The impact of palladium(II) Reduction pathways on the structure and activity of palladium(0) catalysts

Article abstract of DOI:10.1002/anie.201210252

Two roads diverged: The mechanism of insitu Pd^II catalyst activation to generate an active {L_nPd⁰} catalyst from an air-stable Pd^II precursor was examined using the standard conditions of a Miyaura borylation reaction. Two pathways for catalyst activation exist under these conditions, producing two structurally and chemically distinct {L_nPd⁰} complexes (see scheme). Copyright

Full text of DOI:10.1002/anie.201210252

Angewandte
Chemie
DOI: 10.1002/anie.201210252
Catalyst Activation
The Impact of Palladium(II) Reduction Pathways on the Structure and
Activity of Palladium(0) Catalysts**
Carolyn S. Wei,* Geraint H. M. Davies, Omid Soltani, Jacob Albrecht, Qi Gao,
Charles Pathirana, Yi Hsiao, Srinivas Tummala, and Martin D. Eastgate
Over the past decade, the scientific community has witnessed
a dramatic increase in the number of catalytic transformations
promoted by palladium complexes.[1] At the same time,
continued improvements to both new and existing Pd-
catalyzed reactions have resulted in milder conditions and
greater substrate generality. These developments in Pd
catalysis can be largely attributed to an increased under-
standing of the individual steps involved in catalytic reactions,
particularly oxidative addition,[2] transmetalation,[3] and
reductive elimination.[4] Because these elementary processes
factor prominently in most catalytic cycles, improvements to
palladium-catalyzed reactions have mainly focused on alter-
ing the electronic and steric properties of ligands coordinated
to the Pd center to accelerate one or more of these steps.[5]
However, a key step that remains poorly understood, yet
directly impacts the overall rate and performance of a Pd0-
catalyzed transformation, is the catalyst activation step. This
step involves the reduction of a stable PdII precursor to an
active, zero-valent palladium catalyst and must occur prior to
entering the catalytic cycle (Scheme 1). Despite the obvious
we present studies that provide an in depth understanding of
the in situ generation of {LnPd0} (n = 1 or 2) catalysts under
the standard conditions of a common Pd-catalyzed trans-
formation, the Miyaura borylation [Eq. (1)]. Two pathways
for catalyst activation were identified, which provide distinct
{LnPd0} complexes: (1) a bisphosphine Pd0 species resulting
from the diboron-mediated reduction of {L2PdII} and (2)
a monophosphine Pd0 species resulting from the base-
promoted reduction of {L2PdII} by a ligated phosphine.
Direct comparison of the catalytic activity of the resulting
{LnPd} species reveals the impact that catalyst activation has
on both the identity and reactivity of a palladium catalyst.
We began our studies by determining the reagent(s)
responsible for the reduction of a PdII precatalyst to an active
Pd0 species during the Miyaura borylation. The air-stable
catalyst precursor [(Cy3P)2Pd(OAc)2] (1),[7] which is readily
formed from the combination of Pd(OAc)2 and 2.0 equiv
PCy3, was chosen for these investigations owing to its
widespread application in the borylation of aryl halides.[8]
A
series of stoichiometric reactions were conducted between
1 and the typical reagents utilized in the borylation reaction to
determine the effectiveness of each reagent towards the
reduction of 1 (Table 1).
The intramolecular reduction of the related complex
[(Ph3P)2Pd(OAc)2] to form an anionic Pd0 species and
triphenylphosphine oxide has been reported by Amatore[9]
and others.[10] However, we found that prolonged heating of
1 at 708C in toluene,[11] either alone or with added PCy3, gave
no observable formation of a Pd0 species based on 31P NMR
spectroscopy, indicating that such a mechanism is not
operative for 1 (Table 1, entries 1 and 2). Reports by Ozawa
and Hayashi,[12] and more recently by Buchwald,[13] indicate
that in many cases water can promote the reduction of
[LnPd(OAc)2] to {LnPd0} and phosphine oxide. After heating
1 for 5 h at 708C in the presence of 5.0 equiv H2O, less than
5% conversion of 1 was observed, suggesting that the
predominant pathway for activation of the PCy3-ligated PdII
precatalyst is not solely mediated by adventitious water.
