C(sp3)-O bond-forming reductive elimination of ethers from bisphosphine-ligated benzylpalladium(II) aryloxide complexes

Article abstract of DOI:10.1002/anie.201101088

On the contrary: Isolated benzylpalladium aryloxide complexes undergo C(sp³)-O bond-forming reductive elimination by a stepwise ionic mechanism (see scheme) distinct from the accepted concerted pathway for reductive elimination of aromatic ethers from arylpalladium(II) species. The mechanism is proposed to result from dissociation of the aryloxide ligand followed by nucleophilic attack on the benzylic carbon atom. Copyright

Full text of DOI:10.1002/anie.201101088

DOI: 10.1002/anie.201101088
À
C O Bond Formation
3
À
C(sp ) O Bond-Forming Reductive Elimination of Ethers from
Bisphosphine-Ligated Benzylpalladium(II) Aryloxide Complexes**
Seth L. Marquard and John F. Hartwig*
3
À
Reductive elimination to form aryl ethers and arylamines
from arylpalladium(II) alkoxide or amido complexes has
been documented, but the formation of alkyl ethers or
alkylamines by the same process is less common. The
ination to form C(sp ) O bonds in ethers and to gain
mechanistic information that would allow comparisons to be
made to the mechanisms of other types of reductive
eliminations.
2
2
À
À
formation of C(sp ) O or C(sp ) N bonds occurs by con-
certed reductive elimination from arylpalladium(II) com-
plexes as stoichiometric reactions and during catalytic pro-
cesses,[1–8] but analogous reactions of palladium alkoxide
Here, we report thermal reductive eliminations from
palladium(II) aryloxide complexes to form a C(sp ) O bond
and a series of experiments that provide detailed mechanistic
insight. In short, our data show that the mechanism of this
reaction is more akin to reductive eliminations to form
3
À
3
[9]
À
complexes to form C(sp ) O bonds is unknown.
3
3
À
À
Instead, all of the known C(sp ) O reductive elimination
reactions from alkoxide or aryloxide complexes occur from
metal centers in oxidation states higher than palladium(II),
despite the diversity of reductive elimination processes that
occur from palladium(II). For example, reductive elimina-
tions to form alkyl acetates and alkyl aryl ethers is docu-
mented from methylplatinum(IV) centers.[10,11] Reductive
eliminations from the methylplatinum acetate and aryloxide
complexes occur by a mechanism involving ionic intermedi-
ates, while reductive eliminations from platinum(IV) metal-
laoxetanes to form epoxides are proposed to occur by a
concerted pathway.[12] Reductive eliminations of tetrahydro-
furan and tetrahydropyran from metallacyclic NiII alkylalk-
oxide complexes also has been reported. These reductive
eliminations occur after initial reaction with an oxidant,
presumably to generate a NiIII intermediate.[13–15]
C(sp ) N bonds from palladium(II) than those that form
2
À
À
À
C(sp ) O bonds from palladium(II) or any type of C O or C
N bond from higher-valent metal centers, but indicate that
substantial differences exist between reductive eliminations
to form the C(sp3) bonds in ethers and amines from
palladium(II). The stereochemical outcome of the reaction
indicates an ionic pathway, but the process lacks many of the
effects of electronic and solvent perturbations that typically
signal an ionic intermediate.
