
dimethoxypyrimidine and benzo[b]furan-2-boronic
acid under the optimized conditions for allyl
with the exception of the unsubstituted  -allyl
precatalyst, which is slightly slower. The most likely
[7]
precatalysts in the literature (Figure 5A). Under
Figure 5. Comparative yields for Suzuki-Miyaura couplings of (A) 2-chloro-4,6-dimethoxypyrimidine and
benzo[b]furan-2-boronic acid and (B) 2-chloro-4,6-dimethoxypyrimidine and 3-furan boronic acid. Reaction
conditions A: [ArCl] = 0.3 M, [Boronic Acid] = 0.45 M, [Base] = 0.6 M, [Precatalyst] = 0.0003 M, 0.66 mL
MeOH, and 0.33 mL THF. Reaction conditions B: [ArCl] = 0.3 M, [Boronic Acid] = 0.45 M, [Base] = 0.6 M,
[
Precatalyst] = 0.0015 M, 0.66 mL MeOH, and 0.33 mL THF. Product yield was determined through comparison
of product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is the
average of two trials.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Figure 6. Yield versus time for the Suzuki-Miyaura coupling of 2,6-dimethyl-1-chlorobenzene and 2,4,6-
trimethylphenyl boronic acid with different precatalysts. Reaction conditions: [ArCl] = 0.25 M, [Boronic Acid] = 0.375
M, [Base] = 0.5 M, [Precatalyst] = 0.00125 M, and 1 mL THF. Product yield was determined through comparison of
product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is the average of
two trials.
explanation for the relatively similar activity of all of
the precatalysts is that the steric bulk of the IPr*OMe
ligand inhibits the formation of palladium(I) dimers.
proposed to activate more rapidly than other allyl
based systems.
[10]
[6e]
As a result, precatalyst performance is based mainly
on the rate of activation of the precatalyst from
palladium(II) to palladium(0). In this reaction,
precatalyst activation likely involves nucleophilic
Non-traditional electrophiles: The vast majority of
Suzuki-Miyaura reactions use aryl halides (or pseudo
halides) as the electrophile, but in recent times cross-
coupling reactions have been extended to include a
-
[1h]
attack by OH on the allyl-type ligand, as there is no
variety of non-traditional electrophiles.
For
alcoholic solvent with
a
-hydride and
example, it has been demonstrated that palladium
precatalysts can couple phenyl esters through cleavage
of the Cacyl-O bond to generate ketones as products.
transmetallation is likely slow due to the steric bulk of
the substrates. Based on the relatively similar rates of
product formation for all precatalysts, it appears that
activation via this pathway occurs at similar rates for
all systems. This stands in contrast to activation via a
solvent assisted pathway, where the Yale precatalyst is
[19]
We evaluated IPr-ligated precatalysts in a Suzuki-
Miyaura reaction between phenyl benzoate and 4-
methoxy phenyl boronic acid (Figure 7).
tBuInd
Pd(IPr)Cl shows the highest activity with the rate
of product formation being slightly slower for
Figure 7. Yield versus time for the Suzuki-Miyaura coupling of phenyl benzoate and 4-methoxy phenyl boronic acid
with different precatalysts. Reaction conditions: [.Phenyl Benzoate] = 0.2 M, [Boronic Acid] = 0.3 M, [Base] = 0.4 M,
[
2
Precatalyst] = 0.002 M, 0.2 mL H O, and 0.8 mL THF. Product yield was determined through comparison of product
signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is the average of two trials.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Cinnamyl
Pd(IPr)Cl. Almost no conversion was observed
with AllylPd(IPr)Cl or
Crotyl
Pd(IPr)Cl. The improved
Cinnamyl
performance of
Pd(IPr)Cl relative to
tBuInd
Pd(IPr)Cl in this reaction with the IPr ligand is
likely because activation of the precatalyst from
palladium(II) to palladium(0), which likely occurs via
nucleophilic attack, is faster under these conditions
which reduces the amount of off-cycle palladium(I)
dimer formation.
Summary: Our data on the performance of allyl-type
precatalysts with NHC ligands is consistent with
performance being related to palladium(I) dimer
formation and the rate of activation from palladium(II)
to palladium(0) (Figure 8). For systems, where
palladium(I) dimer formation can occur, typically with
ancillary ligands with moderate steric bulk, such as IPr,
Figure 8. Decision tree for selecting NHC ligated
precatalysts.
