Carbon−Heteroatom Coupling Using Pd-PEPPSI Complexes (1)

Carbon−Heteroatom Coupling Using Pd-PEPPSI Complexes
Cory Valente,†
Matthew Pompeo,‡
Mahmoud Sayah,‡
and Michael G. Organ*,‡
†
The Dow Chemical Company, 400 Arcola Road, Collegeville, Pennsylvania, United States 19426
‡
Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada
ABSTRACT: In this contribution, recent advances with the PEPPSI style of Pd−NHC catalysts in aryl aminations and aryl
sulfinations are reviewed and summarized from both applications and mechanistic standpoints.
■ INTRODUCTION
The ubiquitous presence of C−S and C−N bonds in organic
and materials chemistry, coupled with the advent of relatively
mild, selective, and highly efficient Pd-catalyzed methodologies,
has made aminations and sulfinations of functionalized carbon
backbones via cross-couplings one of the most popular
transformations in organic synthesis over the past decade.1,2
Aiding the gain in popularity of these reactions has been the
success in designing tailored ligands for Pd that enable
historically difficult steps in the catalytic cycle. In effect,
substrates that were inactive in cross-couplings and/or not
compatible with the reactions conditions even 5 years ago now
couple efficiently under increasingly mild reaction conditions.
The summary of the Pd-catalysis community’s collective efforts
is a wider substrate scope and a more efficient and applicable
reaction. In this perspective, recent advances with the PEPPSI
(pyridine-enhanced precatalyst preparation stabilization and
initiation; see Figure 1 for general structure of the PEPPSI
system)3
brand of Pd-catalysts in aryl aminations and aryl
sulfinations are reviewed and summarized from both an
applications and mechanistic standpoint.
1. ARYL SULFINATIONS WITH Pd-PEPPSI
PRE-CATALYSTS
Relative to Pd-catalyzed aryl amination chemistry, far less
progress has been made on generating efficient aryl sulfination
protocols, this despite the prevalence of thioethers in the
pharmaceutical arena.4
Although recent strides in Pd-mediated
catalysis are a significant improvement over the forcing
conditions of nucleophilic aromatic substitution5
and reactions
invoking elemental sulfur,6
there is still much headway to be
made.7
Advanced phosphine ligands such as JosiPhos8
have
been instrumental in bridging the gap between the forcing
conditions of old and the efficiency and control that Pd-
mediated catalysis has become known.
Historically, the siphoning of PdII
intermediates into thiolate-
derived off-cycle resting states (Scheme 1, resting states A, B
and C) has plagued Pd-catalyzed sulfinations and in turn
limited widespread adoption of this transformation.9,10
One
approach to this problem is to lower the activation barrier of
reductive elimination (RE) so as to keep the catalyst engaged in
the catalytic cycle and in effect reposition the equilibrium away
from the nonproductive resting states of the higher order
(resting state B) and thiolate-bridged (resting state C) PdII
oxidative addition adducts (vide infra). Ligand design and
optimization through iterative modifications is an obvious and
productive means to fine-tune the steric topography around the
Pd center and alter the kinetics of RE. Although bulky
phosphines have been shown to enable facile RE, they typically
require elevated temperatures to effect efficient catalysis.11
Moreover, when the steric topography around Pd is essential
for catalyst turnover and limiting sulfur-poisoning pathways
that lead to catalyst resting states, even the most transient
dissociation of the ligand can be detrimental. Attenuating the
basicity of the phosphine atom by modifying the substituents at
phosphorus can certainly help minimize ligand dissociation;
however, this is more readily accomplished through the use of
the inherently more basic NHC ligand.12
To that end, the
PEPPSI class of Pd−NHC complexes has been investigated and
systematically modified to enable one of the most generally
mild sulfinating protocols to date.13,14
Pd-PEPPSI-IPent (1, Figure 1) was found to be more effective
at aryl sulfinations than its predecessors Pd-PEPPSI-IPr (2) and
Pd-PEPPSI-IMes (3) due to the increased sterics of the NHC
ligand.13
In the presence of LiOi
Pr and KOt
Bu, a range of
(hetero)aryl bromides and chlorides were efficiently coupled
with aryl and alkyl thiols at 40 °C in toluene (Table 1, 4−19).13
Primary, secondary, and tertiary alkyl thiols, which are known
to be sluggish coupling partners,15
were routinely coupled
(leading to 11−15) in high yields under the mildest reactions
conditions reported to date. The coupling of triisopropylsila-
nethiol also proceeded well, furnishing silyl-protected arylthiols
16 and 17 in excellent yields. As reported by Hartwig,5
these
substrates are useful precursors to free aryl thiols, which is of
considerable value as there are a limited number of these
derivatives that are commercially available. Reactions were
conducted for 24 h; however, rate studies revealed that most
reactions were complete within 4−5 h. This observation led to
the development of a room temperature coupling protocol,
wherein several thioethers (20−24) were prepared to illustrate
the generality of these mild reaction conditions. This marked
the first time that Pd-catalyzed aryl sulfinations could be carried
out at ambient temperature.
