doi.org/10.26434/chemrxiv.12573608.v1
Differences in the Performance of Allyl Based Palladium Precatalysts forSuzuki-Miyaura ReactionsMatthew R. Espinosa, Angelino Doppiu, Nilay Hazari
Submitted date: 26/06/2020 • Posted date: 29/06/2020Licence: CC BY-NC-ND 4.0Citation information: Espinosa, Matthew R.; Doppiu, Angelino; Hazari, Nilay (2020): Differences in thePerformance of Allyl Based Palladium Precatalysts for Suzuki-Miyaura Reactions. ChemRxiv. Preprint.https://doi.org/10.26434/chemrxiv.12573608.v1
We evaluate the activity of different allyl-based precatalysts in Suzuki-Miyaura reactions as the ancillaryligand (NHC or phosphine), reaction conditions, and substrates are varied. In some cases, we connect relativeactivity to both the mechanism of activation and the prevalence of the formation of inactive palladium(I)dimers.
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1
Differences in the Performance of Allyl Based Palladium Precatalysts for
Suzuki-Miyaura Reactions
Matthew R. Espinosa,a Angelino Doppiu,b and Nilay Hazaria,*
aDepartment of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut, 06520,
USA. E-mail: [email protected].
bPrecious Metals Chemistry, Umicore AG & Co. KG, Rodenbacher Chaussee 4, Hanau-
Wolfgang, Germany.
Abstract
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 (3-allyl)PdCl(L), (3-crotyl)PdCl(L), (3-cinnamyl)PdCl(L), and (3-
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.
2
Introduction
Palladium-catalyzed cross-coupling
reactions are widely used in both
industry and academia due to their
reliability and versatility.[1] 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 the elementary steps in catalysis.[2] 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 the palladium source.[3] 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 developed and are now commercially
available.[3] Common examples of palladium(II) precatalysts include Buchwald palladacycles,[4]
Organ’s PEPPSI precatalysts,[5] Nolan’s allyl-based systems,[2d,6] and the related 1-tert-
butylindenyl-based precatalyst developed at Yale (Figure 1).[7] Although it would be valuable for
researchers to understand the relative performance of the different types of precatalysts, comparing
catalytic activity across different 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.
Allyl-based precatalysts, which were developed by Nolan, can feature either an unsubstituted 3-
allyl, 3-crotyl, or 3-cinnamyl ligand and are used to facilitate a plethora of cross-coupling
reactions.[2d] 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 2).[6e,8-9] The formation of palladium(I) dimers sequesters the active catalyst in a less
Figure 1: Selected examples of commercially available
palladium(II) precatalysts for cross-coupling reactions.
3
reactive form and is
proposed to lower catalytic
activity. To prevent dimer
formation, the bulkier Yale
precatalyst, which features
a 3-1-tert-butylindenyl
ligand, was developed and
showed improved activity, although it was only directly compared to allyl-based precatalysts in a
limited number of cross-coupling reactions.[7,9]
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).[7,9] To date, three main pathways have been proposed for activation
of allyl-type precatalysts[10] (Figure 3): (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[11]; (B) a process in which a nucleophile such as OH- or OtBu- 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.[13] Preliminary activation studies
indicate that the Yale precatalyst activates faster than other allyl-based systems when the reaction
proceeds through a solvent assisted pathway, but information on the relative rates of activation of
the different allyl-based systems is limited.[10] In fact, more generally, there is a lack of knowledge
Figure 3: The three main pathways of precatalyst activation proposed for allyl-type precatalysts: (A)
solvent assisted activation, (B) nucleophilic attack, and (C) transmetallation.
Figure 2: Comproportionation of palladium(0) active catalyst and
palladium(II) precatalyst to form inactive palladium(I) dimers.
4
about the relative catalytic activity of the different types of allyl-based precatalysts, especially
when supported by different ancillary ligands.
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 common palladium precursors, such as Pd(OAc)2 or
Pd2dba3, and free ligand. Our results may assist researchers in selecting a precatalyst when they
are performing Suzuki-Miyaura reactions.
Results and Discussion
To understand the activity of the different types of 3-allyl-based precatalysts, we selected systems
with a chloride ancillary ligand as these are commercially available for the 3-allyl, 3-crotyl, 3-
cinnamyl, and 3-1-tert-butylindenyl scaffolds (Figure 1). We note that Colacot et al. have
reported 3-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 all of the different allyl
systems.[6e] Precatalysts supported by both monodentate phosphine and NHC ligands were
evaluated as these ligands are the most commonly used in cross-coupling reactions and comparing
results with ligands of both types would enable us to understand the generality of our
conclusions.[3] The Suzuki-Miyaura reaction was used as the model reaction as it is by far the most
prevalent cross-coupling reaction in synthetic chemistry.[14],[15] Reactions were performed using a
range 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.
5
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,16] This 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 compatible with the weak base K2CO3 (Figure 4A) and the other with the strong base
KOtBu (Figure 4B).[7] In a similar fashion to what we have observed previously,[7] the same trend
is observed under both sets of conditions. Specifically, tBuIndPd(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 CinnamylPd(IPr)Cl, CrotylPd(IPr)Cl, and AllylPd(IPr)Cl are caused by their
tendency to comproportionate and form off-cycle palladium(I) dimers with the IPr ligand (Figure
2).[9] CinnamylPd(IPr)Cl is slightly more active because it is less likely to form palladium(I) dimers
due to its increased steric bulk.[9] In contrast, the steric bulk of tBuIndPd(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 a solvent-mediated pathway (Figure 3),[10]
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).
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 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
6
elevated temperatures to promote the catalytic reaction, and at these temperatures, palladium(I)
dimer formation is reversible.[9,17] In these cases, catalyst performance is presumably primarily
related to the rate of initial solvent assisted activation, which with some NHC ligands follows the
trend 3-1-tert-butylindenyl > 3-allyl > 3-crotyl ~ 3-cinnamyl ligand under these reaction
conditions (vide supra).[10] 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.
Heteroaryl substrates: Active pharmaceutical ingredients often contain heteroaromatic groups, but
heteroaryl substrates can be challenging to couple due to heteroatom coordination and/or
protodeborylation.[2f,18] We evaluated the performance of different IPr-supported precatalysts in
the Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-2-boronic
acid under the optimized conditions for allyl precatalysts in the literature (Figure 5A). Under these
Figure 4: Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid using a weak base (K2CO3) (A) or a strong base (KOtBu) (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.
7
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,
CinnamylPd(IPr)Cl displayed higher activity than either AllylPd(IPr)Cl or CrotylPd(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-2-boronic acid (Figure 5B).
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.
8
Sterically demanding substrates: Tetra-ortho substituted biaryls have historically been difficult to
form through cross-coupling reactions.[5d] As the 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 boronic acid (Figure
6).[19] For this transformation, all of the systems examined give comparable activity, with the
exception of the unsubstituted 3-allyl precatalyst, which is slightly slower. The most likely
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.[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 attack by OH- on
the allyl-type ligand, as there is no alcoholic solvent with a -hydride and 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
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.
9
all systems. This stands in contrast to activation via a solvent assisted pathway, where the Yale
precatalyst is proposed to activate more rapidly than other allyl based systems.[10]
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 variety of non-traditional electrophiles.[1h] For example, it has been
demonstrated that palladium precatalysts can couple phenyl esters through cleavage of the Cacyl-O
bond to generate ketones as products.[20] We evaluated IPr-ligated precatalysts in a Suzuki-
Miyaura reaction between phenyl benzoate and 4-methoxy phenyl boronic acid (Figure 7).
tBuIndPd(IPr)Cl shows the highest activity with the rate of product formation being slightly slower
for CinnamylPd(IPr)Cl. Almost no conversion was observed with AllylPd(IPr)Cl or CrotylPd(IPr)Cl. The
improved performance of CinnamylPd(IPr)Cl relative to tBuIndPd(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
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, [Precatalyst] = 0.002 M, 0.2 mL H2O, 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.
10
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, tBuIndPd(NHC)Cl will
likely give the highest activity, followed by CinnamylPd(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 results
suggest that when activation occurs via a solvent assisted pathway tBuIndPd(NHC)Cl will give the
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.
Phosphine Ligands
Phosphine ligands are more commonly used in Suzuki-Miyaura reactions than NHC
ligands.[1h,2f,2g] This section compares the performance of phosphine ligated allyl-type precatalysts
for a variety of different reactions.
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 ligands used in cross-coupling) under both weak (K2CO3) and strong
(KOtBu) base conditions (Figure 9). Similar to results found with NHC ligands, tBuIndPd(XPhos)Cl
gives the highest activity, which is likely due to its more rapid activation in methanol, via a solvent
assisted pathway (Figure 3).[10] In this case, palladium(I) dimer formation is unlikely to be a
significant factor in catalysis as previous results from Colacot, suggest that XPhos is too sterically
Figure 8: Decision tree for selecting NHC ligated precatalysts.
11
bulky to allow dimer formation.[6e] Consistent with this proposal, the less sterically bulky
CrotylPd(XPhos)Cl outperforms CinnamylPd(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
Figure 9: Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid with K2CO3 (A), KOtBu (B), and K3PO4 (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 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.
12
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, K3PO4, in order to prevent activation via a solvent 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 evaluated the relative performance of precatalysts supported by SPhos, RuPhos, and PtBu3
(see SI). As the ancillary ligand was changed, tBuIndPd(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. 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 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.
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. Although tBuIndPd(XPhos)Cl is
still the most active system, CrotylPd(XPhos)Cl is the least active. AllylPd(XPhos)Cl is the second
most active and gives slightly superior activity to CinnamylPd(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 ligand (vide supra).[6e]
To further evaluate the effect of heteroatoms, we performed a coupling reaction between 2-
chlorothiophene and 3-furan boronic acid (Figure 11). To our surprise, CrotylPd(XPhos)Cl and
CinnamylPd(XPhos)Cl give the best activity, followed by AllylPd(XPhos)Cl and tBuIndPd(XPhos)Cl.
We propose 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
13
3-furan boronic acid is used as a substrate, we hypothesize that the heteroatom assists activation
via a pathway involving transmetallation and reductive elimination by facilitating pre-coordination
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.
Figure 10: Yield versus time for the Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine
and benzo[b]furan-2-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.
