Mechanistic studies on direct arylation of pyridine N -oxide: Evidence for cooperative catalysis between two distinct palladium centers

Article abstract of DOI:10.1021/ja2122156

Direct arylations of pyridine N-oxide (PyO), a convenient method to prepare 2-arylpyridines, catalyzed by Pd(OAc)₂ and PtBu₃ have been proposed to occur by the generation of a PtBu₃-ligated arylpalladium acetate complex, (PtBu₃)Pd(Ar)(OAc) (1), and the reaction of this complex with PyO. We provide strong evidence that 1 does not react directly with PyO. Instead, our data imply that the cyclometalated complex [Pd(OAc)(tBu₂PCMe₂CH₂)]₂, which is generated from the decomposition of 1, reacts with PyO and serves as a catalyst for the reaction of PyO with 1. The reaction of PyO with 1 occurs with an induction period, and the reaction of 1 with excess PyO in the presence of [Pd(OAc)(tBu₂PCMe₂CH₂)]₂ is zeroth-order in 1. Moreover, the rates of reactions of PyO with bromobenzene catalyzed by [Pd(OAc)(tBu₂PCMe₂CH₂)] ₂ and [Pd(PtBu₃)₂] depend on the concentration of [Pd(OAc)(tBu₂PCMe₂CH₂)]₂ but not on the concentration of [Pd(PtBu₃)₂]. Finally, the reaction of 1 with a model heteroarylpalladium complex containing a cyclometalated phosphine, [(PEt₃)Pd(2-benzothienyl)(tBu ₂PCMe₂CH₂)], rapidly formed the arylated heterocycle. Together, these data imply that the rate-determining C-H bond cleavage occurs between PyO and the cyclometalated [Pd(OAc)(tBu ₂PCMe₂CH₂)]₂ rather than between PyO and 1. In this case, the resulting heteroarylpalladium complex transfers the heteroaryl group to 1, and C-C bond-formation occurs from (PtBu ₃)Pd(Ar)(2-pyridyl oxide). This mechanism proposed for the direct arylation of PyO constitutes an example of C-H bond functionalization in which C-H activation occurs at one metal center and the activated moiety undergoes functionalization after transfer to a second metal center.

Full text of DOI:10.1021/ja2122156

Communication
pubs.acs.org/JACS
Mechanistic Studies on Direct Arylation of Pyridine N-Oxide: Evidence
for Cooperative Catalysis between Two Distinct Palladium Centers
Yichen Tan, Fabiola Barrios-Landeros,‡ and John F. Hartwig*
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
the aryl or heteroaryl C−H bond is cleaved. Phosphine-ligated aryl-
ABSTRACT: Direct arylations of pyridine N-oxide (PyO),
a convenient method to prepare 2-arylpyridines, catalyzed by
Pd(OAc)2 and PtBu3 have been proposed to occur by the
generation of a PtBu3-ligated arylpalladium acetate complex,
(PtBu3)Pd(Ar)(OAc) (1), and the reaction of this complex
with PyO. We provide strong evidence that 1 does not react
directly with PyO. Instead, our data imply that the cyclo-
metalated complex [Pd(OAc)(tBu2PCMe2CH2)]2, which is
generated from the decomposition of 1, reacts with PyO and
serves as a catalyst for the reaction of PyO with 1. The reac-
tion of PyO with 1 occurs with an induction period, and the
reaction of 1 with excess PyO in the presence of [Pd(OAc)-
(tBu2PCMe2CH2)]2 is zeroth-order in 1. Moreover, the rates
of reactions of PyO with bromobenzene catalyzed by
[Pd(OAc)(tBu2PCMe2CH2)]2 and [Pd(PtBu3)2] depend
on the concentration of [Pd(OAc)(tBu2PCMe2CH2)]2 but
not on the concentration of [Pd(PtBu3)2]. Finally, the reac-
tion of 1 with a model heteroarylpalladium complex contain-
ing a cyclometalated phosphine, [(PEt3)Pd(2-benzothienyl)-
(tBu2PCMe2CH2)], rapidly formed the arylated heterocycle.