Phosphine Ligands
Phosphine ligands are more commonly used in Suzuki-
[1h,2f,2g]
Miyaura reactions than NHC ligands.
This
section compares the performance of phosphine
ligated allyl-type precatalysts for a variety of different
reactions.
tBuInd
Pd(NHC)Cl will likely give the highest activity,
Cinnamyl
followed by
Pd(NHC)Cl. In contrast, in systems
where the ancillary ligand is sufficiently sterically
bulky to prevent palladium(I) dimer formation,
precatalyst performance is related to the rate of
activation from palladium(II) to palladium(0). Our
Simple aryl substrates: Initially, we performed a
Suzuki-Miyaura coupling between 4-chlorotoluene
and phenyl boronic acid with precatalysts ligated with
the XPhos ligand (one of the most common phosphine
results suggest that when activation occurs via a
ligands used in cross-coupling) under both weak
tBuInd
solvent assisted pathway
Pd(NHC)Cl will give the
t
(
K
2
CO
3
) and strong (KO Bu) base conditions (Figure
best performance. However, for systems where
activation can occur via another mechanism, such as
nucleophilic attack, the relative ordering of activity of
the allyl-type precatalysts is not clear and in some
cases all systems may give comparable activity.
9
). Similar to results found with NHC ligands,
tBuInd
Pd(XPhos)Cl gives the highest activity, which is
likely due to its more rapid activation in methanol, via
a solvent assisted pathway (Figure 3). In this case,
palladium(I) dimer formation is unlikely to be a
significant factor in catalysis as previous results from
[10]
Figure 9. Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid with K
2
CO
(C) using XPhos ligated precatalysts. Reaction conditions (A and B): [ArCl] = 0.5 M,
Boronic Acid] = 0.55 M, [Base] = 0.55 M, [Precatalyst.] = 0.0025 M, 0.95 mL MeOH, and 0.05 mL THF. Reaction
3
t
(
[
3 4
A), KO Bu (B), and K PO
conditions (C): [ArCl] = 0.5 M, [Boronic Acid] = 0.55 M, [Base] = 1.0 M, [Precatalyst] = 0.0025 M, 0.66 mL MeOH,
and 0.33 mL THF. Product yield was determined through comparison of product signal with an internal naphthalene
standard on a gas chromatogram with an FID detector and is the average of two trials.
6
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Colacot, suggest that XPhos is too sterically bulky to
these cases. In contrast, for sterically bulky systems,
the rate of activation from palladium(II) to
palladium(0), which is not completely understood, is
presumably the predominant factor.
allow dimer formation.[
6e]
Consistent with this
Crotyl
proposal, the less sterically bulky
outperforms
Pd(XPhos)Cl
Cinnamyl
Pd(XPhos)Cl. In an analogous
fashion to the IPr supported systems, the same trends
in precatalyst activity are observed when the catalyst
loading is reduced to 0.1 mol% (see SI). Given that the
rate of activation from palladium(II) to palladium(0) is
proposed to be the determining factor in precatalyst
activity with sterically bulky phosphines, we explored
the relative activity of allyl precatalysts, supported by
the bulky ligand XPhos, under different conditions. To
this end, we coupled 4-chlorotoluene and phenyl
boronic acid using THF and water with a weak base,
Heteroaryl substrates: We next evaluated XPhos
ligated precatalysts in Suzuki-Miyaura couplings
involving heteroaryl substrates. Initially, we
performed
a
reaction between 2-chloro-4,6-
dimethoxypyrimidine and benzo[b]furan-2-boronic
acid (Figure 10). The performance of the precatalysts
is different from that observed for simple substrates.
tBuInd
Although
Pd(XPhos)Cl is still the most active
Pd(XPhos)Cl is the least active.