14
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 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 examined the coupling
of 2-chloro-4,6-dimethoxypyrimidine and 2-furan boronic acid, which allows direct comparison
to the reaction of 2-chloro-4,6-dimethoxypyrimidine and the less coordinating benzo[b]furan-2-
boronic acid (Figure 12). As expected, for tBuIndPd(XPhos)Cl, there is relatively 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 catalysis. In contrast, for CrotylPd(XPhos)Cl and
CinnamylPd(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 that we do not understand at this stage, AllylPd(XPhos)Cl did not give a significantly higher
yield with 2-furan boronic acid compared to benzo[b]furan-2-boronic acid, although we note that
it is often difficult to understand the performance of the unsubstituted system. Overall,
CrotylPd(XPhos)Cl and CinnamylPd(XPhos)Cl are the most active precatalysts for the coupling of 2-
furan boronic acid but tBuIndPd(XPhos)Cl is the most active precatalyst for the coupling of
benzo[b]furan-2-boronic acid. This set of experiments introduces another variable in assessing the
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.
15
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.
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.[21] We examined our series of precatalysts in the coupling of
1-naphthyl sulfamate and 4-methoxyphenyl boronic acid using reaction conditions previously
described in the literature (Figure 13).[22] The only precatalyst that achieved yields above 90%
after 6 hours was tBuIndPd(XPhos)Cl. CrotylPd(XPhos)Cl was slightly more active than
CinnamylPd(XPhos)Cl, while AllylPd(XPhos)Cl only gives 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.
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.
16
The vast majority of cross-coupling reactions involve the formation of Csp2–Csp2 bonds, but there
is also significant interest in the formation of Csp2–Csp3 bonds, which are ubiquitous in
pharmaceuticals, using cross-coupling.[23] For example, palladium complexes supported by PtBu3
are known to be active for cross-coupling reactions between aryl halides and alkyl trifluoroborates
to generate Csp2–Csp3 bonds.[24] Here, we examined the coupling of 3-chloroanisole and potassium
sec-butyltrifluoroborate with our library of precatalysts (Figure 14). The most active system was
tBuIndPd(PtBu3)Cl. CrotylPd(PtBu3)Cl also displayed high activity, but there was a notable decrease
in yield when either CinnamylPd(PtBu3)Cl or AllylPd(PtBu3)Cl were used as precatalysts. Explaining
the relative performance of the precatalysts in this case is complicated as with the relatively less
bulky PtBu3 ligand palladium(I) dimer 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 dissociation, which generates the active
species.[9,17]
Summary: Our experiments indicate that because sterically bulky phosphine ligands, such as
XPhos, which do not allow for palladium(I) dimer formation, are commonly used to facilitate
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] = 1 M, [Precatalyst] = 0.0033 M, 0.67 mL Toluene, and 0.33 mL
H2O. Product yield was determined through comparison of product signal with an internal naphthalene
standard on a gas chromatogram with an FID detector.
17
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) dimer
formation, are the most commonly used. When activation is the dominant factor, CrotylPd(PR3)Cl
typically outperforms CinnamylPd(PR3)Cl regardless of the exact mechanism. Further,
tBuIndPd(PR3)Cl, which activates the fastest under the solvent assisted pathway, 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.
Coupling Reactions with Precatalysts Generated In Situ
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
systems. The allyl,[6b] crotyl,[6d] cinnamyl,[6d], and Yale systems,[7] have unligated dimeric
precursors (Figure 16), which can be converted into ligated precatalysts through reactions with
free ligand in situ. In this section, we compare the activity of precatalysts generated in situ from
these dimeric precursors with both NHC and phosphine ligands. Additionally, researchers often
Figure 15: Decision tree for selecting phosphine ligated precatalysts.
Figure 16: Unligated dimeric palladium(II)
precursors used for in-situ precatalyst
generation.
18
generate in situ systems for cross-coupling through the reaction of commercially available
palladium sources such as tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3),
bis(acetonitrile)palladium dichloride (Pd(CH3CN)2Cl2), and palladium acetate (Pd3(OAc)6) with
free ligand. These systems are also included in our comparison. Finally, it was recently reported
that commercially available palladium acetate often contains a nitrate impurity
(Pd3(OAc)5(NO2).[25] Here, 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(CH3CN)2Cl2 was challenging
due to their rapid generation of product (see SI). We, therefore, lowered the catalyst loading to
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.
19
0.25 mol% (Figure 17) and observed that the dimeric 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
acetate and Pd(CH3CN)2Cl2 resulted in high yields and 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 Pd2dba3 was
used as the palladium source.
We subsequently evaluated the ability of the different palladium precursors to couple 4-
chlorotoluene and phenyl boronic acid when treated with XPhos in situ (Figure 18). As for the IPr
supported systems, the trends in precatalyst performance for the in situ generated XPhos ligated
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.
20
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 crotyl system. Pd(CH3CN)2Cl2 gives comparable
activity to the cinnamyl system, and Pd2dba3 does not result in the formation of active catalyst.
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 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
Pd(CH3CN)2Cl2 as the palladium source, the yield decreased by a factor of sixteen from 64% to
4%. In contrast, when Pd3(OAc)6 is used as the palladium source, changing the ligand to metal
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.
21
ratio from 0.8 to 1.2 equivalents nearly doubled the yield from 44% to 84%. In this case, we suggest
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.[26] 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.
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 (Figure 20). Under the optimized conditions for allyl-type
precatalysts, the same trends in catalyst performance were observed for the in situ generated
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.
22
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 Pd2dba3 gives almost no activity.
Non-traditional electrophiles: To conclude this section, we evaluated the activity of our different
palladium sources in the in situ Csp2–Csp3 Suzuki-Miyaura coupling of 3-chloroanisole and
potassium 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 relatively less
active. This implies that the coordination of PtBu3 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(CH3CN)2Cl2, Pd2dba3, and palladium acetate, give low yields of
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.
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-
butyltrifluoroborate] = 0.5 M, [Base] = 1 M, [Pd] = 0.0033 M, [PtBu3] = 0.0033 M, 0.67 mL Toluene,
and 0.33 mL H2O. Product yield was determined through comparison of product signal with an internal
naphthalene standard on a gas chromatogram with an FID detector.
23
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 Pd2dba3 is commonly 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 use a well-defined system than an in situ
generated system.
Conclusions
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
24
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.
Acknowledgements
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 discussion and Dr. Damian
Hruszkewycz and Dr. Patrick Melvin for comments on the manuscript.
Additional information
Additional information about selected experiments, NMR spectra, and other details are available
via the Internet.
Competing Financial Interests
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.
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26
TOC Graphic
download fileview on ChemRxivManuscript.pdf (1.26 MiB)
S1
Supporting Information
Differences in the Performance of Allyl Based Palladium Precatalysts for
Suzuki-Miyaura Reactions
Matthew R. Espinosaa, Angelino Doppiub, and Nilay Hazaria,*
aDepartment of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut, 06520,
USA. E-mail: [email protected].
bPrecious Metals Chemistry, Umicore AG & Co. KG, Rodenbacher Chaussee 4, Hanau-
Wolfgang, Germany.
SI: Experimental Details S2
SII: Synthesis and Characterization of Precatalysts S4
SIII: Catalytic Procedures – Reactions with Well-Defined Precatalysts S8
SIV: Catalytic Procedures – In-Situ Generated Precatalysts S15
SV: Isolation and Characterization of Catalytic Products S20
SVI: Comparison of NHC and Phosphine Ligated Precatalysts in Buchwald-Hartwig
Couplings
S24
SVII: The Effects of Catalyst Loading on Suzuki-Miyaura Couplings using IPr Precatalysts S26
SVIII: NHC Ligand Effects on the Suzuki-Miyaura Coupling of Aryl Chlorides S27
SIX: The Effects of Catalyst Loading on Suzuki-Miyaura Couplings using XPhos Precatalysts S29
SX: Phosphine Ligand Effects on the Suzuki-Miyaura Coupling of Aryl Chlorides S30
SXI: Suzuki-Miyaura Coupling of Aryl Chlorides with In-Situ Generated IPr Precatalysts S32
SXII: In-situ Coupling of Aryl Chlorides with XPhos using water and K3PO4 S33
SXIII: Buchwald-Hartwig Coupling of Secondary Amines with In-Situ Generated Precatalysts S34
SXIV: Comparison of the Activity of Isolated and In-Situ Generated Precatalysts S35
SXV: Selected Spectra S40
SXVI: References S53
S2
SI. Experimental Details
All catalytic experiments were performed under an N2 atmosphere using an MBraun glovebox.
Under standard operating procedures for glovebox use: purging was not performed between uses
of pentane, benzene, toluene, diethyl ether, and THF. Solvents used in catalysis were deoxygenated
by sparging with nitrogen and dried through an activated alumina column on an Innovative
Technology Inc. system unless otherwise noted.
Methanol (99.8%, Fisher) and Isopropanol (histological grade, Fisher) were not dried but were
degassed and stored under N2 prior to use in catalysis. 4-chlorotoluene (98%, Alfa Aesar), 2-
chlorothiophene (98+%, Alfa Aesar), 2-chloro-m-xylene (97%, Alfa Aesar), and 3-chloroanisole
(98%, Alfa Aesar) were degassed through three freeze-pump-thaw cycles and then distilled under
nitrogen. 2-chloro-4,6-dimethoxypyrimidine (>98%, TCI) was sublimed and dried under vacuum
prior to use. Phenyl benzoate (99%, Alfa Aesar), phenyl boronic acid (98+%, Acros),
benzo[b]furan-2-boronic acid (98%, Alfa Aesar), 3-furan boronic acid (97%, Alfa Aesar), 2,4,6-
trimethylbenzeneboronic acid (97%, Alfa Aeasar), 4-methoxyphenylboronic acid (97%, Acros),
2-furanboronic acid (97%, Acros), potassium sec-butyltrifluoroborate (Santa Cruz), potassium
tert-butoxide (sublimed grade, 99.99% trace metals, Sigma Aldrich), naphthalene (99%, Sigma-
Aldrich), SIPr (98%, Strem Chemicals), IPr*OMe (98%, Strem Chemicals), IMes (98%, Strem
Chemicals), XPhos (98%, Strem Chemicals), SPhos (>98%, Strem Chemicals), RuPhos (98%,
Strem Chemicals), and PtBu3 (99%, Strem Chemicals) were used as received. Potassium carbonate
(anhydrous, granular, 99.8%, Mallinckrodt) was ground using a mortar and pestle and dried
overnight at 150 °C. Potassium hydroxide (pellets, >85%, Sigma-Aldrich) was ground using a
mortar and pestle prior to use.
Gas chromatography (GC) analyses were performed using a Shimadzu GC-2010 Plus equipped
with a flame ionization detector and SHRXI-5MS column (30m, 250 mm inner diameter, 0.25 mm
film). The following conditions were utilized for GC analyses: flow rate 1.23 mL/min constant
flow, column temperature 50 °C (held for 5 min), 20 °C /min increase to 300 °C (held for 5 min),
total time 22.5 min.
Deuterated solvents were obtained from Cambridge Isotope Laboratories and used as received.