After a survey of complexes containing different phos-
phine ligands, we found that benzylpalladium aryloxide
complexes ligated by dppf (1,1’-Bis(diphenylphosphino)fer-
rocene) displayed the appropriate balance of stability, reac-
tivity, and synthetic accessibility to observe reductive elimi-
3
À
nations that form C(sp ) O bonds from fully characterized
complexes. The dppf-ligated palladium aryloxide complexes
We recently reported reductive eliminations to form the
1–10 were synthesized as shown in Scheme 1. Benzyl com-
3
À
C(sp ) N bond in N-benzyl diarylamines and provided
evidence that these reactions occur by a stepwise process
through ionic intermediates.[16] Because of the differences in
stabilities of alkoxide and amide anions, differences in
abilities of low and high-valent complexes to cleave to form
ion pairs, differences in nucleophilicities of alkoxides and
amides, and differences in the stabilities of nitrogen- and
oxygen-centered radicals, the relationship between the mech-
3
À
anisms of reductive eliminations to form C(sp ) N and
3
À
C(sp ) O bonds from low-valent and high-valent metal
centers are difficult to predict. Thus, we sought to identify
palladium(II) complexes that would undergo reductive elim-
[*] S. L. Marquard, Prof. Dr. J. F. Hartwig
Department of Chemistry
University of Illinois Urbana-Champaign
Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: jhartwig@illinois.edu
[**] This work was supported by the NSF as part of the Center for
Enabling New Technologies through Catalysis (CENTC), CHE-
0650456. We thank Luc Boisvert and Karen Goldberg at the
University of Washington for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101088.
Scheme 1. Synthesis of palladium aryloxide complexes.
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Communications
plexes 1–6 were prepared by allowing the known
To distinguish between reductive elimination from com-
plexes 1–9 through a concerted, radical or ionic pathways, we
studied reactions in the presence of a trap for a phenoxy
radical[22] and prepared a diastereomeric benzylpalladium
aryloxide complex that enabled us to determine the relative
configuration of the benzylic carbon atom in the reactant and
product. Reductive elimination from complex 2 in the
presence and absence of 2 equiv of BHT (butylated hydroxy-
toluene) as a radical trap occurred with indistinguishable rate
constants (2.8 ꢀ 10À4 sÀ1 and 2.9 ꢀ 10À4 sÀ1). The rate of reac-
tion of BHT with another phenoxy radical is expected to be
about 107 mÀ1 sÀ1.[22] Although rapid trapping of a potential
phenoxy radical with the metal complex could be occurring,
these data and stereochemical data (see below) argue against
the intermediacy of a phenoxy radical.
To determine the relative configuration of the palladium-
bound carbon in the reactant and product, we prepared a
monodeuterated benzylpalladium aryloxide complex contain-
ing a chiral, non-racemic aryloxide and bisphosphine. The
presence of a chiral, non-racemic bisphosphine allowed us to
determine the relative ratio of benzylpalladium halide
precursors having the R and S configurations at the benzylic
position. The inclusion of a chiral, non-racemic aryloxide in
the complex allows determination of the configuration of the
benzylic carbon in the benzyl aryl ether formed by reductive
elimination. This strategy is based on the one we developed
for determining the stereochemical outcome of the reductive
elimination of benzylamines.[16]
[(cod)Pd(Bn)Cl][17] (cod = cyclooctadiene) to react with
dppf, followed by the potassium aryloxide in THF. Naph-
thylmethyl and mesitylmethyl complexes 7 and 8 were
synthesized by allowing [CpPd(h3-allyl)][18] to react with
dppf, followed by naphthylmethyl or mesitylmethyl bromide.
These bromide precursors were then converted to the
aryloxide complexes by reaction with the potassium aryloxide
in diethyl ether or THF. The acetate complex 9 was prepared
by allowing [(cod)Pd(Bn)Cl] to react with dppf, followed by
the addition of silver acetate in THF. Methylpalladium
aryloxide complex 10 was synthesized by the reaction of
[(cod)Pd(Me)Cl][19] with dppf, followed by addition of the
potassium aryloxide. Complexes 1–10 were characterized by
conventional one-dimensional NMR spectroscopic methods
and elemental analysis.
To assess the ability of complexes 1–10 to undergo
reductive elimination, benzene solutions of these complexes
were heated with excess dppf to trap the Pd0 product. As
shown in Table 1, benzyl complexes 1–6 and naphthylmethyl
3
À
Table 1: C(sp ) O bond reductive elimination.