Special Issue: Transition Metal-Mediated Carbon-Heteroatom Cou-
pling Reactions
Received: October 3, 2013
Published: December 11, 2013
Review
pubs.acs.org/OPRD
© 2013 American Chemical Society 180 dx.doi.org/10.1021/op400278d | Org. Process Res. Dev. 2014, 18, 180−190

Whereas precatalyst activation occurs routinely at or near
room temperature in Negishi,16,17
Suzuki−Miyaura,17,18
Stille−
Migita19
and Kumada−Tamao−Corriu20
cross-couplings and in
aryl amination chemistry where the organometallic or alky-
amine is sufficient to reduce PdII
,21
the mechanism of reduction
in aryl sulfinations is less clear. Although the aryl sulfinations
themselves proceeded at 40 °C or below (Table 1), activation
of the precatalyst required a preheating step in the presence of
LiOi
Pr to reduce PdII
to Pd0
. Clearly, this additional preheating
step complicates the procedure and lessens the practicality of
the otherwise efficient and mild aryl sulfinations. Although
catalyst activation can be achieved at room temperature with
catalytic Bu2Mg or at 40 °C with catalytic morpholine, these
approaches are similarly impractical.
A significant improvement in these transformations would be
achieved by the design of a catalyst that could be activated at
low temperature while maintaining a high TON, once in cycle.
To that end, a systematic evaluation of substituents on the
pyridine ligand and NHC core of the precatalyst was conducted
to determine their effect on catalyst activation using the
coupling of thiophenol (26) with sterically hindered 2-
bromoxylene (25) as the model reaction (Table 2).14
LiOi
Pr
was removed from the reaction conditions to simplify the study
and limit the number of activation modes available to the
precatalyst. As a start, Pd-PEPPSI-IPr (2) was found to be active
at 80 °C but failed to provide coupled product at 70 °C.
Surprisingly, unsubstituted pyridine facilitated precatalyst
activation (28) at 10 °C lower than 3-chloropyridine, as did
2-picoline (precatalyst 29). Addition of a second ortho methyl
group to 2-picoline (precatalyst 30) lowered the activation
temperature another 10 °C. The original design of the PEPPSI
series of catalysts (Figure 1) was predicated on the assumption
that the electron-withdrawing effects of the meta chlorine
substituent would facilitate ligand dissociation and thus
precatalyst activation.22
However, given the coupling results,
it appears that for aryl sulfinations, ligand sterics may play a
more pivotal role. In the absence of isopropoxide, double RS−
/
Cl−
anion exchange followed by RE to the disulfide is
presumably the only mode of activation available to the
precatalyst. Therefore, it stands to reason that increased steric
bulk of the pyridine ligand would facilitate this initial RE to
generate Pd0
and thus enable the catalytic cycle. X-ray
crystallography reveals that the Pd−S bond is lengthened in
the presence of 2,6-dimethylpyridine, which supports this
Figure 1. Structures of Pd-PEPPSI-IPent, Pd-PEPPSI-IPr and Pd-PEPPSI-IMes.
Scheme 1. General catalytic cycle for aryl sulfinations
highlighting thiol-poisoning pathways that lead to catalyst
resting states
Table 1. Low-temperature aryl sulfinations with aryl-, alkyl-,
and silylthiols using Pd-PEPPSI-IPent (1)
Organic Process Research & Development Review
dx.doi.org/10.1021/op400278d | Org. Process Res. Dev. 2014, 18, 180−190181

hypothesis.14
There does appear to be an upper limit on the
steric topography around Pd as 2,6-diethylpyridine (precatalyst
31) only provides trace product at 70 °C, likely because the
steric environment around Pd is now too encumbered to allow
for the prerequisite RS−
/Cl−
ion exchange. The addition of two
chlorine atoms to the NHC backbone (precatalyst 32) enables
activation at 50 °C, again likely stemming from a favorable
change in the steric topography around Pd for RE, as the Cl
atoms serve to push the N-aryl groups inward toward Pd (vide
infra).23
Given the observed role of sterics on catalyst
activation, the NHC ligand was switched from IPr to IPent,
and in combination with 2-picoline (precatalyst 34) near
quantitative conversion to 27 was observed at 50 °C. The
addition of two chlorine atoms to the NHC backbone
(precatalyst 35) had a similar effect on the IPent catalyst,
lowering the activation temperature by a further 10 °C enabling
near quantitative conversion to 27 at only 40 °C.
Using catalyst 35 under the optimized reaction conditions in
Table 1, a range of (hetero)aryl sulfides were efficiently coupled
with sterically congested aryl chlorides and bromides to provide
thioethers 6, 27, and 36−44 (Table 3). The finely tuned steric
topography of the Pd catalyst facilitated the formation of tetra-
ortho-substituted thioethers (6, 36, and 39) and the coupling of
electronically deactivated/heterocyclic sulfides (37, 38, 40, 41,
and 43) in high yield under the mildest reaction conditions
reported to date for this transformation.
