Phosphine-Scavenging Cationic Gold(I) Complexes: Alternative Applications of Gold Cocatalysis in Fundamental Palladium-Catalyzed Cross-Couplings

Article abstract of DOI:10.1021/acs.organomet.9b00294

We have demonstrated that air-stable cationic gold(I) cocatalysts have the capacity to enhance the efficiency of palladium-catalyzed cross-couplings. Specifically, we determined that a 1:1 [Pd{P(t-Bu)₃}₂]/[Au{P(t-Bu)₃}(NTf₂)] system provides superior reactivity relative to [Pd{P(t-Bu)₃}₂], across Suzuki-Miyaura, Stille, and Mizoroki-Heck reactions performed under mild conditions. Our results are consistent with cationic gold(I) species serving primarily as phosphine scavengers in this chemistry, as recently predicted by density functional theory (DFT).

Full text of DOI:10.1021/acs.organomet.9b00294

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Cite This: Organometallics XXXX, XXX, XXX−XXX
Phosphine-Scavenging Cationic Gold(I) Complexes: Alternative
Applications of Gold Cocatalysis in Fundamental Palladium-
Catalyzed Cross-Couplings
Curtis C. Ho,† Alireza Ariafard,† Christopher J. T. Hyland,‡ and Alex C. Bissember*,†
†School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania7001, Australia
‡School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales 2522, Australia
S
* Supporting Information
ABSTRACT: We have demonstrated that air-stable cationic
gold(I) cocatalysts have the capacity to enhance the efficiency
of palladium-catalyzed cross-couplings. Specifically, we
determined that a 1:1 [Pd{P(t-Bu)3}2]/[Au{P(t-Bu)3}-
(NTf2)] system provides superior reactivity relative to
[Pd{P(t-Bu)3}2], across Suzuki−Miyaura, Stille, and Mizor-
oki−Heck reactions performed under mild conditions. Our
results are consistent with cationic gold(I) species serving
primarily as phosphine scavengers in this chemistry, as
recently predicted by density functional theory (DFT).
cocatalysts in Pd-catalyzed Stille reactions to facilitate efficient
cross-couplings with sterically hindered nucleophiles, and tin/
gold transmetalation mechanisms are suggested to operate in
this system.8 Other modes of reactivity have also been invoked.
For example, Blum and co-workers reported a detailed study
demonstrating the viability of a Pd/Au cocatalyst system to
promote the carbostannylation of alkynes.9 The mechanism is
consistent with the coordination of a Lewis acidic Au(I)
species to the alkyne, which is key to activation in this
manifold.9,10
In 2017, Ariafard’s density functional theory (DFT)
computational study first predicted the phosphine-scavenging
ability of cationic Au(I) complexes (Figure 1).11 Specifically,
this work suggested that this property could be exploited to
lower the barrier leading to the catalytically active mono-
phosphine-ligated [Pd{P(t-Bu)3}] from its stable (catalytically
inactive) bis-ligated precursor. This prompted us to postulate
INTRODUCTION
■
Palladium-catalyzed cross-couplings represent a fundamentally
important class of synthetic transformations of both academic
and industrial significance.1 Arylphosphine ligands have been
employed to great effect as versatile supporting ligands in these
reactions, as have bulky, electron-rich trialkylphosphines.1 The
latter family of ligands, particularly venerable P(t-Bu)3, has
enabled efficient Pd-catalyzed reactions under mild con-
ditions.2 Indeed, in 2010, P(t-Bu)3 was described as “the
most widely used single ligand in modern cross coupling
chemistry”.2d
In contrast to many other Pd/PR3 catalyst systems, it is
generally accepted that the oxidative addition of aryl
electrophiles to P(t-Bu)3-ligated Pd(0) species predominantly
proceeds via monophosphine-ligated intermediate [Pd{P(t-
Bu)3}].3,4 It has also been reported that catalytically inactive
[Pd{P(t-Bu)3}2] comprises the catalyst resting state in various
Mizoroki−Heck and Suzuki−Miyaura couplings.3a,c Thus,
∼1:1 ratios of Pd/P(t-Bu)3 are often employed in catalysis
performed at lower temperatures, and the active species is
often generated in situ from standard palladium precata-
lysts.2c,3a,5
Beyond the development of new ligands that provide
enhanced reactivity, a number of strategies have been used
to augment various features of Pd-mediated couplings, and the
emergence of homo- and heterobimetallic systems in
homogeneous catalysis are examples of this.6 Gold complexes
have been employed in the latter capacity.6a,b Many of these
studies describe Au(I) species serving as transmetalating
intermediates derived from various alkyne/allene activation
processes characteristic of Au(I) complexes or from preformed
organogold complexes.7 Au(I) species have been employed as
Figure 1. Calculated Gibbs free energies (kcal/mol) for the formation
of [Pd{P(t-Bu)3}] from [Pd{P(t-Bu)3}2] in the presence or absence
of [Au−L]+.11
Received: May 3, 2019
© XXXX American Chemical Society
A
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that Pd/Au cocatalysis could be exploited to enhance the
reactivity of this catalyst system and perhaps other Pd/PR3
catalyst systems under mild conditions by sequestering free
phosphine. Herein, we illustrate the validity of this postulate in
practice.