NMR spectra were taken on Agilent DD2 -400, -500, -600 spectrometers at ambient probe
temperatures. Chemical shifts for 1H and 13C{1H} NMR spectra are reported in ppm and referenced
to residual internal protio solvent. Chemical shifts for 31P{1H} NMR spectra are referenced using
S3
1H resonances based on relative gyromagnetic ratios of the nuclei.[1] Synthetic procedures for
tBuIndPd(L)Cl (L = SIPr, IMes), CinnamylPd(PtBu3)Cl, CrotylPd(L)Cl (L = SIPr, IPr*OMe, IMes), and
AllylPd(IPr*OMe)Cl can be found below. 1-naphthyl sulfamate[2], IPr[3], tBuIndPd(L)Cl (L = IPr,
IPr*OMe, XPhos, SPhos, RuPhos, PtBu3)[4], CinnamylPd(L)Cl (L = IPr[5], SIPr[5], IPr*OMe[6],
IMes[7], XPhos[8], SPhos[8], RuPhos[8]), CrotylPd(L)Cl (L = IPr[5], XPhos[8], SPhos[8], RuPhos[8],
PtBu3[9]), and AllylPd(L)Cl (L = IPr[10], SIPr[10], IMes[10], XPhos[8], SPhos[8], RuPhos[8], PtBu3
[9])
were synthesized according to literature procedures.
S4
SII. Synthesis and Characterization of Precatalysts
tBuIndPd(IMes)Cl
(tBuIndPdCl)2 (98.0 mg, 0.156 mmol) and IMes (100.0 mg, 0.329 mmol, 2.1 equiv.) were added to
a 100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the solids under N2.
The reaction was stirred for 1 hour at which time it became homogenous. The resulting dark red
solution was exposed to air and passed through a pad of silica. THF was then removed under
vacuum to yield a red oil. This oil was triturated in hexanes to yield a bright orange powder with
a yellow supernatant. The orange powder was collected through filtration and washed with hexanes
(3 x 10 mL) (154.3 mg, 80% yield). 1H NMR (C6D6, 600 MHz) 7.14 (d, 2H, IndH, 3JHH= 7.6
Hz), 6.79 (t, IndH, 3JHH = 7.6 Hz), 6.78 (s, IMesH), 6.68 (s, IMesH), 6.61 (t, IndH, 3JHH= 7.5 Hz),
6.49 (d, IndH, 3JHH= 7.4 Hz), 6.14 (s, IMesH), 6.01 (d, IndH, 3JHH = 2.8 Hz), 4.97 (d, IndH, 3JHH =
2.3 Hz), 2.20 (s, IMesCH3), 2.14 (s, IMesCH3), 2.11 (s, IMesCH3), 1.46 (s, IndC(CH3)3). 13C{1H}
NMR (C6D6, 151 Hz) 174.57, 139.35, 138.92, 138.68, 136.57, 135.96, 135.66, 129.31, 129.22,
125.14, 123.14, 123.05, 119.76, 117.48, 115.29, 107.93, 64.04, 34.23, 29.70, 21.07, 18.87, 18.58.
tBuIndPd(SIPr)Cl
(tBuIndPdCl)2 (76.3 mg, 0.122 mmol) and SIPr (100.0 mg, 0.256 mmol, 2.1 equiv.) were added to a
100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the solids under N2.
The reaction was stirred for 1 hour at which time it became homogenous. The resulting dark red
solution was exposed to air and passed through a pad of silica. THF was then removed under
vacuum to yield a red oil. This oil was triturated in hexanes to yield a bright orange powder with
a yellow supernatant. The orange powder was collected through filtration and washed with hexanes
(3 x 10 mL) (125.0 mg, 73% yield). 1H NMR (C6D6, 600 MHz) 7.26 (d, 1H, IndH, 3JHH = 7.7
Hz), 7.23 (t, 2H, SIPrH, 3JHH = 7.7 Hz), 7.15 (obscured by solvent, 2 H, SIPrH), 7.07 (d, 2H, SIPrH,
3JHH = 7.6 Hz), 6.81 (t, 1H, IndH, 3JHH = 7.5 Hz), 6.40 (t, 1H, IndH, 3JHH = 7.4 Hz), 6.07 (d, IndH,
3JHH = 2.7 Hz), 5.84 (d, 1H, IndH, 3JHH = 7.4 Hz), 5.20 (d, 1H, IndH, 3JHH = 2.6 Hz), 3.65 (br, 2H,
SIPrCH2), 3.56 (m, 2H, SIPrCH(CH3)2), 3.44 (m, SIPrCH(CH3)2), 1.57 (d, 6H, SIPrCH(CH3)2,
3JHH = 6.3 Hz), 1.42 (s, 9H, IndC(CH3)3), 1.18 (d, 6H, SIPrCH(CH3)2, 3JHH = 6.2 Hz), 1.14 (d, 6H,
SIPrCH(CH3)2, 3JHH = 6.9 Hz), 1.07(d, 6H, SIPrCH(CH3)2,
3JHH = 6.9 Hz). 13C{1H} NMR (C6D6,
151 Hz) 206.61, 139.29, 138.96, 137.16, 129.24, 124.67, 124.54, 124.26, 119.37, 116.97, 115.98,
107.43, 63.96, 53.71, 34.46, 34.23, 29.84, 28.87, 26.70, 26.46, 24.39, 23.48, 22.75, 14.30.
S5
CinnamylPd(PtBu3)Cl
(CinnamylPdCl)2 (61.1 mg, 0.118 mmol) and PtBu3 (0.30 L, 0.25 mmol, 2.1 equiv.) were added to
a 100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the reaction under
N2. The reaction was stirred for 1 hour, at which time it became homogenous. The resulting yellow
solution was exposed to air, and the volatiles were removed under vacuum to yield a yellow oil.
This oil was triturated in hexanes to yield a yellow powder with a clear supernatant. The yellow
powder was collected through filtration and washed with hexanes (3 x 10 mL) (65.0 mg, 60%
yield). 1H NMR (CDCl3, 600 MHz) m, 2H, Cinnamyl-PhH), 7.34 (m, 2H, Cinnamyl-PhH),
5.80 (m, 1H, CinnamylH), 5.23 (m, 1H, CinnamylH), 4.02 (br, 1H, CinnamylH), 2.83z (br, 1H,
CinnamylH), 1.55 (d, PC(CH3)3, 3JHH = 12.3 Hz). 31P NMR (CDCl3, 202 MHz) 13C{1H}
NMR (CDCl3, 600 MHz) , 128.69, 128.67, 128.36, 128.34, 128.11,
127.96, 127.79, 107.31, 103.17, 103.01, 52.02, 39.86, 39.83, 33.06, 33.02, 30.26.
CrotylPd(SIPr)Cl
(CrotylPdCl)2 (24.0 mg, 0.0610 mmol) and SIPr (50.0 mg, 0.128 mmol, 2.1 equiv.) were added to a
100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the reaction under N2.
The reaction was stirred for 1 hour at which time it became homogenous. The resulting colorless
solution was exposed to air and passed through a pad of silica. THF was then removed under
vacuum to yield a colorless oil. This oil was triturated in hexanes to yield a colorless powder with
a clear supernatant. The colorless powder was collected through filtration and washed with
hexanes (3 x 10 mL) (84.9 mg, 78% yield). 1H NMR (C6D6, 600 MHz) 7.13 (d, 2H, SIPrH, 3JHH
= 7.6 Hz), 7.08 (t, 4H, SIPrH, 3JHH = 7.4 Hz), 4.31 (m, 1H, CrotylH), 3.69 (2H, SIPr-CH(CH3)2),
3.59 (m, 6H, SIPr-CH(CH3)2 and SIPr-CH2), 3.36 (m, 1H, CrotylH), 2.79 (d, 1H, CrotylH, 3JHH =
6.6 Hz), 1.51 (m, 12H, SIPr-CH(CH3)2), 1.35 (d, 4H, CrotylCH3 and CrotylH, 3JHH = 6.6 Hz), 1.16
(m, 12H, SIPr-CH(CH3)2). 13C{1H} NMR (C6D6, 151 Hz) 215.57, 147.71, 147.54, 137.07,
129.36, 124.49, 113.36, 90.53, 54.05, 44.86, 28.82, 28.79, 26.66, 26.62, 24.22, 23.98, 17.01.
CrotylPd(IPr*OMe)Cl
(CrotylPdCl)2 (19.9 mg, 0.0504 mmol) and IPr*OMe (100.0 mg, 0.106 mmol, 2.1 equiv.) were added
to a 100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the reaction under
N2. The reaction was stirred for 1 hour at which time it became homogenous. The resulting
colorless solution was exposed to air and passed through a pad of silica. THF was then removed
S6
under vacuum to yield a colorless oil. This oil was triturated in hexanes to yield a colorless powder
with a clear supernatant. The colorless powder was collected through filtration and washed with
hexanes (3 x 10 mL) (107.0 mg, 93% yield). 1H NMR (C6D6, 600 MHz) 7.69 (m, 8H, IPr*OMe-
ArH), 7.14 (m 8H, IPr*OMe-ArH), 7.01 (m, 12H, IPr*OMe-ArH), 6.90 (m, 8H, IPr*OMe-ArH),
6.84 (m, 8H, IPr*OMe-ArH), 6.41 (s, 2H, IPr*OMe-CH(CPh)2), 6.27 (s, 2H, IPr*OMe-
CH(CPh)2), 5.39 (s, 2H, IPr*OMe-CH), 4.53 (m, 1H, CrotylH), 3.87 (m, 1H, CrotylH), 3.04 (s,
6H, IPr*OMe-ArOCH3), 2.75 (d, 1H, CrotylH), 1.83 (d, 3H, CrotylCH3), 1.43 (d, 1H, CrotylH)
13C{1H} NMR (C6D6, 151 Hz) , 144.32, 144.22, 144.19, 144.16,
132.28, 131.18, 131.10, 129.80, 129.74, 128.59, 128.55, 128.47, 126.89, 126.66, 123.54, 115.22,
114.13, 89.47, 54.51, 52.21, 46.32, 17.46.