Crotyl
system,
Allyl
K
3
4
PO , in order to prevent activation via a solvent
Pd(XPhos)Cl is the second most active and gives
slightly superior activity to
Cinnamyl
assisted pathway (Figure 9C). Despite the change in
the activation pathway, presumably to nucleophilic
attack, the relative precatalyst activity did not change,
suggesting that the rates of activation via a pathway
involving nucleophilic attack are the same as those
involving a solvent assisted pathway. We also
examined the relative catalytic activities of our library
Pd(XPhos)Cl. This
data suggests that the presence of heteroatoms makes
a significant difference to the relative rates of
precatalyst activation, which is presumably the sole
determinant of activity, as palladium(I) dimer
formation is not a significant issue with the XPhos
[6e]
ligand (vide supra).
To further evaluate the effect of heteroatoms, we
performed coupling reaction between 2-
chlorothiophene and 3-furan boronic acid (Figure 11).
i
[6d]
of precatalysts in neat PrOH.
Under these
conditions, the relative performance of the precatalysts
was similar (see SI).
a
Crotyl
To
our
surprise,
Pd(XPhos)Cl
and
Cinnamyl
We also evaluated the relative performance of
Pd(XPhos)Cl give the best activity, followed by
t
Allyl
tBuInd
precatalysts supported by SPhos, RuPhos, and P Bu
3
Pd(XPhos)Cl and
Pd(XPhos)Cl. We propose
(
see SI). As the ancillary ligand was changed,
that the different trends in precatalyst performance are
related to the ability of the substrate to participate in
precatalyst activation with some allyl-type systems.
Specifically, when 3-furan boronic acid is used as a
tBuInd
Pd(L)Cl remained the most active precatalyst,
which is consistent with results found using XPhos.
However, the relative activities of the other allyl
precatalysts varied as the ancillary ligand was changed. substrate, we hypothesize that the heteroatom assists
No clear trends could be discerned from our data, but
it did appear that in systems with smaller ancillary
ligands, cinnamyl supported systems are more active
than crotyl or allyl supported systems, presumably
because palladium(I) dimer formation is important in
activation via a pathway involving transmetallation
and reductive elimination by facilitating pre-
coordination of the substrate to the metal. In contrast,
when the less nucleophilic benzo[b]furan-2-boronic
acid is used, this pathway is less favorable. Further, we
Figure 10. Yield versus time for the Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-
-boronic acid with different precatalysts. Reaction conditions: [ArCl] = 0.3 M, [Boronic Acid] = 0.45 M, [Base] = 0.6
2
M, [Precatalyst] = 0.0003 M, 0.33 mL THF, and 0.67 mL MeOH. Product yield was determined through comparison of
product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is the average of
two trials.
7
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Figure 11. Yield versus time for the Suzuki-Miyaura coupling of 2-chlorothiophene and 3-furan boronic acid with
different precatalysts. Reaction conditions: [ArCl] = 0.3 M, [Boronic Acid] = 0.45 M, [Base] = 0.6 M, [Precatalyst] =
0
.0015 M, 0.33 mL THF, and 0.67 mL MeOH. Product yield was determined through comparison of product signal with
an internal naphthalene standard on a gas chromatogram with an FID detector and is the average of two trials.
propose this effect is more notable for less sterically
bulky precatalysts as coordination of the heteroatom is
more facile. To more rigorously understand the effect
of the boronic acid on relative precatalyst activity, we
boronic acid compared to benzo[b]furan-2-boronic
acid, although we note that is often difficult to
understand the performance of the unsubstituted
Crotyl
system.
Overall,
Pd(XPhos)Cl
and
Cinnamyl
examined
the
coupling
of
2-chloro-4,6-
Pd(XPhos)Cl are the most active precatalysts for
dimethoxypyrimidine and 2-furan boronic acid, which
allows direct comparison to the reaction of 2-chloro-
the coupling of 2-furan boronic acid but
tBuInd
Pd(XPhos)Cl is the most active precatalyst for the
4
,6-dimethoxypyrimidine and the less coordinating
coupling of benzo[b]furan-2-boronic acid. This set of
experiments introduces another variable in assessing
the relative activity of precatalysts as it shows that
performance is not only affected by reaction
conditions but also by the exact nature of the substrates.