1.1. Mechanistic Considerations of Aryl Sulfinations.
The mechanism for catalyst activation, in particular the role that
the additive LiOi
Pr serves in this process, was investigated in
more detail to better understand the entryway of the active
NHC−Pd0
species into the catalytic cycle.24
The results from
this mechanistic study are summarized in Scheme 2 and
elaborated on below.
• The signature 3-chloropyridine ligand that is most
common in the PEPPSI series of catalysts (represented
by D), which was believed to improve precatalyst
activation kinetics relative to pyridine, actually undergoes
Pd-mediated hydrodehalogenation under the reducing
conditions of the high-temperature preactivation proto-
col to provide precatalyst intermediate E. Alternatively,
removing this “precatalyst preactivation step” (i.e., step D
→ E) by replacing 3-chloropyridine with pyridine lowers
the temperature required to produce active NHC−Pd0
catalyst (see Table 2).
• Ligand exchange of sulfide for each chloride produces
disulfide precatalyst intermediate F, itself a resting state,
of which up to 50% disproportionates into the Pd-trimer
G, yet another resting state. Empirical evidence suggests
that the remaining fraction of F undergoes a mono-
substitution of isopropoxide for sulfide to produce the
unsymmetrical Pd adduct H. For each iteration of F →
G, there is a concomitant loss of one NHC ligand, which
effectively erodes the level of precatalyst available to the
cross-coupling reaction.
• There is a significant base and counterion effect that
underpins the catalyst activation pathway. Whereas
KOt
Bu, LiOt
Bu, and LiOi
Pr alone are not effective
additives, KOi
Pr (or a mixture of KOt
Bu and LiOi
Pr)
facilitates efficient reduction of NHC−PdII
to NHC−Pd0
(I) and ensuing catalysis. The counterion effect appears
to originate from the solubility difference between
Table 2. Optimization of NHC and pyridine ligand sterics in
aryl sulfinations
Table 3. Room temperature aryl sulfinations mediated by
pre-catalyst Pd-PEPPSI-IPentCl
-picoline (35)

potassium and lithium thiolate salts. Whereas LiSAr salts
are soluble in toluene, their corresponding potassium
salts are not, which is essential to minimize thiolate
concentration in solution so that the equilibrium favors
intermediate H. The use of soluble lithium thiolates,
however, repositions the equilibrium toward resting state
F and in turn, G, essentially turning off the precatalyst
activation pathway. The base effect appears to be one of
sterics. Whereas MOt
Bu is too large to degrade the stable
trimeric adduct G, MOi
Pr is small enough to facilitate the
return of monomeric PdII
complex H to the catalyst
activation pathway. Although KOi
Pr is the preferred
additive as it contains both the counterion and base
required for efficient catalysis, the lack of commercial
availability prompted the use of the KOt
Bu/LiOi
Pr mixed
salt system throughout the sulfination work. Owing to
the relatively strong reducing power of −
Ot
Bu and −
Oi
Pr,
these bases also serve to prevent the accumulation of
disulfide should it form in situ. This is imperative as
disulfide can oxidatively add to Pd0
, which will arrest the
catalytic cycle (see Scheme 1), pushing the equilibrium
toward thiol-derived catalyst resting states F and G.
• Reduction of the unsymmetical Pd intermediate H can
take place by one of two mechanisms. In the first, β-
hydride elimination of isopropoxide renders ArS−Pd−H
that can undergo RE to provide ArSH, which in the
presence of KOt
Bu ions will precipitate out of solution.
Alternatively, deprotonation of the isopropoxide methine
proton on the Pd adduct H by a second molecule of base
would provide Pd0
directly with concomitant elimination
of the insoluble ArSK salt.
2. ARYL AMINATIONS WITH Pd-PEPPSI
PRE-CATALYSTS
The Pd-catalyzed amination of aryl halides has become one of
the most widely used methods for the construction of aryl C−
N bonds.25
The popularity of this reaction has benefited from
the optimization of ancillary ligands that have served to
improve the scope and efficiency of this transformation.2,3,26,27
Electron-rich, bulky tertiary phosphines have served well as a
ligand platform due to their proven activity and relatively
straightforward tunability.10,15,26,28,29
Some notable, highly
active phosphine ligands (45−52) for aryl aminations are
presented in Figure 2.
Recently, much work has been focused on the use and
optimization of the PEPPSI catalyst platform that relies on the
unique electronic and steric properties that are inherent to
NHC ligands.3
In 2008, Organ and co-workers disclosed that
Pd-PEPPSI-IPr (2) was an effective precatalyst for the
amination of aryl chlorides and bromides with anilines and
secondary amines using KOt
Bu as the base.30
Despite the high
reactivity of the reported reaction conditions, the strongly basic
medium was not compatible with base-sensitive functionality.