Other reported methods for the generation of LnPd0
include the treatment of [LnPdCl2] with aqueous alkaline
base (KOH) to give phosphine oxide and the {LnPd0}
species.[14] As the weak base KOAc is commonly used for
Scheme 1. Role of palladium(II) catalyst activation in palladium-cata-
lyzed reactions.
implications of catalyst activation on a palladium-catalyzed
reaction, there is a scarcity of detailed studies concerning the
mechanism and efficiency of this reduction process.[6] Herein,
[*] C. S. Wei, G. H. M. Davies, O. Soltani, J. Albrecht, Q. Gao,
C. Pathirana, Y. Hsiao, S. Tummala, M. D. Eastgate
Chemical Development, Bristol-Myers Squibb
One Squibb Drive, New Brunswick, NJ 08903 (USA)
E-mail: carolyn.wei@bms.com
[**] We thank Bristol-Myers Squibb, in particular Dr. David Kronenthal
and Dr. Robert Waltermire, for support of this work. We also thank
the reviewers of this manuscript for many helpful suggestions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210252.
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mixture by 1H and 11B NMR spectroscopy after the reduction
of 1 by B2pin2 indicated that 2.0 equiv AcOBpin is formed
along with the {L2Pd0} complex, with no detectable formation
of phosphine oxide or Pd black.
A visual comparison of the two methods of catalyst
activation is shown in Figure 1. As previously indicated, the
base-promoted reduction of 1 leads to significant formation of
Pd black and only 50% net conversion of the PdII source into
[Pd(PCy3)2] (pathway A), whereas the B2pin2-mediated
Table 1: Evaluation of various reagents for the reduction of 1 to 2.
Entry
Reagent
Equiv
t
Yield [%][a]
1
2
3
None
PCy3
H2O
5 h
5 h
5 h
0
0
4
1.0
5.0
4
5
6
7
8
9
10
11
12
KOAc
10.0
10.0
10.0
10.0
10.0
1.1
1.1
10.0
1.1
5 h
5 h
20 min
1 h
1 h
3
TBAOAc
TBAOAc[b]
TBABF4
TBAOTf
KOH[c]
TBAOH
B2pin2
B2pin2
12
47
0
3
1 h
49
50
96
84
20 min
10 min
16 h
[a] Yield determined by 31P NMR spectroscopy with triphenylphosphine
oxide as an internal standard. [b] Addition of 1.0 equiv of H2O.
[c] Addition of 2.0 equiv of [18]crown-6.
the Pd-catalyzed borylation of aryl halides, we evaluated the
possibility that the acetate base in the reaction could promote
catalyst activation. However, heating 1 and excess KOAc in
toluene gave only trace reduction after 5 h (Table 1, entry 4).
Owing to the poor solubility of KOAc in toluene, we also
evaluated the more soluble base, tetrabutylammonium ace-
tate (TBAOAc). The reaction of 1 and excess oven-dried
TBAOAc stalled at 30% conversion of the PdII complex into
[Pd(PCy3)2] (2, 12%), with concomitant formation of phos-
phine oxide and Pd black (entry 5). As trace amounts of water
are typically present in catalytic reactions containing base,[15]
we allowed 1 to react with TBAOAc in the presence of
1.0 equiv H2O. Under these conditions, complete reduction of
1 was observed to give 50% yield of 2 along with 1.0 equiv of
Figure 1. Reduction of 1 by TBAOAc (pathway A)[15] and by B2pin2
(pathway B).