The particular effect observed here, coordination of
the boronic acid to promote activation via
transmetallation, is likely limited to a relatively small
number of substrates. Nevertheless, it provides an
important reminder about the complexity of
precatalyst comparison and suggests that when new
substrates are utilized, there are likely benefits to
evaluating different systems.
benzo[b]furan-2-boronic acid (Figure 12). As
expected, for
little difference in the yields after one hour, consistent
with activation not involving the boronic acid, and
oxidative addition being the turnover-limiting step in
tBuInd
Pd(XPhos)Cl, there is relatively
Crotyl
catalysis. In contrast, for
Pd(XPhos)Cl and
Cinnamyl
Pd(XPhos)Cl, the yield of product is
significantly higher after one hour in the reaction
involving 2-furan boronic acid compared to the
reaction with benzo[b]furan-2-boronic acid. In a result
we do not understand at this stage,
did not give a significantly higher yield with 2-furan
Allyl
Pd(XPhos)Cl
Figure 12. Comparative yields of the Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine with
benzo[b]furan-2-boronic acid or 2-furan boronic acid with different precatalysts. Reaction conditions: [ArCl] = 0.3 M,
[
Boronic Acid] = 0.45 M, [Base] = 0.6 M, [Precatalyst] = 0.0003 M, 0.33 mL THF, and 0.67 mL MeOH. Product yield
was determined through comparison of product signal with an internal naphthalene standard on a gas chromatogram with
an FID detector and is the average of two trials.
8
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202000987
cross-coupling.[22] For example, palladium complexes
Figure 13. Yield versus time for the Suzuki-Miyaura coupling of 1-naphthyl sulfamate and 4-methoxyphenyl boronic
acid with different precatalysts. Reaction conditions: [1-naphthyl sulfamate] = 0.1 M, [Boronic Acid] = 0.15 M, [Base] =
0
.2 M, [Precatalyst] = 0.0025 M, 0.67 mL Toluene, and 0.33 mL MeOH. Product yield was determined through
comparison of product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is
the average of two trials.
t
Non-traditional substrates: Aryl sulfamates are robust
non-traditional electrophiles for cross-coupling that
can be readily synthesized from ubiquitous phenols
and are directing groups for C–H bond
functionalization reactions. We examined our series
of precatalysts in the coupling of 1-naphthyl sulfamate
and 4-methoxyphenyl boronic acid using reaction
supported by P Bu
3
are known to be active for cross-
coupling reactions between aryl halides and alkyl
2
3
[23]
trifluoroborates to generate Csp –Csp bonds. Here,
we examined the coupling of 3-chloroanisole and
potassium sec-butyltrifluoroborate with our library of
precatalysts (Figure 14). The most active system was
[20]
tBuInd
t
Crotyl
t
Pd(P Bu
3
)Cl.
Pd(P Bu )Cl also displayed high
3
conditions previously described in the literature
activity, but there was a notable decrease in yield when
Figure 13).[ The only precatalyst that achieved
21]
either
Cinnamyl
Pd(P Bu
t
)Cl or
Allyl
Pd(P Bu )Cl were used
t
(
3
3
tBuInd
yields above 90% after 6 hours was
Pd(XPhos)Cl.
as precatalysts. Explaining the relative performance of
Crotyl
Pd(XPhos)Cl was slightly more active than
the precatalysts in this case is complicated as with the
Cinnamyl
Allyl
t
Pd(XPhos)Cl, while Pd(XPhos)Cl only gives
relatively less bulky P Bu
3
ligand palladium(I) dimer
a yield of around 10%. This trend in precatalyst
performance is likely related to the relative rates of
activation, which is proposed to occur via a solvent
assisted pathway for the allyl-type systems under these
reaction conditions.
formation likely occurs. However, at this temperature
palladium(I) dimer formation is probably reversible
for some systems and as a result the observed trends
likely depend on the rate of activation from
palladium(II) to palladium(0) and the kinetics and
thermodynamics associated with palladium(I) dimer
[9,16]
The vast majority of cross-coupling reactions involve
dissociation, which generates the active species.
2
2
the formation of Csp –Csp bonds, but there is also
2
3
significant interest in the formation of Csp –Csp
bonds, which are ubiquitous in pharmaceuticals, using
Summary: Our experiments indicate that because
sterically bulky phosphine ligands, such as XPhos,
Figure 14. Yield versus time for the Suzuki-Miyaura coupling of 3-chloroanisole and potassium sec-butyltrifluoroborate
with different precatalysts. Reaction conditions: [ArCl] = 0.33 M, [potassium sec-butyltrifluoroborate] = 0.5 M, [Base]
=
2
1 M, [Precatalyst] = 0.0033 M, 0.67 mL Toluene, and 0.33 mL H O. Product yield was determined through comparison
of product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is the average
of two trials.