Together, these data imply that the rate-determining C−H
bond cleavage occurs between PyO and the cyclometalated
[Pd(OAc)(tBu2PCMe2CH2)]2 rather than between PyO and
1. In this case, the resulting heteroarylpalladium complex
transfers the heteroaryl group to 1, and C−C bond-formation
occurs from (PtBu3)Pd(Ar)(2-pyridyl oxide). This mechanism
proposed for the direct arylation of PyO constitutes an example
of C−H bond functionalization in which C−H activation
occurs at one metal center and the activated moiety under-
goes functionalization after transfer to a second metal center.
palladium carboxylate complexes LPd(Ar)(OC(O)R) are typically
proposed to react with heteroarenes or arenes to form biarylpalla-
dium complexes through a concerted metalation−deprotonation
pathway,7 but we recently reported that a “ligandless” species is
involved in the direct arylation of benzene,8 not the proposed
phosphine-ligated complex.
In contrast, DFT calculations suggested that phosphine-
ligated arylpalladium acetates are competent to undergo C−H
bond cleavage with various heteroarenes, including PyO's.7c
A
recent experimental study showed that the reaction of isolated
(PtBu3)Pd(Ph)(OAc) with 4-nitro-PyO formed the arylated
product, but the yield of this reaction (48%) was lower than
that for the analogous catalytic process.9 Thus, the detailed
mechanism of the cleavage of the aromatic C−H bonds in the
direct arylation of PyO's remains uncertain.
We report the synthesis and full characterization of the PtBu3-
ligated arylpalladium acetate complex (PtBu3)Pd(Ar)(OAc) (1)10
and detailed mechanistic studies of the direct arylation of PyO with
this isolated complex. Inconsistent with previous proposals, the
direct reaction of isolated 1 with PyO does not form arylated pro-
ducts. Instead, the cyclometalated complex [Pd(OAc)(tBu2PCMe2-
CH2)]2 generated via decomposition of 1 catalyzes the reaction
between 1 and PyO to form the arylated product. Our data imply that
this cyclometalated complex directly reacts with PyO to cleave the
aromatic C−H bond. Thus, our data imply that this reaction occurs by
a cooperative C−H bond functionalization process in which one metal
fragment cleaves the C−H bond and a second fragment functionalizes
the moiety resulting from this C−H bond cleavage event.
The synthesis of 1 is outlined in Scheme 1. The reaction of
Pd(PtBu3)2 with 3-(fluoromethyl)phenyl iodide in the presence
of AgOAc formed 1 in acceptable yield for our studies.
Complex 1 was characterized by elemental analysis and NMR
spectroscopy. The fluoromethyl moiety allowed us to monitor
reactions by 19F NMR spectroscopy. The F atom does not
affect the catalytic process; the reaction of 3-(fluoromethyl)-
phenyl bromide with PyO catalyzed by Pd(OAc)2 and PtBu3
formed the 2-aryl-PyO in good yield (77%).
In contrast to the 77% yield of the catalytic reaction, the stoichio-
metric reaction of isolated 1 with PyO at 120 °C in toluene formed
the arylated PyO in a lower 52% yield. This observation was consis-
tent with a previous report in which a similar difference in yield
was obtained between the stoichiometric reaction of an isolated
PtBu3-ligated arylpalladium acetate complex (PtBu3)Pd(Ph)(OAc)
irect arylation, the reaction of aryl halides with arenes or
Dheteroarenes to form biaryl or aryl-heteroaryl products, is an
attractive alternative to traditional cross-coupling because it occurs
without the need to prepare organometallic or main-group reagents.1
For example, the direct arylation of pyridine N-oxide (PyO) with aryl
halides,2 the subject of the mechanistic studies in this paper, leads to
the selective formation of 2-arylpyridine derivatives after reduction to
the pyridine. This sequence occurs without 2-pyridyl organometallic
reagents, which are often unstable and difficult to synthesize. The
scope of direct arylation has broadened to encompass various hetero-
arenes,3 arenes with directing groups,4 electron-deficient arenes,5 and
even simple arenes such as benzene6 as coupling partners.
However, little experimental information on the mechanism of
direct arylations is available, especially on the mechanism by which
Received: December 31, 2011
Published: February 7, 2012
© 2012 American Chemical Society
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Scheme 1. Synthesis of 1 and Its Reaction with PyO under
a
the Previously Reported Conditions
Figure 2. Plots of rate vs [PyO] and [2]1/2 in toluene at 60 °C for the
reaction of 1 with PyO.
a
Yield of arylated product determined by 19F NMR.
measured. Figure 2 shows plots of the reaction rate versus [PyO]
and [2]1/2. The linear fit of the rate vs the concentration of PyO
from 0.2 to 0.6 M showed that the reaction is first-order in PyO. A
linear fit of the rate vs [2]1/2 and a nonlinear fit of the rate vs [2]
revealed a half-order, or at least partial order, dependence on [2]
from 0.015 to 0.15 M. This partial order in [2] implies that the
reaction occurs by a pre-equilibrium between the observed dimeric
2 and a catalytically active monomer before the rate-determining
C−H bond cleavage step. These results, along with the zeroth-
order dependence on [1], clearly support the proposal that the
C−H cleavage occurs by reaction of PyO with 2 rather than 1.