To improve the practicality of this methodology, and thus
widen the substrate scope, a more mildly basic set of reaction
conditions was developed wherein Cs2CO3 was shown to be a
suitable replacement for KOt
Bu for the coupling of secondary
amines with electron-deficient aryl halides.30,31
As oxidative
addition (OA) was found not to be rate limiting, a mechanistic
investigation was undertaken to determine why alkyl amines
only couple effectively with electron-deficient aryl halides when
employing a weak carbonate base, whereas no such dependence
on the electronic nature of the aryl halide was observed when
employing a stronger alkoxide base.21
Moreover, the type of
Scheme 2. Proposed activation pathway of Pd-PEPPSI catalysts under the reaction conditions for aryl sulfination

base used in the analogous aryl amination with aniline
derivatives appeared to be less dependent on the electronic
nature of the electrophile.32
The results of this mechanistic
study are provided at the end of this section.
More recently, the bulkier Pd-PEPPSI-IPent precatalyst (1)
was shown to greatly outperform Pd-PEPPSI-IPr (2) in the
coupling of secondary amines with a wide variety of aryl
chlorides at 80 °C using Cs2CO3 as the base (leading to
products 53−57, Table 4).21,32
Notably, even sterically
hindered and electronically deactivated substrates coupled in
high yields (for example 56). Pd-PEPPSI-IPent (1) was also able
to effectively promote the coupling of a diverse array of weakly
nucleophilic anilines (leading to 58−62) with electron-rich aryl
chlorides, the most challenging electronic combination for aryl
aminations, compared to Pd-PEPPSI-IPr (2), which was almost
completely inactive in these cases (Table 5). However, these
reactions required high temperature (110 °C) to achieve
modest yields (40−79%).
In light of the modest reactivity of Pd-PEPPSI-IPent (1) in
coupling electron-deficient anilines, backbone modification of
the NHC ligand was investigated with the hypothesis that
placing electron-withdrawing groups on the backbone would
render the metal centre more electrophilic, similar in concept to
the precatalyst development in the sulfination work.14
In doing
so, the equilibrium of the amine coordination step would favor
the Pd−anilinium complex and in turn render this adduct more
susceptible to carbonate-mediated deprotonation (Scheme 3).
In practice, the backbone-modified IPr ligands do generate
more active catalysts in aryl aminations with anilines; however,
the observed improvement in catalysis was essentially
independent of the donating ability of the backbone
substituent, suggesting that the enhancement is actually steric
and not electronic in origin.33
Following this logic, a more rewarding path forward would
be to modify the backbone of the IPent ligand, given its superior
ancillary effects relative to the IPr ligand (vide supra).14
The
IPentCl
analogue (84, see Table 9) was synthesized and
evaluated in the challenging coupling of electron-deficient
Figure 2. Selection of state-of-the-art phosphine ligands used in the
aryl aminations.
Table 4. Comparative study of Pd-PEPPSI-IPr (2) and Pd-
PEPPSI-IPent (1) in aryl aminations with dialkylamines
Table 5. Comparative study of Pd-PEPPSI-IPr (2) and Pd-
PEPPSI-IPent (1) in aryl aminations with electron-deficient
anilines
Scheme 3. Proposed NHC−Pd-catalyzed amination pathway
for alkyl and aryl amines

anilines with electron-rich aryl chlorides (Table 6). Pd-PEPPSI-
IPentCl
(84) was found to be significantly more active than the
unmodified IPent complex (1), effectively coupling both 3-
trifluoromethylaniline and 3,4,5-trifluoroaniline with 4-chloro-
anisole, furnishing 58 and 59 in 96 and 94% yield, respectively.
Remarkably, even strongly deactivated pentafluoroaniline could
be coupled with 4-chloroanisole in 58% yield (leading to 63),
whereas no reaction was observed with Pd-PEPPSI-IPent (1).
To our knowledge, this is the first example of Pd-catalyzed
arylation of pentafluoroaniline, demonstrating the unprece-
dented reactivity of Pd-PEPPSI-IPentCl
(84).
2.1. Mechanistic Considerations. It is not obvious how
the increased steric topography around Pd for Pd-PEPPSI-
IPentCl
(84) relative to Pd-PEPPSI-IPent (1) would have such a
dramatic effect on aryl amination chemistry involving
electronically unreactive arenes (i.e., electron-deficient anilines
and electron-rich aryl chlorides). For aryl aminations involving
primary and secondary alkyl amines, kinetic studies show that
the rate-determining step (RDS) is deprotonation of the Pd−
ammonium complex (K in Scheme 3).21,30,32
Whereas KOt
Bu
is sufficiently basic to complete this step, Cs2CO3 relies more
heavily upon the electronic nature of the aryl halide.29,34
This
dependence exists because, once oxidative addition is complete,
the electrophile itself becomes a ligand on Pd that can attenuate
the Lewis acidity of Pd which in turn affects the Brønsted
acidity of the Pd−ammonium complex (see intermediate K).