Complex
R1
R2
kobs [sÀ1
]
Yield
[%][a]
t1/2
[min]
104
The required materials for this analysis were prepared as
shown in Scheme 2. The monodeuterio benzylpalladium
chloride complex 11 was synthesized in an 85:15 diastereo-
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Naphthyl
Mesityl
Ph
C6H4-p-OMe
C6H4-p-Me
C6H4-p-Cl
C6H4-p-CF3
C6H3-3,5-CF3
C6H3-3,5-CH3
C6H3-3,5-CF3
C6H3-3,5-CF3
Ac
2.4
2.8
3.3
2.6
2.6
1.7
3.8
14
94
73
84
92
79
48
41
35
44
44
75
68
99[b]
100[c,d]
64
31[b]
8[c]
170
–
0.68
–
10
H
C6H4-p-OMe
0[e]
1
[a] Yields were determined by H NMR spectroscopy, relative to trime-
thoxybenzene as an internal standard on reactions conducted in
[D6]benzene at 708C, unless otherwise noted. [b] Reaction conducted
at 308C. [c] Reaction conducted at 558C. [d] The products were a mixture
of the 2,4,6-trimethylbenzyl ether and the 2,3,5-trimethylbenzyl ether.
[e] Hexamethylbenzene was used as an internal standard.
Scheme 2. Synthesis of the monodeuterated complex; binap=2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl.
complex 7 underwent reductive elimination in high yields.
The mesitylmethyl complex 8 also underwent reductive
elimination, in this case to form a mixture of the 2,4,6-
trimethylbenzyl ether (65%) and the isomeric 2,3,5-trime-
thylbenzyl ether (35%). The acetate complex 9 underwent
reductive elimination more slowly than did any of the other
complexes studied. The observed reductive elimination of
complex 9 contrasts with the previously described oxidative
addition of benzyl trifluoroacetate to Pd0.[20] The less hindered
methyl complex 10 did not form products from reductive
elimination when heated for extended reaction times at 708C;
instead methane and free phenol (95%) were observed. The
source of the protons and electrons remains unclear at this
time.[21]
meric ratio enriched in the Ra,RC isomer from [CpPd(h3-
allyl)], (R)-binap, and (S)-monodeuterio benzylchloride.
Complex 11 was converted to the corresponding Ra,Ra,RC-
benzylpalladium binaphthylaryloxide complex (12) by addi-
tion of potassium Ra-binaphthylaryloxide in THF. Complex
12 was characterized using conventional NMR spectroscopic
methods and elemental analysis.
Complex 12 underwent reductive elimination of the O-
benzyl binaphthyl ether 13 in 88% yield after 4 h at 808C, as
1
determined by H NMR spectroscopy relative to an internal
1
standard [Eq. (1)]. H NMR spectroscopy indicated that the
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product 13 consisted of the same 85:15 ratio of diastereomers
as was present in the reactant 12. Comparison of the 1H NMR
spectrum of the ether product 13 to that of the ether product
prepared independently indicated that the reductive elimi-
nation occurred with inversion of configuration to form
predominately Ra,SC-13 (see Supporting Information). We
envision the stereochemical outcome results from dissocia-
tion of the aryloxide, followed by nucleophilic attack of the
aryloxide anion on the benzylic carbon. Reactions that occur
by dissociation of aryloxide ligands to form ionic intermedi-
ates during organometallic processes in nonpolar solvents are
unusual. Nucleophilic attack of phenoxide onto a p-bound
allyl ligand is known,[23–26] but none of the reported reactions
begin with an allylalkoxide complex.
observed is not likely due to the stability of the anion alone
because a similar small (2.8 times) difference in rate of
reductive elimination to form a benzylamine in polar and
non-polar solvents was observed previously.[16] In contrast,
reactions to form methyl aryl ethers from PtIV complexes
were an order of magnitude faster in nitrobenzene than in
benzene.[10] This solvent effect for reaction of PtIV complexes
parallels the classic prediction by Hughes and Ingold[28] of
faster rates in more polar solvents for elementary reactions
that generate two ions from a neutral species.
