differences in the performance of allyl based palladium

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.

mailto:[email protected]

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


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


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


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



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


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


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


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



[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


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


[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



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


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

mailto:[email protected]

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


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


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





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





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)


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






acid (Procedure for Figure 12)



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,


Suzuki-Miyaura Coupling of Aryl Sulfamates

9) Suzuki-Miyaura coupling of 1-naphthyl sulfamate and 4-methoxyphenyl boronic (Procedure for

Figure 13)



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


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





S14

12) Buchwald-Hartwig coupling of 2-chloroanisole and morpholine with RuPhos ligated

precatalysts (Procedure for Figure S2)




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


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





reported.

*To generate the data reported in Figure S7 the procedure was modified so the catalyst loading

was 0.5 mol%.


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


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





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.


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.



S17

Suzuki-Miyaura Coupling of Heteroaromatic Substrates


acid with in-situ generated XPhos precatalysts (Procedure for Figure 20A)


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)


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,


19) Buchwald-Hartwig Coupling of 2-chloroanisole and morpholine with in-situ generated

RuPhos precatalysts (Procedure for Figure S9)

S19



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.



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


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



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.


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


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


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.



[Boronic Acid] = 0.55 M, [Base] = 0.55 M, [Pd] = 0.0025 M, [IPr] = 0.0025 M, 0.95 mL MeOH, and



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



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


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



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.


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


S38


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


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



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


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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