Scheme 2. Investigating the Capacity of Au Complexes 1
and 5−7 and Cu Complex 8 to Promote the Oxidative
Addition of a Pd Species to p-Bromotoluene
Our results provide evidence for the capacity of cationic
Au(I) complexes to formally abstract P(t-Bu)3 from [Pd{P(t-
Bu)3}2]. Furthermore, we determined that [Pd{P(t-Bu)3}2]/
[Au{P(t-Bu)3}(NTf2)] systems can provide superior efficiency
relative to [Pd{P(t-Bu)3}2] in key couplings, including
Suzuki−Miyaura, Stille, and Mizoroki−Heck reactions. These
data are consistent with the gold cocatalyst playing a key role
primarily as a phosphine scavenger.
RESULTS AND DISCUSSION
■
First, we investigated the capacity of [Au{P(t-Bu)3}(NTf2)]
(1) to formally abstract P(t-Bu)3 from bis(phosphine)-ligated
Pd(0) complex [Pd{P(t-Bu)3}2] (2) (Scheme 1). After the
Scheme 1. Reaction of Au Complex 1 with Pd Complex 2 to
a
Afford [Au{P(t-Bu)3}2]NTf2 (3)
the efficiency of transmetalation in Suzuki−Miyaura and Stille
cross-coupling reactions mediated by Pd/PPh3 systems.16,17
The capacity of substoichiometric quantities of copper salts
to accelerate and enhance the efficiency of Pd-catalyzed Stille
and Suzuki−Miyaura couplings is well established.18,19 Much
of the pioneering work exploring the role of copper additives in
Stille chemistry was undertaken by Liebeskind, and excellent
reviews discussing this “copper effect” within the context of Pd
cross-coupling chemistry have been published more recen-
tly.6b,20 Although it can be difficult to unambiguously
determine the mechanistic basis of this phenomenon in
every instance, two primary effects have been proposed.6b
Specifically, the operation of possible tin/copper trans-
metalation mechanisms have been invoked in these Stille
processes (particularly in very polar solvents such as NMP,
DMF, and DMSO),6b,17b,21 in addition to the phosphine-
scavenging capacity of copper species.17b,c,18a,22 The latter
effect is thought to be most pronounced when free, strong
donor phosphine ligands are present in ethereal solutions
because their presence can impede transmetalation.6b,17b,c,23
Donnelly and Finet first suggested that phosphine-
scavenging processes may be operative in Suzuki−Miyaura
reactions performed in the presence of CuI.19a Furthermore,
Hobbs noted that a specific 1:2 Pd/Cu cocatalyst ratio
provided optimal results in Sonogashira reactions employing
[Pd(PPh3)4] and proposed that this type of behavior may also
be present.24 Ariafard’s DFT studies also support the
phosphine-scavenging ability of cationic Cu(I) complexes.11
Consequently, we also determined that [Cu(MeCN)4]PF6 (8)
could rapidly promote the oxidative addition of p-bromoto-
luene to an active species derived from [Pd{P(t-Bu)3}2]
(Scheme 2). We also isolated and crystallographically
characterized mononuclear complex [Cu{P(t-Bu)3}2]PF6
(9).25
a
In the structural representation of Au complex 3, thermal ellipsoids
are drawn at the 50% probability level and the [NTf2]− counteranion
and hydrogen atoms are omitted for clarity.
addition of Au complex 1 to Pd complex 2, a new signal (δ
97.0 ppm) appeared, consistent with the rapid formation of
[Au{P(t-Bu)3}2]+, as judged by 31P NMR spectroscopy.12,13
We also isolated and crystallographically characterized linear
mononuclear [Au{P(t-Bu)3}2]NTf2 (3).14
Next, we explored the capacity of Au complex 1 to promote
the oxidative addition of p-bromotoluene to a Pd species
derived from [Pd{P(t-Bu)3}2] (2). In the absence of Au
complex 1, reaction of the aryl bromide with Pd complex 2 was
not observed after 24 h, as judged by 31P NMR spectroscopy
(Scheme 2). This is in agreement with germane findings.3a In
stark contrast, the presence of equimolar quantities of Au
complex 1 rapidly promoted oxidative addition in minutes.