9
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
which do not allow for palladium(I) dimer formation,
are commonly used to facilitate cross-coupling
reactions, the rate of activation from palladium(II) to
palladium(0) is often the crucial factor in determining
the relative precatalyst performance of allyl-based
systems. This stands in contrast to NHC systems,
where ligands like IPr, which do allow for palladium(I)
section, we compare the activity of precatalysts
generated in situ from these dimeric precursors with
both NHC and phosphine ligands. Additionally,
researchers often generate in situ systems for cross-
coupling through the reaction of commercially
available
tris(dibenzylideneacetone)dipalladium(0) (Pd
bis(acetonitrile)palladium dichloride
(Pd(CH CN) Cl ), and palladium acetate (Pd (OAc)
palladium
sources
such
as
2
dba
3
),
dimer formation, are the most commonly used. When
Crotyl
activation is the dominant factor,
Pd(PR
3
)Cl
3
2
2
3
6
)
Cinnamyl
typically outperforms
Pd(PR
3
)Cl regardless of
with free ligand. These systems are also included in
our comparison. Finally, it was recently reported that
tBuInd
the exact mechanism. Further,
Pd(PR )Cl, which
3
activates the fastest under the solvent assisted pathway, commercially available palladium acetate often
[
24]
is normally the most active catalyst (Figure 15).
However, our results indicate that the relative rates of
precatalyst activation are dependent on the chosen
substrates and conditions, and in cases where
activation is the dominant factor and alternative
mechanistic pathways are possible, such as
coordination based transmetallation, a number of
precatalysts should be evaluated.
contains a nitrate impurity (Pd
3
(OAc)
5
(NO ). Here,
2
we compare the performance of pure palladium acetate
with samples containing a nitrate impurity. The goal of
this section is to assess if the trends elucidated for
ligated versions of the precatalysts also apply to in situ
generated systems and evaluate how the different
precatalysts compare to simple commercially
available palladium sources.
Simple aryl substrates: The first reaction we used for
our comparison was the Suzuki-Miyaura coupling of
4-chlorotoluene with phenyl boronic acid using IPr as
the ancillary ligand. In these reactions, the precatalysts
were mixed with IPr for approximately 10 minutes
before the substrates and base were added. Under the
optimized conditions for allyl-type precatalysts, we
found that differentiation between the Yale system,
palladium acetate, and Pd(CH
3
CN)
2
Cl
2
was
Figure 15. Decision tree for selecting phosphine ligated
precatalysts.
challenging due to their rapid generation of product
(see SI). We, therefore, lowered the catalyst loading to
0
.25 mol% (Figure 17) and observed that the dimeric
Coupling Reactions with Precatalysts Generated In
Situ
version of the Yale precatalyst gives better
performance than the cinnamyl, crotyl, or allyl systems.
In fact, the allyl and crotyl systems give almost no
activity, mirroring trends observed for the well-
defined precatalysts (Figure 4). In general, for all the
reactions evaluated in this section, the activity of well-
defined precatalysts is always either comparable or
higher than in situ generated systems, although there
are some exceptions (see SI). This suggests that
precatalyst performance is not related to the ligation
event but connected to palladium(I) dimer formation
and the rates of activation as observed using well-
defined precatalysts. Surprisingly, precatalysts
generated from both pure and impure palladium
When researchers are assessing if new substrates can
undergo cross-coupling reactions, the identity of the
optimal ancillary ligand is often unclear. Given that the
synthesis and isolation of a large number of well-
defined precatalysts with different ligands is time-
intensive, it is valuable to have methods to rapidly
screen a variety of ligands using in situ generated
[
6b]
[6d]
[6d]
systems. The allyl, crotyl, cinnamyl, , and Yale
systems,[ have unligated dimeric precursors (Figure
7]
16), which can be converted into ligated precatalysts
through reactions with free ligand in situ. In this
3
acetate and Pd(CH CN)
2
Cl resulted in high yields and
2
give comparable activity to the dimeric version of the
Yale precatalyst, demonstrating that for ligand
screening purposes a system based on a precatalyst is
not necessarily required. No activity, however, was
observed when Pd
source.