reduction of 1 leads to the quantitative formation of [Pd-
(PCy3)2] (pathway B). In the former pathway, one phosphine
ligand coordinated to the PdII center is converted into the
corresponding phosphine oxide, leaving an unstable mono-
phosphine {L1Pd0} species that undergoes rapid disproportio-
nation to {L2Pd0} and Pd black. Owing to the oxidation of one
equivalent of phosphine during the base-mediated reduction,
standard preparations of {LnPd0} complexes from [LnPdCl2]
and KOH typically require the addition of excess free
phosphine.[14a,c]
In the case of B2pin2-mediated reduction, no phosphine
oxide is formed; therefore, catalyst activation through this
pathway proceeds cleanly and forms the Pd0 complex 2 in high
yield. To determine the generality of using a diboron species
as a reductant for {LnPdII}, we examined the reduction of
[LnPd(OAc)2] complexes of P(iPr)3, P(tBu)3, PPhCy2, and A-
taPhos as well as the analogous dichloride PdII complex
[(Cy3P)2PdCl2]. For each of the acetoxy–PdII complexes, full
conversion into the corresponding [(R3P)2Pd0] species was
observed after 1 h at 708C using 10 equiv B2pin2. In contrast,
[(Cy3P)2PdCl2] proved unreactive under these conditions,
suggesting that acetoxy groups on the PdII center are
necessary for the reduction to occur.
=
O PCy3 after 20 min at 708C (entry 6). Based on our
observation that increasing amounts of water enhances the
rate of reduction, we hypothesized that hydroxide, rather than
ammonium cation or acetate anion, was responsible for
promoting the reduction of 1. Indeed, ammonium salts such as
TBABF4 and TBAOTf gave less than 5% reduction of 1 to 2
(entries 7 and 8), while hydroxide bases such as KOH[16] or
TBAOH reduced 1 to a mixture of 2, phosphine oxide, and Pd
black (entries 9 and 10).
Although the experiments summarized in entries 1–10 of
Table 1 are consistent with a base-promoted, phosphine-
mediated PdII reduction process, they do not rule out the
existence of alternative reduction pathways in the Miyaura
borylation. Along with phosphine-mediated reduction, nucle-
ophilic coupling partners such as organolithium reagents,[17]
organostannanes,[18] arylboronic acids,[19] alcohols,[20] and
amines[21] have also been reported to effect the reduction of
PdII to Pd0. Therefore, we conducted the reaction of 1 with the
diboron reagent, B2pin2. Heating 1 with 10 equiv B2pin2 led to
the quantitative conversion of 1 into [Pd(PCy3)2] (2) within
10 min at 708C (entry 11).[22] Further investigation revealed
that only one equivalent of B2pin2 is required for complete
reduction of 1 to 2, but the rate of the reduction is slower
under these conditions (entry 12). Analysis of the reaction
Based on our understanding of the available pathways for
PdII reduction, we next examined the impact of catalyst
activation on the Pd/PCy3-catalyzed borylation of bromoben-
zene (Figure 2). Using a standard “dump-and-stir” procedure,
wherein all reagents are charged simultaneously with no prior
catalyst pre-aging, the borylation of PhBr catalyzed by
0.2 mol% 1 formed the corresponding phenylboronate ester
(PhBpin) in 84% yield after 5 h at 708C (condition A).
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To identify the Pd species generated from the reduction of
1 by TBAOAc in the presence of PhBr, we conducted the
stoichiometric reaction of 1 with 5.0 equiv TBAOAc and
10 equiv of PhBr [Eq. (2)].[26] After 1 h at 708C, the PdII
Figure 2. Kinetic experiments comparing different reaction setups for
the Pd/PCy3-catalyzed borylation of PhBr using 1.1 equiv B2pin2 and
2.0 equiv TBAOAc at 708C. Condition A: “dump-and-stir” with
0.2 mol% 1; condition B: pre-age 0.2 mol% 1 with B2pin2 in toluene
for 10 min at 708C, then add PhBr and TBAOAc; condition C:
0.2 mol% 2; condition D: pre-age 0.2 mol% 1 with PhBr and TBAOAc
in toluene for 1 h at 708C, then add B2pin2. All of the reactions were
monitored by HPLC using 1,3,5-trimethoxybenzene as an internal
standard.
complex 1 was fully converted into a single species that
exhibited a 31P peak at 33.9 ppm along with one equivalent of
tricyclohexylphosphine oxide (45.8 ppm). The chemical shift
at 33.9 ppm was comparable to the 30–37 ppm chemical shifts
previously
reported
for
monophosphine
dimers
[{(R3P)Pd(Ph)(m-OH)}2][14b]
and [{(R3P)Pd(Ph)(m-
OAc)}2].[27] Subsequent isolation from acetone gave the air-
stable, crystalline monophosphine phenyl PdII complex 3 in
59% yield (Figure 3).