Specifically, 31P NMR spectroscopy indicated the presence of a
new signal (δ 61.5 ppm),15 which was consistent with the
presence of Pd(II) species 4. The conversion of Pd(0)
complex 2 to Pd(II) complex 4 was complete within 0.25 h,
and we also observed the concomitant formation of [Au{P(t-
Bu)3}2]+ by 31P NMR spectroscopy.12
We obtained analogous results employing other commer-
cially available, air-stable cationic Au(I) complexes 5−7 in
equivalent experiments. In each case, oxidative addition to
form Pd(II) complex 4 promptly occurred at ambient
temperature. This property of species 1 and 5−7 is notable
as Fu and co-workers have suggested that (catalytically
inactive) Pd complex 2 comprises the catalyst resting state in
various Mizoroki−Heck and Suzuki−Miyaura couplings.3a,c
The presence of free phosphine has also been shown to reduce
To explore the viability of our proposed phosphine-
scavenging strategy in synthesis, we investigated the effects
of Pd complex 2/Au complex 1 (and Pd complex 2/Cu
complex 8) cocatalyst systems in Pd-catalyzed cross-coupling
processes under simple and mild reaction conditions. In each
case, we compared the respective rates of product formation
employing these two cocatalyst systems and benchmarked
B
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a b
,
these data against equivalent experiments featuring Pd complex
2 exclusively.
Scheme 3. Suzuki−Miyaura Reactions
The enhanced efficiency provided by our Pd/Au cocatalyst
system was clearly evident in a Suzuki−Miyaura cross-coupling
involving p-bromotoluene and phenylboronic acid (Figure 2).
Figure 2. Effects of cocatalysts Au complex 1 (red line) or Cu
complex 8 (blue line) on the progress of Pd-mediated Suzuki−
Miyaura cross-couplings. The experiment employing only Pd catalyst
2 is represented with a black line.29
a
b
Yields after 0.25 h are provided in parentheses.29 (A) Reported
inefficient Pd-catalyzed Suzuki−Miyaura couplings of aryl iodides.16
(B) Reported poor turnover of trans-[Pd(PPh3)2(Ar)(I)] in the
presence of free PPh3.16 (C) Investigation of the effects of cocatalyst 5
or 8 on the efficiency of Pd-catalyzed Suzuki−Miyaura reactions with
p-iodotoluene. (D) Reaction of Au complex 5 with [Pd(PPh3)4] to
afford [Au(PPh3)3]+ (10).
In the absence of additive 1, the reaction essentially featured an
induction period (∼0.5 h). In contrast, the process using 1%
[Au{P(t-Bu)3}(NTf2)] (1) provided an enhanced rate of
product formation.26,27 Employing 3% Au complex 1 afforded
negligible differences in reactivity relative to 1% loading
(Supporting Information), which is consistent with the
phosphine-scavenging capacity of Au complex 1 playing a
key role in improving the efficiency of this transformation.28
Similar results were also obtained when a 1% Pd(dba)2/1%
[HP(t-Bu)3]BF4 catalyst system was utilized in this trans-
formation (Supporting Information).
complex 5 playing a role in enhancing the efficiency of this
process.28,32 We also investigated the ability of [Au(PPh3)-
(NTf2)] (5) to formally abstract PPh3 from [Pd(PPh3)4]
(Scheme 3D). After the addition of Au complex 5 to a solution
containing this Pd(0) species, a new signal (δ 22.1 ppm) was
observed, consistent with the formation of [Au(PPh3)3]+ (10)
as judged by 31P NMR spectroscopy.33 This demonstrates the
capacity for Au complex 5 to scavenge PPh3.34
Next, we demonstrated the superior results provided by our
Pd/Au cocatalyst system in a Stille cross-coupling involving p-
iodotoluene and tributylphenylstannane (Figure 3). Specifi-
cally, the process featuring 1% Au complex 1 provided a more
efficient process relative to the reaction featuring only Pd
complex 2.26,27 Employing 3% Au complex 1 provided
negligible improvements in reactivity relative to 1% Au
complex 1 (Supporting Information). However, we cannot
exclude the possibility that tin/gold transmetalation mecha-
nisms may also be operative under these conditions. The
enhanced efficiency we observed in each of the Pd-catalyzed
Stille and Suzuki−Miyaura cross-couplings investigated in this
study is consistent with the Au cocatalyst scavenging
phosphine, thus accelerating the respective rates of trans-
metalation in these processes.