CrotylPd(IMes)Cl
(CrotylPdCl)2 (61.5 mg, 0.156 mmol) and IMes (100.0 mg, 0.329 mmol, 2.1 equiv.) were added to
a 100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the reaction under
N2. The reaction was stirred for 1 hour at which time it became homogenous. The resulting
colorless solution was exposed to air and passed through a pad of silica. THF was then removed
under vacuum to yield a colorless oil. This oil was triturated in hexanes to yield a colorless powder
with a clear supernatant. The colorless powder was collected through filtration and washed with
hexanes (3 x 10 mL) (111.4 mg, 71% yield). 1H NMR (C6D6, 600 MHz) 6.76 (s, 2H, IMesH),
6.73 (s, 2H, IMesH), 6.21 (s, 2H, IMesH), 4.45 (m, 1H, CrotylH), 3.42 (m, 1H, CrotylH), 2.94 (d,
1H, CrotylH, 3JHH = 6.6 Hz), 2.30 (s, 6H, IMesCH3), 2.25 (s, 6H, IMesCH3), 2.04 (s, 6H,
IMesCH3), 1.34 (d, 3H, CrotylCH3 3JHH = 6.2 Hz). 13C{1H} NMR (C6D6, 151 Hz) 186.07, 138.77,
136.73, 135.96, 135.90, 129.34, 129.28, 122.63, 112.82, 90.21, 43.48, 21.07, 18.60, 18.50, 16.86.
AllylPd(IPr*OMe)Cl
(AllylPdCl)2 (18.4 mg, 0.0504 mmol) and IPr*OMe (100.0 mg, 0.106 mmol, 2.1 equiv.) were added
to a 100 mL round bottom equipped with a stir bar. THF (40 mL) was added to the reaction under
N2. The reaction was stirred for 1 hour at which time it became homogenous. The resulting
colorless solution was exposed to air and passed through a pad of silica. THF was then removed
under vacuum to yield a colorless oil. This oil was triturated in hexanes to yield a colorless powder
with a clear supernatant. The colorless powder was collected through filtration and washed with
hexanes (3 x 10 mL) (88.9 mg, 78% yield). 1H NMR (C6D6, 600 MHz) 7.65 (m, 8H, IPr*OMe-
S7
ArH), 7.14-7.08 (m, 8H, IPr*OMe-ArH), 7.04-6.98 (m, 12 H, IPr*OMe-ArH), 6.93-6.80 (m, 16H,
IPr*OMe-ArH), 6.36 (d, 4H, IPr*OMe-CH(CPh)2, 3JHH = 13.8 Hz), 5.34 (s, 2H, IPr*OMe-CH),
4.66 (m, 1H, AllylH), 4.26 (d, 1H, AllylH, 3JHH = 7.3 Hz), 3.17 (d, 1H, AllylH, 3JHH = 13.4 Hz),
3.05 (s, 6H, IPr*Ome-OCH3), 2.93 (d, 1H, AllylH, 3JHH = 6.0 Hz), 152 (d, 1H, AllylH, 3JHH = 12.2
Hz). 13C{1H} NMR (C6D6, 151 Hz) 187.00, 159.74, 144.97, 144.55, 144.33, 144.11, 144.03,
132.14, 131.12, 131.05, 129.81, 129.79, 128.58, 128.55, 128.54, 128.51, 126.92, 126.90, 126.73,
126.63, 123.57, 115.36, 115.19, 114.79, 71.82, 54.55, 52.23, 52.09, 51.10.
S8
SIII. Catalytic Procedures – Reactions with Well-Defined Precatalysts
Suzuki-Miyaura Coupling of Simple Substrates
1) Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using K2CO3 (Procedure
for Figure 4A and Figure 9A)
Under air, K2CO3 (76.0mg, 0.55 mmol) was added to 10 one-dram vials, each equipped with a stir
bar. These vials were then moved into a N2 glovebox. In the glovebox, 59 L of 4-chlorotoluene
(0.5 mmol) and 0.95 mL of a MeOH stock solution containing phenyl boronic acid (0.579 M) and
naphthalene (0.211 M) was added to each vial. 0.05 mL of THF containing precatalyst (0.0500 M)
was added to the vials, and they were subsequently sealed with a Teflon cap. The vials were then
added to an aluminum block and allowed to stir at room temperature in the glove box. Hourly
timepoints were taken by removing the Teflon cap and taking 100 L of the catalytic mixture using
a 1 mL syringe. The aliquots were purified through pipet filters containing silica and eluted with
ethyl acetate directly into GC vials. Yields were determined by comparing the GC response of
product to the internal naphthalene standard. Each precatalyst was run in duplicate, and the average
yield reported.
2) Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using KOtBu (Procedure
for Figure 4B and Figure 9B, Figure S3*, Figure S4, Figure S5*, Figure S6)
In an N2 glovebox, 59 L of 4-chlorotoluene (0.5 mmol) and 0.95 mL of a MeOH stock solution
containing phenyl boronic acid (0.579 M), KOtBu (0.579 M), and naphthalene (0.211 M) was
added to 10 different one-dram vials each equipped with a magnetic stir bar. 0.05 mL of THF
containing precatalyst (0.0500 M) was added to the vials, and they were subsequently sealed with
a Teflon cap. The vials were then added to an aluminum block and allowed to stir at room
temperature in the glove box. Hourly timepoints were taken by removing the Teflon cap and taking
100 L of the catalytic mixture using a 1 mL syringe. The aliquots were purified through pipet
filters containing silica and eluted with ethyl acetate directly into GC vials. Yields were determined
S9
by comparing the GC response of product to the internal naphthalene standard. Each precatalyst
was run in duplicate, and the average yield reported.
*To generate the data reported in Figures S3 and S5 the procedure was modified, so the catalyst
loading was 0.1 mol%.
3) Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using water and K3PO4
(Procedure for Figure 9C)
In an N2 glovebox, 59 L of 4-chlorotoluene (0.5 mmol) and 0.66 mL of a H2O stock solution
containing phenyl boronic acid (0.833 M) and K3PO4 (1.52 M) was added to 10 different one-dram
vials each equipped with a magnetic stir bar. 0.33 mL of THF containing precatalyst (0.00758 M)
and naphthalene (0.606 M) was added to the vials, and they were subsequently sealed with a Teflon
cap. The vials were then added to an aluminum block and allowed to stir at room temperature in
the glove box. Timepoints were taken by removing the Teflon cap and taking 100 L of the
catalytic mixture using a 1 mL syringe. The aliquots were purified through pipet filters containing
silica and eluted with ethyl acetate directly into GC vials. Yields were determined by comparing
the GC response of product to the internal naphthalene standard. Each precatalyst was run in
duplicate, and the average yield reported.
Suzuki-Miyaura Coupling of Heteroaromatic Substrates
4) Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-2-boronic
acid (Procedure for Figure 5A, Figure 10 and, Figure 12)
Under air, K2CO3 (83.0mg, 0.60 mmol) was added to 10 one-dram vials, each equipped with a stir
bar. These vials were then moved into a N2 glovebox. In the glovebox, 0.66 mL of a MeOH stock
solution containing benzo[b]furan-2-boronic acid (0.682 M) and naphthalene (0.303 M) and 0.17
mL of THF containing 2-chloro-4,6-dimethoxypyrimidine (1.76 M) were added to the vials. 0.17
mL of THF containing precatalyst (0.00176 M) was added to the vials, and they were subsequently
sealed with a Teflon cap. The vials were then added to an aluminum block and allowed to stir at
S10
room temperature in the glove box. Timepoints were taken by removing the Teflon cap and taking
100 L of the catalytic mixture using a 1 mL syringe. The aliquots were purified through pipet
filters containing silica and eluted with ethyl acetate directly into GC vials. Yields were determined
by comparing the GC response of product to the internal naphthalene standard. Each precatalyst
was run in duplicate, and the average yield reported.
5) Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-2-boronic
acid (Procedure for Figure 12)
Under air, K2CO3 (83.0mg, 0.60 mmol) was added to 10 one-dram vials, each equipped with a stir
bar. These vials were then moved into a N2 glovebox. In the glovebox, 0.66 mL of a MeOH stock
solution containing furan-2-boronic acid (0.682 M) and naphthalene (0.303 M) and 0.17 mL of
THF containing 2-chloro-4,6-dimethoxypyrimidine (1.76 M) were added to the vials. 0.17 mL of
THF containing precatalyst (0.00176 M) was added to the vials, and they were subsequently sealed
with a Teflon cap. The vials were then added to an aluminum block and allowed to stir at room
temperature in the glove box. The reaction was stopped at 3 hours by opening the Teflon caps and
exposing the reaction to air. The catalytic mixture was diluted in ethyl acetate and run through a
pipet filters containing silica directly into GC vials. Yields were determined by comparing the GC
response of product to the internal naphthalene standard. Each precatalyst was run in duplicate,
and the average yield reported.
6) Suzuki-Miyaura coupling of 2-chlorothiophene and furan-3-boronic acid (Procedure for Figure
5B and Figure 11)
Under air, K2CO3 (83.0 mg, 0.6 mmol) was added to 10 one-dram vials, each equipped with a stir
bar. These vials were then moved into a N2 glovebox. In the glovebox, 27.6 L of 2-
chlorothiophene (0.300 mmol) and 0.66 mL of a MeOH stock solution containing 3-furan boronic
acid (0.682 M) and naphthalene (0.303 M) was added to each vial. 0.33 mL of THF containing
precatalyst (0.00455 M) was added to the vials, and they were subsequently sealed with a Teflon
S11
cap. The vials were then added to an aluminum block and allowed to stir at room temperature in
the glove box. Timepoints were taken by removing the Teflon cap and taking 100 L of the
catalytic mixture using a 1 mL syringe. The aliquots were purified through pipet filters containing
silica and eluted with ethyl acetate directly into GC vials. Yields were determined by comparing
the GC response of product to the internal naphthalene standard. Each precatalyst was run in
duplicate, and the average yield reported.
Suzuki-Miyaura Coupling of Tetra-Ortho Substituted Substrates
7) Suzuki-Miyaura coupling of 2-chloro-m-xylene and 2,4,6-trimethylbenzeneboronic acid
(Procedure for Figure 6)
Under air, KOH (28.0 mg, 0.5 mmol) and 2,4,6-trimethylbenzeneboronic acid (66.0, 0.375 mmol)
were added to 10 one-dram vials each equipped with a stir bar. These vials were then moved into
a N2 glovebox. In the glovebox, 33.0 L of 2-chloro-m-xylene (0.250 mmol) and 1 mL of a THF
stock solution containing precatalyst (0.00150 M) and naphthalene (0.200 M) was added to the
vials, and they were subsequently sealed with a Teflon cap. The vials were then added to an
aluminum block that had been preheated to 40 °C and allowed to stir in the glove box. Timepoints
were taken by removing the Teflon cap and taking 100 L of the catalytic mixture using a 1 mL
syringe. The aliquots were purified through pipet filters containing silica and eluted with ethyl
acetate directly into GC vials. Yields were determined by comparing the GC response of product
to the internal naphthalene standard. Each precatalyst was run in duplicate, and the average yield
reported.