Protic additives that stabilize dissociated anions are
known to increase the rate of reductive eliminations that
occur through ionic intermediates.[10,29] Consistent with this
trend, the reaction of complex 2 in the presence of 2.6 equiv of
cresol occurred with a rate constant (5.1 ꢀ 10À4 sÀ1 at 308C)
that is about 100 times larger than that for reaction of
complex 2 in the absence of added cresol (5 ꢀ 10À6 sÀ1 at
308C). Hydrogen bonding between phenols and phenoxide
ligands has been observed in solution and in the solid
state,[30,31] and stabilization of the phenoxide ion by phenol
likely leads to this large increase in rate. This effect of the
conjugate acid of the nucleophilic anion differs from that of
reductive eliminations to form benzylamines. Reactions from
related diarylamido complexes were unaffected by added
diarylamine, presumably because the greater steric hin-
derance of the diarylamide and the lower acidity of a
diarylamine hydrogen-bond donor weakens this associa-
tion.[16]
The small effect of the electronic properties of the
phenoxide and the small effect of solvent polarity on the
rate of reductive elimination from benzylpalladium phenox-
ide complexes can be rationalized by the combination of
reversible dissociation of the aryloxide from the benzylpalla-
dium aryloxide complex and irreversible collapse of the
charge-separated pair to form the benzyl ether product
[Eq. (2)]. The first equilibrium step would be favored by
electronic[10,32,33] and solvent effects[10,34] that stabilize ion
pairs, but the second step (k2) would be disfavored by factors
that stabilize ion pairs.[35] Thus, the overall effect of substitu-
ents and solvent on the reaction rate is complex and would
depend on the relative effects of the properties of the system
on these two steps, including the effects of these properties on
the partitioning of the ionic intermediate for attack of the
aryloxide at the metal to reform the starting complex and
attack at the benzyl group to form the ether product.
Several experiments were conducted to probe the effect of
parameters that typically stabilize ionic species and accelerate
reactions that occur by ionization of the reactant. The effect
of the electronic properties of the aryloxide ligand on the rate
of the reductive elimination from complexes 1–4 are shown in
Table 1. Reductive elimination from complex 4 containing an
electron-withdrawing p-CF3 group occurred with a rate
constant that is indistinguishable from that of reductive
elimination from the p-tolyl complex 2, and the rate constant
for reductive elimination from complex 1 containing an
electron-donating p-OMe group was nearly identical to that
for reductive elimination from complexes 2 and 4. The p-
chloro complex 3 reacted somewhat faster than the other
para- substituted complexes 1, 2, and 4, but the magnitude of
these differences was small. Thus, the rate of reductive
elimination is not significantly influenced by the electronic
properties of the aryloxide ligand. This result contrasts with
the accelerating effect of electron-withdrawing substituents
3
À
on reductive elimination to form C(sp ) O bonds from
PtIV,[10,11] and the modest but measurable effect of substituents
on the rate of reductive elimination to form C(sp ) N bonds
3
À
from benzylpalladium diarylamido complexes.[16] This lack of
an electronic effect on reductive elimination even contrasts
with the strong effect of the properties of the aryloxide group
on concerted reductive elimination from arylpalladium aryl-
oxide complexes.[27]
Like the effect of substituents, the effect of solvent
polarity on the rate of reductive eliminations from the
benzylpalladium phenoxide complexes was small. The reac-
tion of complex 1 in [D5]nitrobenzene occurred with a rate
constant of 4.6 ꢀ 10À4 sÀ1 at 558C, whereas the reaction of 1 in
[D6]benzene at the same temperature occurred with a rate
constant of 1.8 ꢀ 10À4 sÀ1. Although the reaction is faster in the
more polar solvent, the magnitude of this effect of solvent
polarity is small for a reaction occurring through an ionic
intermediate. Moreover, the difference in rate that is
To test our proposal that dissociation of the aryloxide
group is reversible, we allowed [(dppf)Pd(h3-Bn)]PF6] to react
with a suspension of KO-p-tolyl in C6H6 at room temperature
[Eq. (3)]. This reaction cleanly formed benzylpalladium
aryloxide complex 2. No observable benzyl ether was
formed. Although this system contains potassium and PF6
counterions that are not present in the reactions of 1–9, this
result is consistent with our proposal that dissociation of the
À
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Communications
phenoxide from the benzylpalladium aryloxide complex is
to undergo the same process likely results from a combination
of several factors. For example, a benzyl group is more
electrophilic than a methyl group and a benzyl group would
promote dissociation of the aryloxide anion because it can
stabilize the cationic intermediate through an h3 binding
mode and it is more hindered than a methyl group. Analogous
methylpalladium(II) complexes containing a more nucleo-
philic amido ligand also did not undergo reductive elimina-
tion, indicating that the electronic or steric properties of the
methyl ligand are most strongly affecting the propensity of
these complexes to undergo reductive elimination.[16]
reversible because collapse of the ion pair to regenerate the
benzylpalladium aryloxide complex is faster than nucleophilic
attack of the aryloxide anion on the benzylpalladium cation to
form the benzyl ether product.