2
dba was used as the palladium
3
Figure 16. Unligated dimeric palladium(II) precursors used
for in-situ precatalyst generation.
We subsequently evaluated the ability of the different
palladium precursors to couple 4-chlorotoluene and
1
0
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Figure 17. Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using in-situ
generated palladium XPhos precatalysts. Reaction conditions: [ArCl] = 0.5 M, [Boronic Acid] = 0.55 M, [Base] = 0.55
M, [Pd] = 0.00125 M, [IPr] = 0.00125 M, 0.95 mL MeOH, and 0.05 mL THF. Product yield was determined through
comparison of product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is
the average of two trials.
phenyl boronic acid when treated with XPhos in situ
Figure 18). As for the IPr supported systems, the
XPhos supported couplings of 4-chlorotoluene and
phenyl boronic acid with ligand to metal ratios of 0.8,
1.0, or 1.2 equivalents, respectively (Figure 19). For
most systems, there were differences in catalytic
performance when the ligand to metal ratio was
changed. There was, however, significant variation in
the magnitude and direction of these differences. For
example, when the ratio of ligand to metal was
increased from 0.8 to 1.2 equivalents using
(
trends in precatalyst performance for the in situ
generated XPhos ligated systems are the same as those
for well-defined systems (Figure 9). The Yale system
gives higher activity than the crotyl system, which is
more active than precatalysts formed from the
cinnamyl or allyl dimers. Both the pure and impure
palladium acetate sources give similar activity, which
is approximately the same as that observed from the
Pd(CH
decreased by a factor of sixteen from 64% to 4%. In
contrast, when Pd (OAc) is used as the palladium
source, changing the ligand to metal ratio from 0.8 to
.2 equivalents nearly doubled the yield from 44% to
3
CN)
2
Cl
2
as the palladium source, the yield
crotyl system. Pd(CH
activity to the cinnamyl system, and Pd
result in the formation of active catalyst.
3
CN)
2
Cl
2
gives comparable
2
dba does not
3
3
6
1
One of the problems associated with using in situ
generated systems is that it is possible to have a ligand
to palladium ratio that is not 1:1. This will occur if
there is an error weighing out either the ligand or
palladium source or if the ligation event does not
proceed quantitatively. To evaluate the effect of excess
palladium or ligand on catalytic performance with
different palladium sources, we performed a series of
84%. In this case, we hypothesized that excess
phosphine aids the reaction because some phosphine is
consumed in the reduction of palladium(II) acetate to
the active palladium(0) catalyst, as has been
previously proposed in the literature. To verify this
hypothesis, we treated palladium acetate with 2
equivalents of XPhos and observed that palladium(0)
and phosphine oxide were formed, consistent with
[25]
Figure 18. Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using in-situ
generated palladium XPhos precatalysts. Reaction conditions: [ArCl] = 0.5 M, [Boronic Acid] = 0.55 M, [Base] = 0.55
M, [Pd] = 0.0025 M, [XPhos] = 0.0025 M, 0.95 mL MeOH, and 0.05 mL THF. Product yield was determined through
comparison of product signal with an internal naphthalene standard on a gas chromatogram with an FID detector and is
the average of two trials.
1
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Figure 19. Comparative yields for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using in-
situ generated palladium XPhos precatalysts. Reaction conditions: [ArCl] = 0.5 M, [Boronic Acid] = 0.55 M, [Base] =
0
.55 M, [Pd] = 0.0025 M, [XPhos] = 0.002 M for 0.8 equiv. or 0.0025 M for 1 equiv. or 0.003 M for 1.2 equiv., 0.95
mL MeOH, and 0.05 mL THF. Product yield was determined through comparison of product signal with an internal
naphthalene standard on a gas chromatogram with an FID detector and is the average of two trials.