Suzuki-Miyaura Coupling of Phenyl Esters
8) Suzuki-Miyaura coupling of phenyl benzoate and 4-methoxyphenyl boronic acid (Procedure for
Figure 7)
S12
In an N2 glovebox, 0.2 mL of a H2O stock solution containing 4-methoxyphenyl boronic acid (1.50
M) and KOH (2.00 M) was added to 10 different one-dram vials each equipped with a magnetic
stir bar. 0.8 mL of THF containing precatalyst (0.00250 M), naphthalene (0.250 M), and phenyl
benzoate (0.250 M) was added to the vials, and they were subsequently sealed with a Teflon cap.
The vials were then added to an aluminum block and allowed to stir at room temperature in the
glove box. Timepoints were taken by removing the Teflon cap and taking 100 L of the catalytic
mixture using a 1 mL syringe. The aliquots were purified through pipet filters containing silica
and eluted with ethyl acetate directly into GC vials. Yields were determined by comparing the GC
response of product to the internal naphthalene standard. Each precatalyst was run in duplicate,
and the average yield reported.
Suzuki-Miyaura Coupling of Aryl Sulfamates
9) Suzuki-Miyaura coupling of 1-naphthyl sulfamate and 4-methoxyphenyl boronic (Procedure for
Figure 13)
Under air, K2CO3 (27.6 mg, 0.2 mmol) was added to 10 one-dram vials, each equipped with a stir
bar. These vials were then moved into a N2 glovebox. In the glovebox, 0.33 mL of a MeOH stock
solution containing 4-methoxyphenyl boronic acid (0.455 M) was added to each vial. 0.66 mL of
toluene containing precatalyst (0.00379 M), 1-naphthyl sulfamate (0.152 M), and naphthalene
(0.303 M) was added to the vials, and they were subsequently sealed with a Teflon cap. The vials
were then added to an aluminum block and allowed to stir at room temperature in the glove box.
Timepoints were taken by removing the Teflon cap and taking 100 L of the catalytic mixture
using a 1 mL syringe. The aliquots were purified through pipet filters containing silica and eluted
with ethyl acetate directly into GC vials. Yields were determined by comparing the GC response
of product to the internal naphthalene standard. Each precatalyst was run in duplicate, and the
average yield reported.
Suzuki-Miyaura Coupling of sp3 Hybridized Boronic Acids
10) Suzuki-Miyaura coupling of 3-chloroanisole and potassium sec-butyltrifluoroborate
(Procedure for Figure 14)
S13
Under air, potassium sec-butyltrifluoroborate (81.0 mg, 0.495 mmol) was added to 10 one-dram
vials, each equipped with a stir bar. These vials were then moved into a N2 glovebox. In the
glovebox, 40.4 mL of 3-chloroanisole (0.33 mmol) and 0.33 mL of a H2O stock solution containing
K2CO3 (3.00 M) were added to each vial. 0.66 mL of toluene containing precatalyst (0.00500 M)
and naphthalene (0.303 M) was added to the vials, and they were subsequently sealed with a Teflon
cap. The vials were then added to an aluminum block that had been preheated to 80 °C and allowed
to stir in the glove box. Timepoints were taken by removing the Teflon cap and taking 100 L of
the catalytic mixture using a 1 mL syringe. The aliquots were purified through pipet filters
containing silica and eluted with ethyl acetate directly into GC vials. Yields were determined by
comparing the GC response of product to the internal naphthalene standard. Each precatalyst was
run in duplicate, and the average yield reported.
Buchwald-Hartwig Coupling of Secondary Amines
11) Buchwald-Hartwig coupling of 2-chloroanisole and morpholine with IPr ligated precatalysts
(Procedure for Figure S1)
In an N2 glovebox, 122 L of 2-chloroanisole (1.00 mmol), 104 L of morpholine (1.20 mmol)
and 0.5 mL of a THF stock solution containing NaOtBu (2.40 M) and naphthalene (0.400 M) was
added to 10 different one-dram vials each equipped with a magnetic stir bar. 0.5 mL of THF
containing precatalyst (0.005 M) was added to the vials, and they were subsequently sealed with a
Teflon cap. The vials were then added to an aluminum block that had been preheated to 50 °C and
allowed to stir in the glove box. Timepoints were taken by removing the Teflon cap and taking
100 L of the catalytic mixture using a 1 mL syringe. The aliquots were purified through pipet
filters containing silica and eluted with ethyl acetate directly into GC vials. Yields were determined
by comparing the GC response of product to the internal naphthalene standard. Each precatalyst
was run in duplicate, and the average yield reported.
S14
12) Buchwald-Hartwig coupling of 2-chloroanisole and morpholine with RuPhos ligated
precatalysts (Procedure for Figure S2)
In an N2 glovebox, 122 L of 2-chloroanisole (1.00 mmol), 104 L of morpholine (1.20 mmol)
and 0.5 mL of a THF stock solution containing NaOtBu (2.40 M) and naphthalene (0.400 M) was
added to 10 different one-dram vials each equipped with a magnetic stir bar. 0.5 mL of THF
containing precatalyst (0.005 M) and RuPhos (0.005 M) was added to the vials, and they were
subsequently sealed with a Teflon cap. The vials were then added to an aluminum block that had
been preheated to 50 °C and allowed to stir in the glove box. Timepoints were taken by removing
the Teflon cap and taking 100 L of the catalytic mixture using a 1 mL syringe. The aliquots were
purified through pipet filters containing silica and eluted with ethyl acetate directly into GC vials.
Yields were determined by comparing the GC response of product to the internal naphthalene
standard. Each precatalyst was run in duplicate, and the average yield reported.
S15
SIV. Catalytic Procedures – In-Situ Generated Precatalysts
Suzuki-Miyaura Coupling of Simple Substrates
13) Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using in-situ generated
IPr precatalysts (Procedure for Figure 17 and Figure S7*)
In an N2 glovebox, 59 L of 4-chlorotoluene (0.5 mmol) and 0.95 mL of an MeOH stock solution
containing phenyl boronic acid (0.579 M), KOtBu (0.579 M), and naphthalene (0.211 M) were
added to 18 different one-dram vials each equipped with a magnetic stir bar. 0.2 mL of THF
containing IPr (0.025 M) was added to 9 different one-dram vials containing 0.005 mmol of Pd.
After 10 minutes, 0.05 mL of THF containing in-situ generated precatalyst was transferred to the
18 one-dram vials containing 0.95 mL of MeOH. The vials were then sealed with Teflon caps and
added to an aluminum block where they stirred at room temperature in the glove box. Timepoints
were taken by removing the Teflon cap and taking 100 L of the catalytic mixture using a 1 mL
syringe. The aliquots were purified through pipet filters containing silica and eluted with ethyl
acetate directly into GC vials. Yields were determined by comparing the GC response of product
to the internal naphthalene standard. Each precatalyst was run in duplicate, and the average yield
reported.
*To generate the data reported in Figure S7 the procedure was modified so the catalyst loading
was 0.5 mol%.
14) Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using in-situ generated
XPhos precatalysts (Procedure for Figure 18 and Figure 19*)
In an N2 glovebox, 59 L of 4-chlorotoluene (0.5 mmol) and 0.95 mL of an MeOH stock solution
containing phenyl boronic acid (0.579 M), KOtBu (0.579 M), and naphthalene (0.211 M) were
added to 18 different one-dram vials each equipped with a magnetic stir bar. 0.2 mL of THF
containing XPhos (0.05 M) was added to 9 different one-dram vials containing 0.01 mmol of Pd.
After 10 minutes, 0.05 mL of THF containing in-situ generated precatalyst was transferred to the
S16
18 one-dram vials containing 0.95 mL of MeOH. The vials were then sealed with Teflon caps and
added to an aluminum block where they stirred at room temperature in the glove box. Timepoints
were taken by removing the Teflon cap and taking 100 L of the catalytic mixture using a 1 mL
syringe. The aliquots were purified through pipet filters containing silica and eluted with ethyl
acetate directly into GC vials. Yields were determined by comparing the GC response of product
to the internal naphthalene standard. Each precatalyst was run in duplicate, and the average yield
reported.
*For the ligand titration experiment (Figure 17): The same procedure (vide supra) was used with
the exception of the XPhos concentration. The concentration of XPhos added to each palladium
source was 0.04 M and 0.06 M for 0.4 mol% and 0.6 mol% XPhos, respectively.
15) Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid using in-situ generated
XPhos precatalysts with water and K3PO4 (Procedure for Figure S8)
In an N2 glovebox, 59 L of 4-chlorotoluene (0.5 mmol) and 0.66 mL of a H2O stock solution
containing phenyl boronic acid (0.833 M) and K3PO4 (1.52 M) was added to 10 different one-dram
vials each equipped with a magnetic stir bar. 1 mL of THF containing XPhos (0.00758 M) and
naphthalene (0.606 M) was added to 9 different one-dram vials containing 0.00758 mmol Pd. After
10 minutes, 0.33 mL of THF containing in-situ generated precatalyst was transferred to the 18 one-
dram vials containing the substrates. The vials were then sealed with Teflon caps and added to an
aluminum block where they stirred at room temperature in the glove box. The reaction was stopped
after 1 hour by opening the Teflon caps and exposing the reaction to air. The catalytic mixture was
diluted in ethyl acetate and run through a pipet filters containing silica directly into GC vials.
Yields were determined by comparing the GC response of product to the internal naphthalene
standard. Each precatalyst was run in duplicate, and the average yield reported.
S17
Suzuki-Miyaura Coupling of Heteroaromatic Substrates
16) Suzuki-Miyaura coupling of 2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-2-boronic
acid with in-situ generated XPhos precatalysts (Procedure for Figure 20A)
Under air, K2CO3 (83.0 mg, 0.6 mmol) was added to 18 one-dram vials, each equipped with a stir
bar. In an N2 glovebox, 0.66 mL of an MeOH stock solution containing benzo[b]furan-2-boronic
acid (0.682 M), and naphthalene (0.303 M) and 0.17 mL of THF stock solution containing 2-
chloro-4,6-dimethoxypyrimidine (1.76 M) were added to 18 different one-dram vials each
equipped with a magnetic stir bar. 2 mL of THF containing XPhos (0.00176 M) was added to 9
different one-dram vials containing 0.00353 mmol of Pd. After 10 minutes, 0.17 mL of THF
containing in-situ generated precatalyst was transferred to the 18 one-dram vials containing 0.66
mL of MeOH. The vials were then sealed with Teflon caps and added to an aluminum block where
they stirred at room temperature in the glove box. The reaction was stopped after 30 minutes by
opening the Teflon caps and exposing the reaction to air. The catalytic mixture was diluted in ethyl
acetate and run through a pipet filters containing silica directly into GC vials. Yields were
determined by comparing the GC response of product to the internal naphthalene standard. Each
precatalyst was run in duplicate, and the average yield reported.