In a recent study,16,30 we identified that the poor turnover of
key on-cycle intermediate trans-[Pd(PPh3)2(Ar)(I)] in the
presence of free PPh3 was responsible for the surprisingly poor
reactivity of aryl iodides in [Pd(PPh3)4]-catalyzed Suzuki−
Miyaura cross-couplings performed at relatively low temper-
atures (Scheme 3A,B).31 Our report also illustrated the drastic
difference between this process and the equivalent reaction
utilizing aryl bromides (Scheme 3A). With this in mind, we
investigated whether gold cocatalysis could ameliorate the
aforementioned issues affecting catalyst turnover in this
transformation. Although a 1% loading of [Au(PPh3)(NTf2)]
(5) provided a negligible effect, 2% Au complex 5 facilitated a
much more efficient process (Scheme 3C).
Employing 3% [Au(PPh3)(NTf2)] afforded essentially the
same results relative to 2% 5. Significant reactivity differences
were observed when 1:1 and 1:2 ratios of [Pd(PPh3)4] and
[Au(PPh3)(NTf2)] were employed in these Suzuki−Miyaura
couplings. In contrast, similar results were obtained using 1:2
and 1:3 ratios of [Pd(PPh3)4]/[Au(PPh3)(NTf2)]. These data
are consistent with the phosphine-scavenging capacity of Au
C
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CONCLUSIONS
■
We have demonstrated that substoichiometric quantities of air-
stable cationic Au(I) complexes can accelerate and enhance
the efficiency of Pd-catalyzed cross-coupling reactions. Our
observations are consistent with Au(I) cocatalysts serving
primarily as phosphine scavengers in these processes, and these
findings reinforce the predictions of a recently published DFT
study.11 Our results also suggest that gold additives may be
more effective than copper salts in this regard, which should be
investigated further in the future.
Arguably, the viability and general utility of this Au(I)
cocatalysis approach in augmenting the development of Pd-
catalyzed reactions under mild conditions will be influenced by
factors including the donor capacity of the ligand employed,
the binding affinity of the gold complex, the choice of solvent,
and the additives present. Subsequent studies will seek to
investigate the broader implications and further applications of
this strategy in other metal-catalyzed transformations, includ-
ing olefin polymerization processes,35 and to utilize this
approach to facilitate new reaction development under mild
conditions.
Figure 3. Effects of cocatalysts Au complex 1 (red line) or Cu
complex 8 (blue line) on the progress of Pd-mediated Stille cross-
couplings. The experiment employing only Pd catalyst 2 is
represented with a black line.29
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00294.
■
S
The improved results provided by our Pd/Au cocatalyst
system were also demonstrated in a Mizoroki−Heck cross-
coupling involving p-iodotoluene and ethyl acrylate (Figure
4).26,27 Our results indicated that the process featuring 2%
Experimental procedures and compound characteriza-
tion data (PDF)
Accession Codes
CCDC 1875861−1875862 contain the supplementary crys-
tallographic data for this article. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.C.B.: alex.bissember@utas.edu.au.
■
ORCID
Curtis C. Ho: 0000-0002-7555-0635
Christopher J. T. Hyland: 0000-0002-9963-5924
Alex C. Bissember: 0000-0001-5515-2878
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the University of Tasmania
(UTAS) and the Australian Research Council (grant number
DP180100904) for financial support, the UTAS Central
Science Laboratory for providing access to NMR spectroscopy
services, and Dr. Mairi F. Haddow from Heriot-Watt
University for assistance with X-ray crystallography. Part of
this research was undertaken on the MX2 beamline at the
Australian Synchrotron, Victoria, Australia.
Figure 4. Effects of cocatalysts Au complex 1 (red line) or Cu
complex 8 (blue line) on the progress of Pd-mediated Mizoroki−
Heck cross-couplings. The experiment employing only Pd catalyst 2 is
represented with a black line.29
[Au{P(t-Bu)3}(NTf2)] (1) provided a more efficient process
relative to the reaction featuring only Pd complex 2.
Employing 4% Au complex 1 provided minor improvements
in reactivity relative to 2% Au complex 1 (Supporting
Information). Similar results were also obtained when a 2%
Pd(dba)2/2% [HP(t-Bu)3]BF4 catalyst system was employed
to effect this transformation (Supporting Information).
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D
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(25) CCDC 1875861 (9) contains the supplementary crystallo-
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(26) Essentially no cross-coupled product was formed in reactions
featuring either Au complex 1 or Cu complex 8 in the absence of Pd
complex 2.
(27) The use of Cu complex 8 as an additive was not as effective as
Au complex 1. Experiments were also performed using CuI as an
additive, which was also not as effective as Au complex 1 (Supporting
Information).
(28) The possibility that boron/gold transmetalation mechanisms
may also be operative under these conditions cannot be excluded.
(29) Each data point represents the average of two experiments with
yields determined via GC with the aid of a calibrated internal
standard.
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(31) The results of the study reported in ref 16 were consistent with
transmetalation representing the rate-limiting step of the reaction.
F
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