with 4-nitro-PyO and the catalytic reaction of Ph-Br with
4-nitro-PyO.9
These differences in yield between the catalytic and stoichio-
metric reactions led us to study the reaction of isolated acetate 1 in
more detail. Figure 1 shows the profile of the decay of 1 during the
Scheme 2. Two Possible Modes for C−H Bond Cleavage by
the Cyclometalated Palladium Acetate Complex
Figure 1. Decay of (PtBu3)Pd(Ar)(OAc) (1) in toluene at 60 °C in
the presence of 20 equiv of PyO, 1.0 equiv of PtBu3, and 2.5 equiv of
K2CO3 with no additive (black) or with 1 equiv of added 2 (blue).
To determine whether the cyclometalated PtBu3 ligand or the
acetate ligand is involved in the cleavage of the aromatic C−H
bond (Scheme 2, pathway a vs b), an analogous cyclometalated
palladium bromide complex, [PdBr(tBu2PCMe2CH2)]2 (3), was
added to the reaction of 1 and PyO (eq 2). The yield of the
arylated product from this reaction (37%) was even lower than that
from the reaction between 1 and PyO with no additives. Moreover,
no deuterium incorporation into PtBu3 was observed in the reaction
of 2 with PyO-d5. These results imply that the acetate ligand in the
cyclometalated complex is involved in the C−H bond cleavage.
reaction of 1 with PyO at 60 °C in toluene, as measured by 19F
NMR spectroscopy. This reaction exhibited an induction period
followed by a relatively linear decay of 1. The 19F NMR yield of the
arylated product was 55% at the end of the reaction. Further analysis
of the NMR data showed that <1% of the arylated product was
formed during the induction period. Instead, fluoromethylbenzene
and the cyclometalated complex [Pd(μ2-OAc)(κ2-tBu2PCMe2-
CH2)]2 (2)11 were formed during this period (eq 1). Cyclometalated
2 forms from decomposition of 1; heating 1 in toluene for 8 h at
60 °C gave 2 in 92% yield.
If the rate-determining C−H bond cleavage step occurs
between PyO and 2, then the catalytic reactions of bromoarenes
with PyO should depend on the concentration of 2 but not on the
concentration of 1. To test this prediction, reactions of 3-bromo-
toluene with PyO catalyzed by 2 and Pd(PtBu3)2 were conducted
with different amounts of 2 and Pd(PtBu3)2 (Table 1). The
Pd(PtBu3)2 component, along with the combination of HOAc and
base, provides access to intermediate 1. A series of reactions was
conducted with identical amounts of Pd(PtBu3)2 and varying
amounts of 2 (entries 1−3). The reactions with higher concen-
trations of 2 were faster than those with lower concentrations of 2,
and the dependence on [2] was half-order. Reactions with the
same amount of 2 but varying amounts of Pd(PtBu3)2 were also
conducted (entries 3−5). The rate of these reactions did not
depend measurably on the concentration of Pd(PtBu3)2. These
The formation of cyclometalated 2 during the induction period
suggested that this complex could be involved in the reaction of
acetate 1 with PyO. To test this hypothesis, the reaction of 1 with
PyO and 1 equiv of added 2 was conducted. No induction period
was observed during this process, and the yield of 2-aryl-PyO
(84%) was as high as that of the catalytic process. Moreover, a
zeroth-order decay of 1 was observed in the reaction with added 2,
suggesting that the rate-determining step12 occurred without the
involvement of 1. Finally, the concentration of 2 was constant
during this reaction, making 2 a catalyst for the stoichiometric
reaction of PyO with 1.
To assess whether the C−H cleavage step occurs by reaction
of PyO with 2, the order of the reaction in each reagent was
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studies on 2-benzothienylpalladium complexes. Benzothiophene
(BT) undergoes catalytic direct arylation under conditions similar
to those of PyO.3f To assess more specifically whether studies on the
benzothienyl complexes would be relevant to the mechanism of the
reaction of PyO, we first assessed whether the mechanistic data
implying that the reactions of PyO involve two metal complexes also
would be obtained from studies of the reactions of BT. Indeed, the
reaction of 1 with BT occurred in a lower yield (64%) than for the
catalytic direct arylation of BT (85%), but the rate and yield of the
reaction of 1 with BT, like those of 1 with PyO, were much faster
and higher (88%) in the presence of added 2. The yield of the
reaction of 1 with BT in the presence of 2 matched that of the direct
arylation catalyzed by Pd(OAc)2 and PtBu3. Thus, studies on the
transmetalation between 1 and a 2-benzothienylpalladium complex
should assess whether transmetalation between two Pd complexes
could be part of the reaction of PyO and would assess the scope of
our mechanistic conclusions.