XPhos reducing palladium acetate (see SI). In general,
smaller differences were observed when the ligand to
metal ratio was varied using the allyl based systems,
which is perhaps another reason to use these more
well-defined systems. Further, the trends in precatalyst
performance were similar regardless of the number of
equivalents of ligand. These results highlight that for
some cross-coupling reactions, careful optimization of
the number of equivalents of ligand may also be
beneficial.
(Figure 20). Under the optimized conditions for allyl-
type precatalysts, the same trends in catalyst
performance were observed for the in situ generated
systems as for the well-defined precatalysts (Figures
10 & 11). Specifically, the Yale systems is the most
active for coupling 2-chloro-4,6-dimethoxypyrimidine
and benzo[b]furan-2-boronic acid, but the crotyl and
cinnamyl systems are the most active for coupling 2-
chlorothiophene and 3-furan boronic acid. Of the
common palladium sources, palladium acetate again
displays the highest activity, while Pd
almost no activity.
2
dba gives
3
Heteroaryl substrates: We next explored the relative
activity of in situ generated systems in two more
complex Suzuki-Miyaura reactions, namely the
couplings of 2-chloro-4,6-dimethoxypyrimidine and
benzo[b]furan-2-boronic acid and 2-chlorothiophene
and 3-furan boronic acid in the presence of XPhos
Non-traditional electrophiles: To conclude this
section, we evaluated the activity of our different
2
3
palladium sources in the in situ Csp –Csp Suzuki-
Miyaura coupling of 3-chloroanisole and potassium
Figure 20. Comparative yields for the Suzuki-Miyaura coupling of heteroaryl boronic substrates using in situ generated
XPhos precatalysts. Reaction A: The coupling of 2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-2-boronic acid.
Reaction B: The coupling of 2-chlorothiophene and 3-furan boronic acid. Conditions for reactions A and B: [ArCl] =
0
.3 M, [Boronic Acid] = 0.45 M, [Base] = 0.6 M, [Pd] = 0.003 M, [XPhos] = 0.003 M, 0.33 mL THF, and 0.67 mL
MeOH. Product yield was determined through comparison of product signal with an internal naphthalene standard on a
gas chromatogram with an FID detector and is the average of two trials.
1
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Figure 21. Comparative yields for the Suzuki-Miyaura coupling of 3-chloroanisole and potassium sec-
butyltrifluoroborate with different precatalysts. Reaction conditions: [ArCl] = 0.33 M, [potassium sec-
t
butyltrifluoroborate] = 0.5 M, [Base] = 1 M, [Pd] = 0.0033 M, [P Bu
3
] = 0.0033 M, 0.67 mL Toluene, and 0.33 mL
2
H O. Product yield was determined through comparison of product signal with an internal naphthalene standard on a
gas chromatogram with an FID detector.
sec-butyltrifluoroborate (Figure 21). Under the chosen
conditions, the crotyl system displays higher activity
than the Yale, cinnamyl, and allyl systems. This trend
is slightly different to that observed using well-defined
precatalysts (Figure 14), as the Yale system is
use a well-defined system than an in situ generated
system.
Conclusions
relatively less active. This implies that the
t
In this work, we have compared the activity of a
number of commercially available allyl-type for
Suzuki-Miyaura reactions. In general, precatalysts
based on an unsubstituted allyl ligand give
significantly lower activity than other systems, and
should not be widely utilized. When ligated with NHC
ligands, precatalysts with a cinnamyl ligand typically
give higher activity than precatalysts with a crotyl
ligand, but this order reverses for phosphine supported
species. In most of the reactions performed in this
work, the Yale precatalyst gives higher activity than
both the cinnamyl and crotyl systems with both NHC
and phosphine ligands, but this is dependent on two
factors: (i) whether the irreversible formation of
palladium(I) dimer occurs; and (ii) the pathway for
activation from palladium(II) to palladium(0). These
are related to the ancillary ligand, substrates, and
reaction conditions, and we have developed decision
trees to help researchers choose a precatalyst. We note
that the generality of our results remains to be
determined, and it is not clear if our conclusions will
be relevant to other cross-coupling reactions such as
Buchwald-Hartwig, Negishi, Stille, or Kumada
reactions. Additionally, the allyl-type precatalysts are
also effective for performing initial ligand screening
reactions, and our advice is to use either the Yale
precatalyst or palladium acetate to perform an initial
ligand screen before evaluating a range of well-defined
precatalysts once a ligand has been identified. Overall,
our results demonstrate the advantages of using
precatalysts compared to unligated commercial
palladium sources and provide guidance about which
allyl-type precatalysts to use for different Suzuki-
Miyaura reactions.