Although this reaction gave a high yield of the aryl boronate,
a significant induction period was observed during the course
of the reaction. This induction period could be eliminated by
pre-aging the PdII precatalyst 1 with B2pin2 for 10 min at
708C, followed by subsequent addition of the aryl halide and
TBAOAc (condition B). The reaction rates and profiles
obtained from this pre-aging procedure were identical to
that obtained from using 0.2 mol% 2 (condition C), consis-
tent with our observation that the Pd0 species obtained from
pre-aging 1 with B2pin2 is 2.
In contrast to these results, an alternative pre-aging
procedure that involved heating 1 with TBAOAc prior to
addition of PhBr and B2pin2 gave inconsistent reaction rates,
occasional reaction stalling, and greater amounts of biphenyl
by-product. These observations are consistent with the
presence of ligandless Pd species in the reaction mixture,
which can participate in the catalytic reaction but are often
less reliable and generate greater impurities than ligated Pd
complexes.[23] To stabilize the transient monophosphine
{L1Pd0} species and to prevent the formation of ligandless
Pd, an additional equivalent of free phosphine could be added
to form a more stable bisphosphine {L2Pd0} species. However,
we reasoned that the reactive {L1Pd0} species should also
undergo rapid oxidative addition of an aryl halide to form an
[L1PdII(Ar)X] complex. As aryl halides are substrates for
a variety of Pd-catalyzed reactions, the activation of a PdII
precatalyst in the presence of base and aryl halide would be
an attractive method for converting an [L2Pd(OAc)2] species
such as 1 into a catalytically active Pd complex.
The reaction of 1 with TBAOAc and PhBr at 708C led to
the generation of a colorless solution with no observable
formation of Pd black.[24] Subsequent addition of B2pin2 and
further heating at 708C provided a 92% yield of PhBpin after
1 h (condition D).[25] Notably, this catalyst activation proce-
dure provided a significantly faster reaction than the analo-
gous reaction using [Pd(PCy3)2] as catalyst, which required
approximately 4 h to reach completion.
Figure 3. ORTEP diagram of the complex [(Cy3P)2Pd2Ph2(m-OH)(m-
OAc)] (3) with ellipsoids set at 35% probability (hydrogen atoms,
except for the bridging OH group, are omitted).
As transmetalation during the Miyaura borylation is
commonly proposed to occur between B2pin2 and
a [L2Pd(Ar)(OAc)] species, we sought to determine whether
one or both Pd centers of the acetoxo-, hydroxo-bridged
dimer 3 would undergo reaction with the diboron reagent.
The reaction of 3 and 2.0 equiv B2pin2 at room temperature
resulted in the immediate formation of Pd black and 2.0 equiv
PhBpin, indicating that both of the oxo-bound Pd centers
undergo transmetalation with B2pin2. To determine if 3 is
a competent catalyst for the Miyaura borylation, we con-
ducted the borylation of PhBr with B2pin2 using 0.1 mol% 3
(0.2 mol% Pd). The reaction proceeded rapidly and led to
a 93% yield of PhBpin after 1 h at 708C. No induction period
was observed during this reaction, and the reaction rate was
identical to that of a reaction using 0.2 mol% 1 pre-aged with
TBAOAc and PhBr. The precipitation of Pd black was not
observed until the end of these reactions, indicating that
under the conditions of the catalytic reaction the oxidative
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addition of an aryl halide to {(Cy3P)Pd0} is faster than
disproportionation to form [Pd(PCy3)2] and Pd black.
a catalytic reaction, but also on the identity and reactivity of
the Pd catalyst.