Electron-withdrawing groups on the OA coupling partner lower
the effective pKa of the Pd−ammonium adduct and thereby
improve the kinetics of the RDS. Interestingly, in the presence
of Pd-PEPPSI-IPent (1), both reactions reach near quantitative
conversion, although the latter requires a longer reaction time
to do so. Since deprotonation is the RDS and provided that the
σ-donating ability of both IPr and IPent are not significantly
different, why then does an increase in ligand sterics help
facilitate the kinetics of deprotonation? Recall that this is similar
to the question posed at the beginning of this section, only in
that case the increased sterics of Pd-PEPPSI-IPentCl
(84) over
those of Pd-PEPPSI-IPent (1) have a dramatic effect in aryl
aminations involving electron-deficient anilines and electron-
rich aryl chlorides. Although the answers to these questions are
not yet clear, what is known is that the answers are not one and
the same.
For aryl aminations with alkylamines, the RDS is
deprotonation of the NHC−Pd−ammonium complex (K →
M). This is consistent with the maximum reaction rate being
first order in carbonate and zeroth order in amine and aryl
halide.21
In the above stated case, it appears then that the
IPent−Pd−ammonium complex has a lower effective pKa
relative to that of the analogous IPr−Pd−ammonium complex,
which could account for the improved catalyst reactivity. This
conjecture assumes that the ground state energy leading to the
transition state of the rate-determining deprotonation step is
higher for IPent than it is for IPr due to the increased steric
environment of the former. Although a possibility, the
mechanistic underpinnings for IPent-Pd vs IPr-Pd have not
been conclusively fleshed out.
In the case of aryl amination with anilines, the RDS is no
longer deprotonation but rather RE (L → J). This is consistent
with the maximum reaction rate being first order in aniline and
carbonate and zeroth order in aryl halide.32
This is also
reasonable as the pKa of anilines relative to that of amines is
lower by approximately 10 logarithmic units. As such,
deprotonation by carbonate base is now rapid and less
dependent on the electronic structure of the OA partner.
However, the OA partner does still play a role in the RE step, as
the more electron-deficient derivatives improve the overall
reaction kinetics. This may be due to the better leaving group
ability of these arenes during RE. In contrast, we have observed
that more nucleophilic anilines have overall higher reaction
rates. This is thought to be a result of their better reducing
power during the RE step, with the electronic ‘assist’ placing
less impetus on ligand sterics (i.e., Pd-PEPPSI-IPr (2) is
adequate for these couplings). In turn, when the aniline does
not possess the required basicity for the reduction of PdII
(i.e.,
Table 6), the catalyst must accommodate for this shortcoming
through ligand sterics. Hence, the IPentCl
ligand is superior to
the IPent ligand in the coupling of electron-deficient anilines.
Whatever the detailed mechanistic underpinnings are
eventually elucidated to be, the empirical data reveals that Pd-
PEPPSI-IPentCl
(84) is one of the most active catalysts reported
to date for aryl aminations.
2.2. Synthesis of Triarylamines by Way of Aryl
Aminations. A previous result (see Table 6) wherein an aryl
amination in the presence of Pd-PEPPSI-IPentCl
(84) led to the
formation of a small amount of triarylamine 67 by over-reaction
prompted a follow-up study to assess the feasibility of a general
coupling protocol for the synthesis of these difficult-to-form
and valuable reaction products.
Under a given set of amination reaction conditions involving
primary anilines with a stoichiometric amount of aryl halide, the
exclusive coupling product will almost always be the secondary
aniline. The selectivity results because the diarylamine products
are more challenging coupling partners than even the most
deactivated primary anilines due to the presence of the second
aryl ring, which severely curtails the nucleophilicity of the
amine. However, as the results show, in the presence of a highly
active catalyst and an excess of aryl halide, the preparation of
symmetric triarylamines (67−76) is easily accessible (Table
7).35
In addition, one can prepare unsymmetrical triarylamines
such as 78−80 through the reaction of a diarylamine (i.e., 77)
with an aryl chloride (Table 8). In summary, under a standard
Table 6. Comparative study of Pd-PEPPSI-IPent (1) and Pd-
PEPPSI-IPentCl
(84) in aryl aminations with electron-
deficient anilines and electron-rich aryl chlorides

set of reaction conditions, Pd-PEPPSI-IPentCl
(84) facilitated
the coupling of primary and secondary anilines with an aryl
chloride, leading to the formation of symmetric (Table 7) and
asymmetric (Table 8) triarylamines in good yield at 80 °C
using either KOt
Bu or Cs2CO3 base.