Table 1. Reactions of PyO with 3-Bromotoluene with Varied
Amounts of the Two Pd Cocatalysts
Pd catalyst amounts (mol %)
a
entry
2
Pd(PtBu3)2
initial rate (M/s)
1
2
3
4
5
1
2
5
5
5
5
5
5
2
1
2.8 × 10−6
5.3 × 10−6
8.5 × 10−6
7.7 × 10−6
8.2 × 10−6
a
Calculated by monitoring the reaction by GC during the first hour
(estimated errors are 0.3 × 10−6 M/s)
results further support our assertion that the C−H bond cleavage
occurs by the reaction of PyO with the monomeric form of 2.
To assess the differences in barriers for cleavage of the C−H
bond in PyO by complexes 1 and 2, we used density functional
theory (DFT) to compute the barriers for the reaction of PyO
with (PtBu3)Pd(Ph)(OAc) and PdOAc(tBu2PCMe2CH2). The
calculated ΔG⧧ at 25 °C for the reaction of Pd(OAc)-
(tBu2PCMe2CH2) with PyO was found to be 27 kcal/mol,
whereas that for the reaction of (PtBu3)Pd(Ph)(OAc) with PyO
was found to be 33 kcal/mol (see the Supporting Information for
details). The calculated barrier for the reaction of PyO with 2
matches well with the experimental barrier (27 kcal/mol) obtained
from the kinetic data and is much lower than the barrier computed
for the reaction of (PtBu3)Pd(Ph)(OAc) with PyO. These
computed barriers are, again, consistent with our proposal that
PyO reacts with 2 rather than with 1.
PEt3-stabilized benzothienylpalladium complex 4 containing the
cyclometalated phosphine was prepared in acceptable isolated yield
by reacting cyclometalated bromide complex 3 with 2-benzothi-
enyllithium in the presence of PEt3 and Ag2CO3 (Scheme 4). This
Scheme 4. Reaction of Complexes 4 and 5 with 1
On the basis of these studies, we propose that the reaction
of PyO with 1 occurs by the catalytic cycle shown in Scheme 3.
1
complex was characterized by H and 31P NMR spectroscopy. A
species assigned as the analogous 2-benzothieneyl complex lacking
PEt3 was formed in ∼70% yield by the reaction of 3 with 2-benzo-
thienyllithium in the absence of PEt3 and Ag2CO3. This complex
Scheme 3. Reaction of PyO with 1 Catalyzed by 2
was characterized in situ by H and 31P NMR spectroscopy.
1
The reaction of complex 4 with 1 formed the 2-aryl-BT product
within 5 min at 50 °C in 84% yield (Scheme 4). The analogous
reaction with complex 5 generated in situ was even faster, forming
the arylated product in 74% yield within 5 min at room
temperature. The fast rate and high yield of the reactions of 1 with
4 and 5 containing the cyclometalated phosphine in-
dicate that transmetalation between a heteroarylpalladium inter-
mediate and 1 is kinetically and chemically competent to be part of
the mechanism for the stoichiometric reaction of 1 with PyO and
BT and the catalytic arylations of these heteroarenes in the
presence of Pd(OAc)2 and PtBu3.
The pathway in Scheme 5 for the direct arylation of PyO cata-
lyzed by Pd(OAc)2 and PtBu3 is consistent with our mechanistic
data on the stoichiometric reaction of PyO with 1. This catalytic
network comprises the cooperation of two distinct metal
fragments in two merging catalytic cycles. The left cycle begins
with oxidative addition of the aryl bromide to (PtBu3)Pd(0) to
form an arylpalladium(II) intermediate D. Exchange of acetate for
bromide would generate the arylpalladium acetate intermediate
(1) proposed previously to cleave the heteroaryl C−H bond.