coordination of P Bu
3
occurs less readily for the Yale
system compared to other systems, which may be
related to its steric bulk. Additionally, to our surprise,
all of the common palladium sources, Pd(CH
3
CN)
2
Cl ,
2
Pd dba , and palladium acetate, give low yields of
2
3
product. This stands in contrast to other reactions
performed in this section, which demonstrate that
palladium acetate can give high activity. It suggests
that care must be taken when screening different
precursors as there is no apparent reason for palladium
acetate to give a low yield in this case.
Summary: The results in this section highlight that the
trends in catalyst performance for well-defined
systems are typically the same as those observed using
in situ generated systems. Therefore, the conclusions
we reached about which precatalysts are optimal for
different reactions using well-defined systems are the
same for in situ generated experiments. This suggests
that at least for the ligands studied in this work, the
efficiency of ligation of the allyl precatalysts is
approximately comparable. Interestingly, palladium
acetate (both pure and impure) gives excellent activity
for in situ reactions, and in some cases, it may be
suitable to perform ligand screening using it as the
palladium source. In this case, care needs to be taken
about the exact number of equivalents of ligand that
are added. In contrast, although Pd
2
dba is commonly
3
used in the literature, our results show that for the
reactions described in this paper, it should be avoided
as a palladium source due to its low activity. Finally,
our data indicates that once the optimal ligand and
palladium source has been found, it is likely better to
1
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000987
Acknowledgements
[6] a) M. S. Viciu, R. F. Germaneau, S. P. Nolan, Org. Lett.
2
002, 4, 4053; b) M. S. Viciu, R. F. Germaneau, O. Navarro-
Fernandez, E. D. Stevens, S. P. Nolan, Organometallics
002, 21, 5470; c) O. Navarro, H. Kaur, P. Mahjoor, S. P.
NH acknowledges support from the NIHGMS under Award
Number R01GM120162. MRE acknowledges support from a
Wiberg Graduate Research Fellowship. We are grateful to Amira
Dardir and Vivek Suri for assistance with synthesis and fruitful
discussions, Dr. Damian Hruszkewycz and Dr. Patrick Melvin for
comments on the manuscript, and Dr. Fabian Menges for his help
with mass spectrometry.
2
Nolan, J. Org. Chem. 2004, 69, 3173; d) N. Marion, O.
Navarro, J. Mei, E. D. Stevens, N. M. Scott, S. P. Nolan, J.
Am. Chem. Soc. 2006, 128, 4101; e) A. J. DeAngelis, P. G.
Gildner, R. Chow, T. J. Colacot, J. Org. Chem. 2015, 80,
6
[
794.
7] P. R. Melvin, A. Nova, D. Balcells, W. Dai, N. Hazari,
D. P. Hruszkewycz, H. P. Shah, M. T. Tudge, ACS Catal.
015, 5, 3680.
8] L. L. Hill, J. L. Crowell, S. L. Tutwiler, N. L. Massie, C.
Competing Financial Interests
2
[
This work was primarily funded by Umicore, who own
the rights to all of the allyl-based precatalysts studied
in this work. Additionally, NH is an inventor on
patents relating to the Yale precatalyst.
C. Hines, S. T. Griffin, R. D. Rogers, K. H. Shaughnessy,
G. A. Grasa, C. C. C. Johansson Seechurn, H. Li, T. J.
Colacot, J. Chou, C. J. Woltermann, J. Org. Chem. 2010,
7
5, 6477.
[
9] D. P. Hruszkewycz, D. Balcells, L. M. Guard, N. Hazari,
M. Tilset, J. Am. Chem. Soc. 2014, 136, 7300.
[10] P. R. Melvin, D. Balcells, N. Hazari, A. Nova, ACS
Catal. 2015, 5, 5596.
[11] DFT calculations suggest that the concerted process
involving hydrogen transfer is lower in energy than an
alternative pathway involving β-hydride elimination
followed by reductive elimination. See reference 10 for
more information.
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