2.3. Low-Temperature Aryl Aminations with Pd-
PEPPSI-IPentCl
. Given the superior activity of Pd-PEPPSI-
IPentCl
(84) relative to Pd-PEPPSI-IPent (1) and all other
evaluated NHC-based Pd catalysts, the question arose as to
whether it would be possible to conduct these amination
reactions at lower temperature. If successful, the combination of
a mild base and low reaction temperature offers unique
opportunities for coupling substrates containing highly sensitive
functional groups. Moreover, the developed methodology
would be more amenable to process chemistry. In approaching
this challenge, we took a page from our group’s recent work on
the low-temperature Pd-PEPPSI-catalyzed sulfination chemistry
in which the structure of the pyridine ligand in the precatalyst
was found to have a considerable impact on catalyst
performance (vide supra).14
Although the precatalyst activation
pathways and catalytic cycles are somewhat different, it was
reasoned that a similar dependence on the pyridine substitution
might be manifested in low-temperature amination chemistry.
To this end, a number of Pd-PEPPSI-IPentCl
precatalysts with
various pyridine ligands (35 and 84−87) were prepared and
screened in the coupling of 4-chloroanisole (81) with 3,4,5-
trifluoroaniline (82) at room temperature to generate diaryl-
amine 83an extremely challenging coupling for any catalyst
even at 110 °C! (Table 11).
The standard 3-chloropyridine catalyst Pd-PEPPSI-IPentCl
(84) exhibited good reactivity at this temperature, furnishing
55% conversion to product after 24 h (see Table 9). The fact
that Pd-PEPPSI-IPentCl
(84) is as reactive at room temperature
as Pd-PEPPSI-IPent (1) is at 80 °C is a testament to the sizable
effect that backbone substitution has on modulating the
performance of this NHC ligand. Switching to pyridine
complex 85 resulted in a 15% jump in conversion to 70%.
Placing a methyl or ethyl group in the ortho position of the
pyridine resulted in another 10% improvement in conversion
(35 and 86); however, employing precatalyst 87 with bulkier
2,6-dimethylpyridine resulted in only 39% conversion to
product. Interestingly, 92% of 87 was recovered unreacted
after 24 h; thus, only 8% of the 3 mol % of catalyst added was
responsible for the observed catalysis. This implies that
activation of 87 is slow, but once activated, 87 proceeds to
catalyze product formation with a very high turnover frequency.
From this study, Pd-PEPPSI-IPentCl
-o-picoline (35) was
identified as one of the most reactive precatalysts for room
temperature aryl amination, which is coincidentally the same
complex that was identified as the most active for room
temperature aryl sulfination.14
The exact role of the pyridine
ligand in improving catalyst reactivity in aryl aminations is
currently under investigation.
Unexpectedly, these reactions were found to be somewhat
sensitive to the level of dissolved O2 in commercially available
anhydrous DME. The initial pyridine optimization studies were
Table 7. Formation of symmetric triarylamines with Pd-
PEPPSI-IPentCl
(84) in the presence of excess aryl chloride
and aniline derivatives
Table 8. Formation of asymmetric triarylamines with Pd-
PEPPSI-IPentCl
(84) using a diarylamine precursor
Table 9. Pyridine optimization of the IPentCl
-Pd-based pre-
catalysts in room temperature aryl aminations

successfully conducted using standard Schlenk techniques and
commercial anhydrous DME. However, when switching to a
new solvent bottle from the same supplier, the reactions
essentially shut down. Reactivity could only be recovered if the
solvent was degassed via three cycles of freeze−pump−thaw
and the entire reaction was set up in an Ar-filled glovebox.
Thus, to ensure consistently reproducible results, all room
temperature aryl aminations were conducted under a strictly
O2-free environment. This increased sensitivity might be due to
competitive oxidative addition of (NHC)Pd(0)Ln towards
molecular oxygen, forming unreactive (NHC)Pd(O2)L com-
plexes which have been documented in the literature.36
For
example, Fantasia and Nolan recently reported that peroxo
complex (IPr)Pd(PPh3)(O2) forms rapidly and irreversibly
from (IPr)Pd(PPh3) upon exposure to atmospheric O2 and is
stable as such for many days without observable decomposition.
The stability of these off-cycle intermediates at room
temperature may account for the heightened O2 sensitivity of
aminations conducted at room temperature relative to those
conducted at elevated temperatures in which sufficient thermal
energy is available to drive off the Pd-bound O2.
To demonstrate the scope of this new catalyst at room
temperature, a variety of functionalized, electron-rich aryl
chlorides were coupled with a series of electron-deficient
anilines (Table 10). Good to excellent yields were achieved
when coupling 4-chloroanisole with polyfluorinated anilines
(leading to 58 and 91) and methyl 4-aminobenzoate (leading
to 61). A chemoselective amination of 4-chlorophenylboronic
acid pinacol ester was also achieved, yielding 91 in good yield
without a trace of biaryl side products that might be observed at
higher temperatures. Finally, higher-molecular weight aryl
chlorides of potential medicinal interest were coupled with 3-
trifluoromethylaniline, forming aminated products 88 and 89 in
excellent yields. Due to the limited solubility of the aryl chloride
from which 89 was derived, this reaction was heated gently at
45 °C to ensure complete conversion to product.