17) Suzuki-Miyaura coupling of 2-chlorothiophene and 3-furan boronic acid with in-situ generated
XPhos precatalysts (Procedure for Figure 20B)
Under air, K2CO3 (83.0 mg, 0.6 mmol) was added to 18 one-dram vials, each equipped with a stir
bar. In an N2 glovebox, 27.6 L of 2-chlorothiophene (0.3 mmol) and 0.66 mL of an MeOH stock
solution containing 3-furan boronic acid (0.682 M), and naphthalene (0.303 M) were added to 18
different one-dram vials each equipped with a magnetic stir bar. 2 mL of THF containing XPhos
(0.00455 M) was added to 9 different one-dram vials containing 0.00909 mmol of Pd. After 10
minutes, 0.33 mL of THF containing in-situ generated precatalyst was transferred to the 18 one-
dram vials containing 0.66 mL of MeOH. The vials were then sealed with Teflon caps and added
S18
to an aluminum block where they stirred at room temperature in the glove box. The reaction was
stopped after 1 hour by opening the Teflon caps and exposing the reaction to air. The catalytic
mixture was diluted in ethyl acetate and run through a pipet filters containing silica directly into
GC vials. Yields were determined by comparing the GC response of product to the internal
naphthalene standard. Each precatalyst was run in duplicate, and the average yield reported.
Suzuki-Miyaura Coupling of sp3 Hybridized Boronic Acids
18) Suzuki-Miyaura coupling of 3-chloroanisole and potassium sec-butyltrifluoroborate using in-
situ generated PtBu3 precatalysts (Procedure for Figure 21)
Under air, potassium sec-butyltrifluoroborate (81.0 mg, 0.495 mmol) was added to 18 one-dram
vials, each equipped with a stir bar. These vials were then moved into a N2 glovebox. In the
glovebox, 40.4 mL of 3-chloroanisole (0.33 mmol) and 0.33 mL of a H2O stock solution containing
K2CO3 (3.00 M) were added to each vial. 2 mL of toluene containing PtBu3 (0.00500 M) and
naphthalene (0.303 M) was added to 9 different one-dram vials containing 0.0100 mmol of Pd.
After 10 minutes, 0.66 mL of toluene containing in-situ generated precatalyst was transferred to
the 18 one-dram vials containing 0.33 mL of H2O. The vials were then sealed with Teflon caps
and added to an aluminum block that was preheated to 80 °C where they stirred at room
temperature in the glove box. The reaction was stopped after 8 hours by opening the Teflon caps
and exposing the reaction to air. The catalytic mixture was diluted in ethyl acetate and run through
a pipet filters containing silica directly into GC vials. Yields were determined by comparing the
GC response of product to the internal naphthalene standard. Each precatalyst was run in duplicate,
and the average yield reported.
19) Buchwald-Hartwig Coupling of 2-chloroanisole and morpholine with in-situ generated
RuPhos precatalysts (Procedure for Figure S9)
S19
In an N2 glovebox, 122 L of 2-chloroanisole (1.00 mmol), 104 L of morpholine (1.20 mmol)
and 0.5 mL of a THF stock solution containing NaOtBu (2.40 M) and naphthalene (0.400 M) was
added to 10 different one-dram vials each equipped with a magnetic stir bar. 2 mL of THF
containing RuPhos (0.01 M) was added to 9 different one-dram vials containing 0.0100 mmol of
Pd. After 10 minutes, 0.5 mL of THF containing in-situ generated precatalysts was transferred to
the 18 one-dram vials containing the substrates. The vials were sealed with a Teflon cap and then
added to an aluminum block that had been preheated to 50 °C. The reaction was stopped after 2
hours by opening the Teflon caps and exposing the reaction to air. The catalytic mixture was
diluted in ethyl acetate and run through a pipet filters containing silica directly into GC vials.
Yields were determined by comparing the GC response of product to the internal naphthalene
standard. Each precatalyst was run in duplicate, and the average yield reported.
S20
SV: Isolation and Characterization of Catalytic Products
To generate authentic samples for calibration of the GC and to demonstrate that product could be
isolated from our catalytic procedures, products from select experiments were isolated.
4-methyl-1,1’-biphenyl
Following procedure 3, 4-methyl-1,1’-biphenyl was synthesized from 4-chlorotoluene and phenyl
boronic acid using tBuIndPd(XPhos)Cl. The reaction was stopped after 2 hours and exposed to air.
The product was extracted into ethyl acetate (2 mL), and the organic phases were dried over
MgSO4. The sample was then filtered and passed through a pad of silica gel. Removal of the
solvent under reduced pressure yielded the desired product as a white solid. 1H NMR data was
consistent with that published in the literature.[11]
2-(benzofuran-2-yl)-4,6-dimethoxyprymidine
Following procedure 4, 2-(benzofuran-2-yl)-4,6-dimethoxyprymidine was synthesized from 2-
chloro-4,6-dimethoxyprymidine and benzo[b]furan-2-boronic acid using tBuIndPd(XPhos)Cl. The
reaction was stopped after 3 hours and exposed to air. Then, water (10 mL) and diethyl ether (10
mL) were added to the reaction mixture. The aqueous phase was extracted into diethyl ether, and
the combined organic phases were dried over MgSO4. The sample was filtered and run down a
silica column eluting hexanes and ethyl acetate (hexanes:ethyl acetate, 9:1). Removal of solvent
under reduced pressure yielded the desired product. 1H NMR data was consistent with that
published in the literature as a colorless solid.[12]
3-(thiophen-2-yl)furan
Following procedure 6, 3-(thiophen-2-yl)furan was synthesized from 2-chlorothiophene and 3-
furan boronic acid using tBuIndPd(XPhos)Cl. The reaction was stopped after 3 hours and exposed
S21
to air. Then, water (10 mL) and diethyl ether (10 mL) were added to the reaction mixture. The
aqueous phase was extracted into diethyl ether, and the combined organic phases were dried over
MgSO4. The sample was filtered and passed through a pad of silica gel. Removal of solvent under
reduced pressure yielded the desired product as a brown oil. 1H NMR data was consistent with that
published in the literature.[13]
2,2’,4,6,6’-pentamethyl-1,1’-biphenyl
Following a modified procedure 7, 2,2’,4,6,6’-pentamethyl-1,1’-biphenyl was synthesized from
2-chloro-m-xylene and 2,4,6-trimethylbenzeneboronic acid using 1 mol% of tBuIndPd(IPr*OMe)Cl
at 80 °C. The reaction was stopped after 12 hours and exposed to air. Then, water (10 mL) and
diethyl ether (10 mL) were added to the reaction mixture. The aqueous phase was extracted into
diethyl ether, and the combined organic phases were dried over MgSO4. The sample was filtered
and passed through a pad of silica gel. Removal of solvent under reduced pressure yielded the
desired product as a colorless oil. 1H NMR data was consistent with that published in the
literature.[14]
(4-methoxyphenyl)(phenyl)methanone
Following procedure 8, (4-methoxyphenyl)(phenyl)methanone was synthesized from phenyl
benzoate and 4-methoxyphenyl boronic acid using tBuIndPd(IPr)Cl. The reaction was stopped after
3 hours and exposed to air. Then, the product was extracted using ethyl acetate, and the solvent
was removed under reduced pressure. The sample was dissolved in toluene (1 mL), and 3 M KOH
(aq) (3mL) was added and stirred for 1 hour. The organic layer was extracted with ethyl acetate (3
x 5 mL), washed with brine, and dried with MgSO4. The reaction was then filtered and run down
a silica column eluting hexanes and ethyl acetate (hexanes:ethyl acetate, 9:1). Removal of solvent
under reduced pressure yielded the desired product as a colorless solid. 1H NMR data was
consistent with that published in the literature. [15]
S22
2-(furan-2-yl)-4,6-dimethoxyprymidine
Following procedure 5, 2-(benzofuran-2-yl)-4,6-dimethoxyprymidine was synthesized from 2-
chloro-4,6-dimethoxyprymidine and 2-furan boronic acid using tBuIndPd(XPhos)Cl. The reaction
was stopped after 3 hours and exposed to air. Then, water (10 mL) and diethyl ether (10 mL) were
added to the reaction mixture. The aqueous phase was extracted into diethyl ether, and the
combined organic phases were dried over MgSO4. The sample was filtered and passed through a
pad of silica gel. Removal of solvent under reduced pressure yielded the desired product as a
colorless solid. 1H NMR (C6D6, 600 MHz) 7.30 (d, 1H, 3JHH = 2.9 Hz), 7.17 (obscured by solvent,
1H), 6.15 (m, 1H), 5.97 (s, 1H), 3.70 (s, 6H). 13C{1H} NMR (C6D6, 151 MHz) 171.8, 157.0,
153.2. 144.7, 113.7, 113.7, 112.1, 88.7, 53.6.
1-(4-(methoxy)phenyl)-naphthalene
Following procedure 9, 1-(4-(methoxy)phenyl)-naphthalene was synthesized from 1-naphthyl
sulfamate and 4-methoxyphenyl boronic acid using tBuIndPd(XPhos)Cl. The reaction was stopped
after 4 hours and exposed to air. Then, water (10 mL) and diethyl ether (10 mL) were added to the
reaction mixture. The aqueous phase was extracted into diethyl ether, and the combined organic
phases were dried over MgSO4. The sample was filtered and passed through a pad of silica gel.
Removal of solvent under reduced pressure yielded the desired product as a colorless solid. 1H
NMR data was consistent with that published in the literature.[2]
1-(sec-butyl)-3-methoxybenzene
Following procedure 10, 1-(sec-butyl)-3-methoxybenzene was synthesized from 3-chloroanisole
and sec-butyltrifluoroborate using tBuIndPd(PtBu3)Cl. The reaction was stopped after 8 hours and
exposed to air. Then, NH4Cl (aq) (10 mL)was added. The product was extracted with ethyl acetate
S23
(3 x 10 mL) and dried using MgSO4. The product was then filtered and run down a silica column
eluting hexanes and diethyl ether (Hexanes:Diethyl ether, 9:1). Removal of solvent under reduced
pressure yielded the desired product as a colorless oil. 1H NMR data was consistent with that
published in the literature.[16]
4-(2-methoxyphenyl)morpholine
Following a modified version of procedure 12, 4-(2-methoxyphenyl)morpholine was synthesized
from 2-chloroanisole and morpholine using 0.5 mol% tBuIndPd(RuPhos)Cl and 0.5 mol% RuPhos
at 85 °C. The reaction was stopped after 6 hours and exposed to air. Then, water (10 mL) and ethyl
acetate (10 mL) were added to the reaction mixture. The aqueous phase was extracted into ethyl
acetate, and the combined organic phases were dried over MgSO4. The sample was filtered and
run down a silica column eluting hexanes and ethyl acetate (hexanes:ethyl acetate, 9:1). Removal
of solvent under reduced pressure yielded the desired product as a yellow oil. 1H NMR data was
consistent with that published in the literature.[13]
S24
SVI: Comparison of NHC and Phosphine Ligated Precatalysts in Buchwald-Hartwig
Couplings
After the Suzuki-Miyaura coupling, the Buchwald-Hartwig reaction is the next most commonly
used coupling reaction in medicinal chemistry.[17] Therefore, we wanted to explore the relative
activity of our library of precatalysts in a representative Buchwald-Hartwig coupling reaction.