Although monophosphine {L1Pd} complexes are com-
monly proposed to be more reactive than analogous bisphos-
phine {L2Pd} complexes owing to the presence of an addi-
tional open coordination site on the metal center,[28] to the
best of our knowledge a direct comparison of an {L1Pd}
complex and an {L2Pd} complex containing the same dative
ligand has not been reported. This is partially due to the
instability of monophosphine {L1Pd0} complexes, which
precludes their direct comparison with {L2Pd0} species, and
the preference of PdII complexes to contain either one or two
phosphines based on the steric properties of the ligand. For
example, PdII complexes containing unhindered trialkyl- or
triarylphosphine ligands, such as PCy3 and PPh3, typically
exist as bisphosphine [L2Pd(Ar)X] species, whereas PdII
complexes containing bulky phosphines, such as P(tBu)3 and
Q-Phos, typically exist as three-coordinate [L1Pd(Ar)X]
complexes.[29] As the monophosphine PdII pseudodimer 3,
containing a single PCy3 ligand on each Pd center, was
determined to be a competent catalyst for Miyaura boryla-
tion, we sought to compare the catalytic activity of 3 with the
analogous bisphosphine PdII complex [(Cy3P)2Pd(Ph)(OAc)]
(4). A comparison of the rate of borylation of PhBr using
0.1 mol% 3 versus 0.2 mol% 4 demonstrates that the reaction
catalyzed by monophosphine PdII species 3 is approximately
four-fold faster than the analogous reaction catalyzed by
bisphosphine PdII species 4 (Figure 4).
Received: December 23, 2013
Published online: && &&, &&&&
Keywords: borylation · catalyst activation · palladium ·
.
reaction kinetics · structure elucidation
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Figure 4. Comparison of the reaction rates for the borylation of PhBr
catalyzed by 0.1 mol% 3 (0.2 mol% Pd) and by 0.2 mol% 4 at 708C.
All of the reactions were monitored by HPLC using 1,3,5-trimethoxybe-
nezene as an internal standard.
In summary, our studies of the reduction pathways for PdII
catalyst precursors and the identification of the catalytically
active Pd species generated from each of these pathways have
yielded new insight into catalyst activation in a widely utilized
Pd-catalyzed transformation. Specifically, we identified two
distinct pathways for PdII reduction during the Miyaura
borylation reaction: 1) a diboron-mediated pathway, which
leads to the formation of a bisphosphine {L2Pd0} species; and
2) a base-promoted pathway to form a monophosphine
{L1Pd0} complex, which is prone to disproportionation but
can be efficiently trapped by oxidative addition of an aryl
halide. The fundamental understanding gained from these
studies highlights the importance of catalyst activation, not
only on the amount of productive Pd species formed in
[11] Reactions performed in THF gave nearly identical results as
toluene. For additional information, see the Supporting Infor-
mation.
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in the full conversion of 1 into [Pd(PCy3)2] and Pd black within
1 h at 708C.
[16] Addition of 1.0 equiv [18]crown-6 was necessary to increase
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0.2 mol% 1 was observed without the addition of water.
[25] The end of the reaction is clearly visualized, because as soon as
all the aryl bromide is consumed, colloidal Pd metal precipitates
and the clear colorless solution turns black.
[26] As only 5.0 equiv TBAOAc was utilized for the reduction of 1,
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Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
Angewandte
Communications
Communications
Catalyst Activation
C. S. Wei,* G. H. M. Davies, O. Soltani,
J. Albrecht, Q. Gao, C. Pathirana, Y. Hsiao,
S. Tummala,
M. D. Eastgate
&&&& — &&&&
The Impact of Palladium(II) Reduction
Pathways on the Structure and Activity of
Palladium(0) Catalysts
Two roads diverged: The mechanism of
in situ PdII catalyst activation to generate
an active {LnPd0} catalyst from an air-
stable PdII precursor was examined using
the standard conditions of a Miyaura
borylation reaction. Two pathways for
catalyst activation exist under these con-
ditions, producing two structurally and
chemically distinct {LnPd0} complexes
(see scheme).
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!