2.4. Development of a Functional Group ‘Safe’
Alkoxide Base. As a consequence of the aggressive reactivity
of alkoxide bases, the tolerance of various sensitive functional
groups, such as ketones and esters, to the reaction conditions
for aryl aminations is limited. To circumvent this drawback, the
use of carbonate bases has gained in popularity (vide supra).
Still, the amine-coordination/deprotonation step for many
amination protocols shows a first-order dependence on base,
and the use of metal alkoxides is required to obtain acceptable
product yields in short reaction times. This is evident when
comparing the relative pKa’s for the Pd−anilinium complex
(∼8−10) with bicarbonate (∼10.3) and t
BuOH (∼18).
Moreover, the limited solubility of carbonate salts in organic
solvent further exacerbates the already slow acid−base
chemistry. In fact, deprotonation by Cs2CO3 has been shown
to be a surface-mediated heterogeneous reaction, wherein the
particle size and thus surface area of Cs2CO3 can affect the
success of the amination protocol.37
Instead, a fully soluble,
weakly nucleophilic base with a conjugate acid pKa between
11−15 would provide the ideal balance between basicity and
functional group tolerance. To that end, potassium 2,2,5,7,8-
pentamethylchroman-6-oxide (92), a truncated version of α-
tocopherol (vitamin E), was developed and evaluated on the
predication that the cyclic ether serves as a conformational lock
to force one of the ether oxygen lone pairs into conjugation
with the aromatic ring.38
In doing so, the pKa is raised from
10.2 (phenol) to 11.4. Indeed, the activity of 92 is significantly
improved relative to that of the acyclic derivative 93 in the aryl
amination of 4-chlorotoluene with morpholine in the presence
of Pd-PEPPSI-IPent at 80 °C. To demonstrate functional group
tolerance, 92 was evaluated directly against KOt
Bu in Pd-
catalyzed aryl aminations leading to diarylamines (94−99)
using base-sensitive coupling partners under two different sets
of reaction conditions (Table 11). For the reactions involving
KOt
Bu, the mass balance of starting material containing the
sensitive functionality could not be assigned, suggesting
decomposition in the presence of this reactive base.
3. COMPARING REACTIVITY OF Pd-PEPPSI
PRECATALYSTS WITH OTHER Pd−NHC
COMPLEXES
Many catalysts have been developed and reported as being
“highly active” in the cross-coupling literature. To those
working in the field, a highly active catalyst would be defined
as one that is able to conduct couplings that other catalysts
simply cannot, or the ability to couple substrates together under
significantly milder conditions than is the current state-of-the-
art in the field. Catalyst turnover numbers (TON) are
sometimes used to compare the relative reactivity between
different catalysts. However, TONs speak more to the stability
of a catalyst and its ability to remain on cycle and is not a
suitable metric to use in the relative ranking of the reactivity of a
catalyst. Moreover, these TON comparisons rarely take into
account the reaction conditions, which must be identical to
hold any comparative value. It is more suitable to use the
turnover frequency (TOF) of a catalyst, which is a better
representation for the efficiency of a catalyst to generate
product while it is active and on cycle, for drawing any
comparative conclusions. For example, an infinitely stable
Table 10. Examining the substrate scope of room
temperature aryl aminations catalyzed by Pd-PEPPSI-
IPentCl
-o-picoline (35)

catalyst may have a high TON, but if the TOF is low, then
conversion to product will limit its practical use.
Direct comparisons have been drawn between the reactivity
of the Pd-PEPPSI-IPent precatalyst (1) and Pd(IPr*) derivatives
(100−102) in both amination- and sulfination-type couplings
(Figure 3). Nolan and co-workers compared the reactivity of a
series of PEPPSI precatalysts in the amination reaction shown
in Scheme 4.39,40
They found that the rates of aryl amination
for this particular substrate pairing were identical under the
reaction conditions used (KOt
Bu base, DME solvent, RT, 1%
catalyst load) for Pd-PEPPSI-IPr (1), Pd-PEPPSI-SIPr, and Pd-
PEPPSI-IPr* (100), and that all three catalysts led to a similar
level of conversion (∼80%) after 6 h.39
The conversion over
time plots are suggestive of a similar TON and TOF among the
three catalysts under these commonly employed aryl amination
reaction conditions.
In a related study, the same group reported the couplings of
chloroanisole to a selection of aniline derivatives (leading to 58,
60, and 103) using modified IPr ligands, and comparisons were
made to the performance of Pd-PEPPSI-IPent (1) in the same
couplings but using different reaction conditions (Table 12).40
The reactivity of Pd-PEPPSI-IPr*OMe
(101) was reported by the
authors as high and on par with that of Pd-PEPPSI-IPent (1)
using the comparatively low catalyst loading as their
justification. Given that different reaction conditions were
used, comparisons in reactivity cannot be based on TON. Aryl
amination reaction conditions employing soluble, highly
aggressive tert-butoxide and its derivatives cannot be drawn
into comparisons with reactions performed using a mild,
insoluble carbonate base. For example, the reaction in Scheme
4 requires approximately 24 h using Pd-PEPPSI-IPr (2) to
complete using carbonate base at 80 °C; the same reaction
using KOt
Bu completes in just 15 s at RT!21
If the same catalyst
performs vastly differently under different reaction conditions,
any attempted comparison between catalysts under different
reactions conditions holds little value.