Specifically, we investigated the coupling of 2-chloroanisole and morpholine with both IPr (Figure
S1) and RuPhos ligated precatalysts (Figure S2).
When using IPr, we found that tBuIndPd(IPr)Cl and AllylPd(IPr)Cl are the most active precatalysts.
It is surprising that the least sterically bulky Nolan/Colacot system, AllylPd(IPr)Cl, demonstrates
higher activity than its more bulky counterparts, CinnamylPd(IPr)Cl and CrotylPd(IPr)Cl. We observed
a different trend in Suzuki-Miyaura reactions where increasing steric properties often correlate
strongly with higher activity. The observed change in the activity of AllylPd(IPr)Cl is likely related
to the increased reversibility of palladium(I) dimer formation at higher temperatures and a more
rapid activation under the chosen conditions that result in higher quantities of palladium(0).[9, 18]
Nevertheless, the high activity of tBuIndPd(IPr)Cl is consistent with trends for Suzuki-Miyaura
reactions.
Figure S1: Yield versus time for the Buchwald-Hartwig coupling of 2-chloroanisole and morpholine
with IPr precatalysts. Reaction conditions: [ArCl] = 1 M, [Morpholine] = 1.2 M, [Base] = 1.2 M,
[Precatalyst] = 0.0025 M, 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.
S25
Phosphine ligands are commonly used in Buchwald-Hartwig coupling reactions.[19] Specifically,
RuPhos has demonstrated exceptional activity in this class of coupling reactions.[19] We examined
the activity of our library of RuPhos ligated precatalysts and found that the most active precatalyst
is CrotylPd(RuPhos)Cl. tBuIndPd(RuPhos)Cl, AllylPd(RuPhos)Cl and CinnamylPd(RuPhos)Cl all
demonstrated similar activities that are lower than CrotylPd(RuPhos)Cl. These results are different
from our trends for Suzuki-Miyaura reactions and suggest that a more in-depth analysis is required
to understand relative precatalyst performance for Buchwald-Hartwig reactions.
Figure S2: Yield versus time for the Buchwald-Hartwig coupling of 2-chloroanisole and morpholine
with RuPhos precatalysts. Reaction conditions: [ArCl] = 1 M, [Morpholine] = 1.2 M, [Base] = 1.2 M,
[Precatalyst] = 0.0025 M, 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.
S26
SVII. The Effects of Catalyst Loading on Suzuki-Miyaura Couplings using IPr Precatalysts
To probe whether catalyst loading affected precatalyst performance, we lowered the catalyst
loading in the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid (Figure S3).
Upon lowering the catalyst loading from 0.5 mol% to 0.1 mol%, we found no change in the relative
activity of the IPr ligated precatalysts. Similar to our observations at 0.5 mol% loading,
tBuIndPd(IPr)Cl is the most active precatalyst. For the Nolan/Colacot allyl systems, CinnamylPd(IPr)Cl
displays the highest activity, although it only reaches a 60% yield, which is likely due to the
formation of inactive palladium(I) dimers. CrotylPd(IPr)Cl and AllylPd(IPr)Cl, which form
significantly higher amounts of palladium(I) dimers, show little to no conversion after 24 hours.[18]
Figure S3: Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid using a strong base (KOtBu) with different precatalysts. Reaction conditions: [ArCl] = 0.5 M,
[Boronic Acid] = 0.55 M, [Base] = 0.55 M, [Precatalyst] = 0.0005 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.
S27
SVIII: NHC Ligand Effects on the Suzuki-Miyaura Coupling of Aryl Chlorides
To test the generalizability of the results found with IPr ligated precatalysts, we examined ligand
effects by changing the NHC ligand to SIPr, IMes, or IPr*OMe (Figure S4). We found that under
the chosen conditions, SIPr, IMes, and IPr*OMe all showed diminished activity compared to IPr.
Using the SIPr ligated precatalysts, the reaction proceeds at room temperature, albeit slower than
with IPr ligated systems. After 3 hours, we observe that tBuIndPd(SIPr)Cl is the most active
precatalyst. The Nolan/Colacot systems give lower activity, with CinnamylPd(SIPr)Cl being the most
active of the set. CrotylPd(SIPr)Cl and AllylPd(SIPr)Cl show lower activity, which is likely because
they more readily form palladium(I) dimers than CinnamylPd(SIPr)Cl.[18] Therefore, we obtain a
similar trend with SIPr as with IPr.
If the less sterically bulky IMes is used instead of IPr, the reaction needs to be heated to 80 °C.
After 3 hours, tBuIndPd(IMes)Cl is the most active precatalyst. In contrast to results with IPr and
SIPr, CrotylPd(IMes)Cl and AllylPd(IMes)Cl are more active than CinnamylPd(IMes)Cl. This change in
Figure S4: Comparative yields for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid using a strong base (KOtBu) with different NHC ligated 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.
S28
relative activity is likely a result of the increased reversibility of palladium(I) dimer formation at
elevated temperatures.[9, 18]
When the more sterically bulky IPr*OMe is used in place of IPr, the reaction temperature must be
increased to 50 °C. Using IPr*OMe, there is a similar trend to that observed with IPr where
tBuIndPd(IPr*OMe)Cl is the most active precatalyst. For the Nolan/Colacot systems, we observe the
highest activity from CrotylPd(IPr*OMe)Cl, with both CinnamylPd(IPr*OMe)Cl and
AllylPd(IPr*OMe)Cl giving lower activity.
Overall, we find that the comparative activity between precatalysts shifts as the ligand set is
changed. These changes are likely the result of diminished palladium(I) dimer formation or
changes in the rate of precatalyst activation. However, despite these changes in relative activity,
tBuIndPd(L)Cl remains the most active precatalyst with all the different ligands examined under the
chosen conditions. Therefore, if a broad set of NHCs needs to be screened, the best choice is the
Yale precatalyst as it maintains high activity across a broader set of ligands, whereas other
precatalysts tend to give fluctuating relative activity depending on the ligand chosen.
S29
SIX: The Effects of Catalyst Loading on Suzuki-Miyaura Couplings using Water and K3PO4
To assess if the activity of XPhos ligated precatalysts was related to catalyst loading, we lowered
the catalyst loading in the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic acid
from 0.5 mol% to 0.1 mol% (Figure S5). We observe the same relative catalytic activity at 0.5 and
0.1 mol% catalyst loading. Specifically, we find that tBuIndPd(XPhos)Cl is the most active
precatalyst. CrotylPd(XPhos)Cl and CinnamylPd(XPhos)Cl also show high catalytic activity under
these conditions. In contrast, AllylPd(XPhos)Cl shows low conversions similar to those found at 0.5
mol%. The observation that catalyst loading does not significantly affect relative precatalyst
performance in this reaction is similar to what was observed for IPr ligated systems for the coupling
of 4-chlorotoluene and phenyl boronic acid under the conditions optimized for allyl precatalysts.
Figure S5: Yield versus time for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid using a strong base (KOtBu) 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.
S30
SX: Phosphine Ligand Effects on the Suzuki-Miyaura Coupling of Aryl Chlorides
In order to evaluate the generalizability of results found with XPhos, we examined the activity of
SPhos, RuPhos, and PtBu3 ligated precatalysts in the Suzuki-Miyaura coupling of 4-chlorotoluene
and phenyl boronic acid (Figure S6). Similar to trends found with XPhos, when RuPhos ligated
precatalysts are used, tBuIndPd(RuPhos)Cl is the most active precatalyst. However, we also observe
a change in the relative activities of the Nolan/Colacot system where AllylPd(RuPhos)Cl is more
active than both CinnamylPd(RuPhos)Cl and CrotylPd(RuPhos)Cl, which display similar activities.
This contrasts trends found with XPhos for the Nolan/Colacot system, where CrotylPd(XPhos)Cl is
the most active precatalyst followed by CinnamylPd(XPhos)Cl and AllylPd(XPhos)Cl, respectively.
If instead the less sterically bulky SPhos ligand is used, we still observe the highest activity from
tBuIndPd(SPhos)Cl. Using SPhos, the Nolan/Colacot precatalysts display a similar trend to that
found with XPhos where CrotylPd(SPhos)Cl is the most active followed by CinnamylPd(SPhos)Cl and
AllylPd(SPhos)Cl, respectively.
If the activity of each scaffold is compared using a simple alkyl phosphine, we observe a trend
similar to that found with IPr where precatalyst activity is correlated with sterics. That is
Figure S6: Comparative yields for the Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid using a strong base (KOtBu) with different phosphine ligated 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.
S31
tBuIndPd(PtBu3)Cl, which is known not to form palladium(I) dimers has the highest activity. Further,
for the Nolan/Colacot systems, CinnamylPd(PtBu3)Cl is the most active, followed by
CrotylPd(PtBu3)Cl and AllylPd(PtBu3)Cl, respectively. The observed trend is likely due to the higher
favorability of forming palladium(I) dimers with less sterically bulky systems.
As the ligand set is varied, our data indicates that the relative activity between the Nolan/Colacot
systems fluctuates depending on the ancillary ligand. It is, therefore, difficult to choose which of
these systems will be the most active with a chosen ligand set. Contrastingly, the Yale precatalysts
display high activity across a broader set of ancillary ligands.
S32
SXI: Suzuki-Miyaura Coupling of Aryl Chlorides with In-Situ Generated IPr Precatalysts
When testing in-situ catalysis with IPr, palladium acetate, and Pd(CH3CN)2Cl2 reached full
conversion after 1 hour at 0.5 mol% (Figure S7). In order to distinguish these common palladium
sources from the Yale system, we lowered the catalyst loading to 0.25 mol% (Figure 18). When
the catalyst loading was lowered, similar activity was still observed from the Yale system,
palladium acetate, and Pd(CH3CN)2Cl2. In addition, changing the catalyst loading for in-situ
systems generated from (CinnamylPdCl)2, (CrotylPdCl)2, (
AllylPdCl)2, and Pd2dba3 seemed to result in
very little change to catalyst activity. These systems continue to display low conversions at the
higher catalyst loadings and would likely need much larger increases in catalyst loading or more
forcing conditions to achieve higher product yields.