Instead, our data imply that an arylpalladium(II) species under-
goes transmetalation with cyclometalated intermediate B to form
the aryl heteroaryl palladium species C. C−C bond-forming reduc-
tive elimination would then form the 2-arylpyridine oxide product
PyO reacts with cyclometalated palladium acetate complex A
(the monomer of 2) to generate heteroarylpalladium inter-
mediate B, which then reacts with 1 via transfer of the aryl group
to form aryl heteroaryl complex C. In this mechanism, it is
complex C that undergoes reductive elimination to form the
Pd(0) product and the 2-arylpyridine.
To assess further the proposed pathway, we prepared an example
of the proposed heteroarylpalladium intermediate containing the
cyclometalated phosphine. With such a complex, we could evaluate
whether the reaction of a cyclometalated heteroaryl complex with the
arylpalladium carboxylate complex 1 was sufficiently fast to be part of
the catalytic cycle. Because of the known difficulty in generating
2-metalated pyridine oxides,13 which would be used to generate
2-pyridyloxide palladium complexes, in high yield, we conducted
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Scheme 5. Revised Mechanism for Direct Arylation of PyO
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
■
Present Address
‡Department of Chemistry, Yeshiva University, New York, NY
10033.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank NIH (GM-58108) for financial support and Dale
Pahls for guidance and suggestions with the DFT calculations.
■
and regenerate the active Pd(0) catalyst to complete the cycle
shown at the left of Scheme 5. In a second cycle, shown at the
right of Scheme 5, monomeric Pd(OAc)(tBu2PCMe2CH2) reacts
with PyO to cleave the C−H bond and form the complex B con-
taining the cyclometalated phosphine.
REFERENCES
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(10) The first synthesis of (PtBu3)Pd(Ph)(OAc): , Barrios-Landeros,
F. Oxidative Addition of Haloarenes by Pd(0) Complexes of Bulky
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Ph.D. Dissertation, Yale University, 2007.
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(12) For results on primary KIEs, see refs 2 and 9. In addition, we
monitored the catalytic reaction by 31P NMR spectroscopy, and 2 was
observed as the catalyst’s resting state.
Our kinetic data imply that the turnover-limiting step in the
catalytic direct arylation of PyO occurs between PyO and the
monomeric Pd(OAc)(tBu2PCMe2CH2). The equilibrium between
the observed dimer 2 and the active monomeric complex A is
consistent with the partial-order behavior in palladium, and the
overall scheme is consistent with the first-order behavior in PyO
and zeroth-order behavior in arylpalladium acetate complex 1.
Calculations of the barrier of the reactions of PyO with
(PtBu3)Pd(Ph)(OAc) and Pd(OAc)(tBu2PCMe2CH2) with DFT
also support the conclusion that the cyclometalated palladium
acetate species is more reactive toward C−H bond cleavage
than is the arylpalladium acetate intermediate. These data are
also consistent with the kinetic data previously obtained on the
catalytic process9 and resolve the inconsistency in the conclusion
from these studies of the partial order in palladium and the
monomeric nature of the proposed catalyst resting state and the
species proposed to react with the pyridine oxide in the turnover-
limiting step. Analogous data on the reaction of BT imply that
our conclusions pertain to direct arylation reactions beyond PyO.
In summary, detailed kinetic studies on the reactions of the
isolated arylpalladium acetate complex 1 with pyridine N-oxide in
the presence of added cyclometalated palladium acetate complex 2,
along with studies on isolated heteroarylpalladium complex 4 con-
taining a cyclometalated phosphine, have revealed an unexpected
mechanism in which the C−H bond of PyO is cleaved by the reac-
tion with cyclometalated complex 2. We propose that the con-
strained ring in 2 makes the metal center less hindered and, there-
by, allows the reaction of PyO with 2 to occur with a lower barrier
than the reaction of PyO with 1. By the proposed mechanism, one
palladium fragment containing P(tBu)3 as ligand adds the aryl
halide and forms the C−C bond, but a second fragment containing
a cyclometalated phosphine undergoes the C−H bond cleavage
step. One can envision many processes for C−H bond func-
tionalization in which one metal cleaves a C−H bond and transfers
the resulting hydrocarbyl ligand to a second metal that leads to
functionalization, but the demonstration of such a process, other
than reactions in which a second metal deprotonates an acidic
substrate, is rarely documented.14 New processes that are based on
such a design will be the subject of future studies.
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Tetrahedron Lett. 2008, 49, 6901.
(14) (a) For a recent example of cooperative catalysis between palladium
and copper in direct arylation of acidic arenes, see: Huang, J.; Chan, J.;
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Chem. Soc. 2010, 132, 3674. (b) For a recent example of cooperative
catalysis between palladium and copper in direct allylation, see: Fan, S.;
Chen, F.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 5918.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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