The [Pd(IPr*OMe
)(cin)Cl)] (102) variant of IPr* has also
very recently been applied to sulfination chemistry with aryl
Table 11. Aryl aminations with sensitive functional groups in
the presence of optimized alkoxide base 92
a
Comparative yields obtained with KOt
Bu are provided. b
Comparison
between catalysts under different reactions conditions carry little value.
Figure 3. Pd−NHC precatalysts reported by Nolan and co-workers.
Scheme 4. Direct comparison of pre-catalysts Pd-PEPPSI-
IPr, Pd-PEPPSI-SIPr and Pd-PEPPSI-IPr* in the coupling of
morpholine with 4-chlorotoluene at room temperature
Table 12. Published comparison of Pd-PEPPSI-IPr (2) with
Pd-PEPPSI-IPr*OMe
(101) under different reaction
conditions
a
When the same reaction was conducted in DME at 80 °C, 62% yield
was obtained. b
When the same reaction was conducted in DME at 80
°C using 85, 62% yield was obtained.

and alkyl sulfides.41
In all cases, the reactions required 110 °C
in dioxane solvent with KOt
Bu base to achieve suitable catalyst
TON. A wide sampling of the same couplings from this work
have been achieved using Pd-PEPPSI-IPent (1) at RT. Further,
as has been discussed above, an even wider group of substrates
that are profoundly sterically and electronically deactivated can
also now be routinely coupled at RT using Pd-PEPPSI-IPentCl
o-
picoline (35).14
In a direct comparison study for the coupling of 2,6-
dimethylchlorobenzene (104) with benzenethiol (26) under
identical reaction conditions (Table 13), Pd-PEPPSI-IPent (1)
furnished quantitative conversion to 27 (entry 1) while Pd-
PEPPSI-IPr* (100) provided only trace product. The mass
balance for the latter is predominately the reduced aryl halide
(entry 2). Under the same reaction conditions, Pd-PEPPSI-
IPent-py (33) provided quantitative conversion to product in
just 5 min (entry 3). These results clearly illustrate the effect
that ligand structure can have on aryl sulfinations and the
importance of using identical reaction conditions (an ‘apples-
to-apples’ approach) for adequately ranking the relative
reactivity of a set of catalysts.
On the basis of the proven ability of Pd−NHC complexes to
effectively conduct both C−N and C−S coupling, we propose
the catalyst performance rank order given in Figure 4.
Again, this assignment is based on relative TOF for couplings
that work for multiple catalysts, the relative demonstrated ease
of the coupling (i.e., low temperature, mild base, etc.), and
most importantly, the demonstrated ability in specific cases to
effect couplings that other catalysts have not demonstrated the
ability to do.
4.0. CONCLUSIONS
A series of Pd-PEPPSI complexes featuring NHC- and pyridine-
modified ligands were evaluated for activity in aryl sulfinations
and aryl aminations. All NHC backbone-modified complexes
exhibited enhanced reactivity relative to their unmodified
counterparts, regardless of the electron-withdrawing or
-releasing ability of the backbone substituents. This implies
that the effect imparted by the NHC backbone substituents is
primarily steric in origin and appears to corroborate the current
mechanistic understandings for the respective catalytic cycles.
The substitution on the pyridine ligand was also found to be
important, with 2-picoline ligand being the most effective for
both aryl aminations and sulfinations. A more thorough
understanding of the role that the pyridine ligand plays in
aryl sulfinations and aminations is being examined.
Since their introduction in 2008, the PEPPSI style of Pd−
NHC precatalysts have been demonstrated to be some of the
most active catalysts available for cross-couplings. They are
efficient catalysts under some of the mildest reaction conditions
reported and have served well in widening the substrate scope
to include functionalized electrophiles and nucleophiles that
historically had proven very challenging to couple. Several Pd-
PEPPSI catalysts are commercially available from Sigma
Aldrich,42
and as of the date of this submission, they have
found widespread application as evidenced by their use in 97
patents or patent applications.43
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: organ@yorku.ca
Notes
The authors declare the following competing financial
interest(s): Some of the catalysts reported in this manuscript
are distributed by Sigma-Aldrich, from which the PI receives a
royalty payment.
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(42) For commercially available catalysts, see: http://www.
sigmaaldrich.com Pd-PEPPSI-IPr (Item #669032) Pd-PEPPSI-IPent
(Item #732117) and http://totalsynthesis.ca/products for Pd-PEPPSI-
IPentCl
, Pd-PEPPSI-IPentCl
-o-picoline, and other related catalysts.
(43) Using the Thomson Innovation patent search engine with
“PEPPSI” as the search string reveals 97 patents or patent applications
within which a Pd-PEPPSI catalyst is utilized. Date of search 08/15/13.

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