Figure S7: 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, [IPr] = 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.
S33
SXII: In-situ Coupling of Aryl Chlorides with XPhos using water and K3PO4
To establish the generalizability of our results, we examined the in-situ Suzuki-Miyaura coupling
of 4-chlorotoluene and phenyl boronic acid using water and K3PO4 (Figure S8). Under these
conditions, similar trends to those observed with well-defined precatalysts are apparent.
Specifically, the in-situ system derived from (tBuIndPdCl)2 is the most active. For the Nolan/Colacot
systems (CrotylPdCl)2 is the most active followed by (CinnamylPdCl)2 and (AllylPdCl)2.
Under these conditions, we were surprised to find that the most active common palladium source
is Pd(CH3CN)2Cl2. Under the optimized conditions for allyl precatalysts, palladium acetate is more
active in almost every case. However, when water and K3PO4 are used, we observe lower activity
from palladium acetate and can see some differentiation between the two qualities of palladium
acetate. Further, there was no appreciable increase in the activity of Pd2dba3, which remained
almost inactive for this reaction.
These results highlight that the activity of the common commercially available palladium sources
can drastically change depending on the chosen conditions. As a result, screening with these
palladium sources may be challenging as there are fluctuations in their activity.
Figure S8: Comparative yields for Suzuki-Miyaura coupling of 4-chlorotoluene and phenyl boronic
acid using water and K3PO4. Reaction conditions: [ArCl] = 0.5 M, [Boronic Acid] = 0.55 M, [Base] =
1.0 M, [Pd] = 0.0025 M, [XPhos] = 0.0025 M, 0.67 mL H2O, 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.
S34
SXIII: Buchwald-Hartwig Coupling of Secondary Amines with In-Situ Generated
Precatalysts
For Suzuki-Miyaura coupling reactions, the relative activity of the precatalysts established a trend
that persisted in the in-situ generated systems. We wanted to determine whether the same was true
for Buchwald-Hartwig reactions and therefore examined the coupling between 2-chloroanisole and
morpholine with RuPhos ligated precatalysts (Figure S9). Under the chosen conditions, we find
comparable activity to the precatalysts, where (CrotylPdCl)2 generates the most active system. In
addition, (tBuIndPdCl)2, (CinnamylPdCl)2, and (AllylPdCl)2 have similar activities. These trends are
similar to those observed with precatalysts. For in-situ systems generated from common palladium
sources, both pure and impure palladium acetate give the highest activity and are slightly more
active than (CinnamylPdCl)2. Pd(CH3CN)2Cl2 is more active for this transformation than (AllylPdCl)2
and (tBuIndPdCl)2. Lastly, Pd2dba3 shows the lowest activity of the system tested.
Figure S9: Comparative yields for the in-situ Buchwald-Hartwig coupling of 2-chloroanisole and
morpholine with IPr precatalysts. Reaction conditions: [ArCl] = 1 M, [Morpholine] = 1.2 M, [Base] =
1.2 M, [Pd] = 0.0025 M, [RuPhos] = 0.005 M, 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.
S35
SXIV: Comparison of the Activity of Isolated and In-Situ Generated Precatalysts
It is widely proposed that precatalysts give higher activity over in-situ systems.[20] To provide
evidence in support of this hypothesis, we compared the performance of well-defined precatalysts
against their corresponding in situ generated systems for several reactions.
We first compared performance for the coupling of 4-chlorotoluene and phenyl boronic acid. For
systems using IPr as the ligand, reactions using in-situ generated and well-defined precatalysts had
similar activity after 2 hours under the conditions optimized for allyl precatalysts (Figure S10). On
the whole, similar results were found with XPhos ligated systems under the conditions optimized
for the allyl system (Figure S11). However, surprisingly, in-situ systems generated from
(CrotylPdCl)2 and (CinnamylPdCl)2 slightly outperformed their precatalyst counterparts. A similar
pattern is found when 4-chlorotoluene and phenyl boronic acid are coupled with water and K3PO4
(Figure S12). Overall, precatalysts and in-situ systems have similar activity within error for the
coupling of simple aryl chlorides, with several exceptions, which cannot be explained at this stage.
Figure S10: Comparison between IPr ligated precatalyst and in-situ precatalysts for the coupling of 4-
chlorotoluene and phenyl boronic acid using a strong base (KOtBu). Reaction conditions: [ArCl] = 0.5
M, [Boronic Acid] = 0.55 M, [Base] = 0.55 M, [Precatalyst] or [In-situ 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.
S36
Figure S11: Comparison between XPhos ligated precatalyst and in-situ precatalysts for the coupling of
4-chlorotoluene and phenyl boronic acid using a strong base (KOtBu). Reaction conditions: [ArCl] =
0.5 M, [Boronic Acid] = 0.55 M, [Base] = 0.55 M, [Precatalyst] or [In-situ 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.
Figure S12: Comparison between XPhos ligated precatalyst and in-situ precatalysts for the coupling of
4-chlorotoluene and phenyl boronic acid using water and K3PO4. Reaction conditions: [ArCl] = 0.5 M,
[Boronic Acid] = 0.55 M, [Base] = 1.0 M, [Precatalyst] or [In-situ precatalyst] = 0.0025 M, 0.67 mL
H2O, 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.
S37
Unlike previous examples, the heteroaryl coupling of 2-chloro-4,6-dimethoxypyrimidine and
benzo[b]furan-2-boronic acid using XPhos shows a substantial difference between precatalysts
and in-situ systems (Figure S13). For this reaction, precatalysts outperform the in-situ systems by
a large margin. This notable difference is likely associated with the low catalyst loading used for
this reaction. The contrast between XPhos ligated precatalysts, and in-situ systems is less notable
for the coupling of 2-chlorothiophene and 3-furan boronic acid (Figure S14). For this reaction, all
of the precatalysts and in-situ systems have activity within error.
Using a simple phosphine, PtBu3, for the in-situ coupling of 3-chloroanisole and potassium sec-
butyltrifluoroborate, led to activity that was comparable between well-defined and in-situ
precatalysts (Figure S15). One notable decrease in activity is with (tBuIndPdCl)2, where the activity
of the precatalyst is higher than that of the in-situ system. In addition, CinnamylPd(PtBu3)Cl shows
lower activity than the in-situ system.
Figure S13: Comparison between XPhos ligated precatalyst and in-situ precatalysts for the coupling of
2-chloro-4,6-dimethoxypyrimidine and benzo[b]furan-2-boronic acid. Reaction conditions: [ArCl] =
0.3 M, [Boronic Acid] = 0.45 M, [Base] = 0.6 M, [Precatalyst] or [In-situ 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.
S38
Figure S14: Comparison between XPhos ligated precatalyst and in-situ precatalysts for the coupling of
2-chloro-4,6-dimethoxypyrimidine and 3-furan boronic acid. Reaction conditions: [ArCl] = 0.3 M,
[Boronic Acid] = 0.45 M, [Base] = 0.6 M, [Precatalyst] or [In-situ 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.
Figure S14: Comparison between PtBu3 ligated precatalysts and in-situ precatalysts 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] = 1 M,
[Precatalyst] or [In-situ precatalyst] = 0.0033 M, 0.67 mL toluene, and 0.33 mL H2O. Product yield was
determined through comparison of product signal with an internal naphthalene standard on a gas
chromatogram with an FID detector.
S39
Comparing precatalysts and in-situ systems in the Buchwald-Hartwig coupling of 3-chloroanisole
and morpholine led to a similar result (Figure S15). As in previous cases, we found that the
precatalysts and in-situ systems displayed similar activity. The only differentiation we observe is
between well-defined AllylPd(RuPhos)Cl and the in-situ system generated from (AllylPdCl)2. In this
case, the precatalyst is much more active than the in-situ system. Across all the examples
investigated thus far, well-defined precatalysts tend to have slightly higher or comparable activity
to in-situ systems, but there are exceptions, and it is not as clear-cut as the literature suggests.
Figure S15: Comparison between RuPhos ligated precatalysts and in-situ precatalysts for the Buchwald-
Hartwig coupling of 2-chloroanisole and morpholine with IPr precatalysts. Reaction conditions: [ArCl]
= 1 M, [Morpholine] = 1.2 M, [Base] = 1.2 M, [Precatalyst] or [In-situ precatalyst] = 0.0025 M, [RuPhos]
= 0.005 M, 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.
S40
SV. Selected Spectra
1H NMR of tBuIndPd(IMes)Cl in C6D6
13C{1H} NMR of tBuIndPd(IMes)Cl in C6D6
S41
1H NMR of tBuIndPd(SIPr)Cl in C6D6
13C{1H} NMR of tBuIndPd(SIPr)Cl in C6D6
S42
1H NMR of CinnamylPd(PtBu3)Cl in CDCl3
13C{1H} NMR of CinnamylPd(PtBu3)Cl in CDCl3
S43
31P NMR of CinnamylPd(PtBu3)Cl in CDCl3
S44
1H NMR of CrotylPd(SIPr)Cl in C6D6
13C{1H} NMR of CrotylPd(SIPr)Cl in C6D6
S45
1H NMR of CrotylPd(IPr*OMe)Cl in C6D6
13C{1H} NMR of CrotylPd(IPr*OMe)Cl in C6D6
S46
1H NMR of CrotylPd(IMes)Cl in C6D6
13C{1H NMR of CrotylPd(IMes)Cl in C6D6
S47
1H NMR of AllylPd(IPr*OMe)Cl in C6D6
13C{1H} NMR of AllylPd(IPr*OMe)Cl in C6D6
S48
1H NMR of 4-methyl-1,1’-biphenyl
1H NMR of 2-(benzofuran-2-yl)-4,6-dimethoxyprymidine in CDCl3
S49
1H NMR of 3-(thiophen-2-yl)furan in CDCl3
1H NMR of 2,2’,4,6,6’-pentamethyl-1,1’-biphenyl in CDCl3
S50
1H NMR of (4-methoxyphenyl)(phenyl)methanone in CDCl3
1H NMR of 2-(furan-2-yl)-4,6-dimethoxyprymidine in C6D6
S51
13C{1H} NMR of 2-(furan-2-yl)-4,6-dimethoxyprymidine in C6D6
1H NMR of 1-(4-(methoxy)phenyl)-naphthalene in CDCl3
S52
1H NMR of 1-(sec-butyl)-3-methoxybenzene in CDCl3
1H NMR of 4-(2-methoxyphenyl)morpholine in CDCl3
S53
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