Indeed, the coordinating ability and steric properties of
the benzyl group had a large influence on the rate of reductive
elimination. Consistent with the proposed ionic mechanism,
naphthylmethyl complex 7 underwent reductive elimination
much faster than benzyl complex 5. The naphthylmethyl
ligand should bind in an h3-fashion more strongly than the
benzyl ligand, and nucleophilic attack on an h3-naphthyl-
methyl complex is known to occur faster than attack on an
analogous h3-benzyl complex.[36] In addition, the mesityl-
methyl complex 8 reacted faster than the benzyl complex 5.[37]
A similar trend of faster reductive elimination from naph-
thylmethyl and mesitylmethyl palladium amido complexes
was observed.[16] Thus, further studies are needed to define
the role of the hydrocarbyl ligand in these reactions, but these
preliminary data imply that several properties of the hydro-
carbyl group affect the rate of reductive elimination.
Considering the strong evidence that reductive elimina-
tion occurs through ion pairs, we probed whether reductive
À
À
elimination to form C O or C N bonds would be faster under
two sets of conditions that would generate alkoxide and
amide ions. First, we conducted a reaction in which the system
would contain both alkali metal diarylamides and phenoxides.
The reaction of 5 equiv of KN(p-tolyl)2 and KO-p-tolyl in
THF with [(dppf)Pd(h3-Bn)]PF6, formed amido complex 14
[Eq. (4)] as the only species observed by 31P NMR spectros-
copy. Heating this mixture formed N-benzyldiarylamine 15
and no benzyl ether 16 [Eq. (5)]. Second, we conducted a
reaction in which the ions would be generated from the
palladium complex or from the conjugate acid of the anions.
The combination of [(dppf)Pd(Bn){N(p-tolyl)2}] and 1 equiv
of HO(p-tolyl) formed phenoxide complex 2. Heating this
mixture led to the formation of benzyl ether 16 in 71% yield
without formation of benzylamine [Eq. (6)], as determined by
1H NMR spectroscopy. These studies are consistent with the
greater nucleophilicity of the diarylamide under the aprotic
conditions of the first experiment, but greater population of
the phenoxide anion under the protic conditions of the second
experiment, and signal the fine balance between the popula-
tion and reactivity of the anions in the systems that undergo
reductive elimination.
In summary, we report reductive eliminations to form the
3
À
C(sp ) O bond in an ether from a low-valent group 10 metal
center without oxidation to form a higher valent intermediate.
A combination of kinetic studies and analysis of the
stereochemical outcome of the reaction indicate that this
process occurs in a stepwise fashion by reversible dissociation
of an aryloxide anion, followed by irreversible nucleophilic
attack of the aryloxide on the resulting cationic benzylpalla-
dium complex.
The data we gained allow comparisons of the elementary
reactions of this system to those of other systems that that
undergo reductive elimination to form carbon–heteroatom
and carbon–carbon bonds. This pathway we revealed con-
trasts the concerted mechanism for coupling of aryl and
aryloxide ligands[3,4] and the coupling of two alkyl ligands,[38]
and the lack of electronic effect of the aryloxide ligand on the
reaction rate contrasts the effect of the anionic ligand on
reductive eliminations from platinum(IV) or arylpalladi-
um(II) systems. These studies also show that the basic steps
of the reductive eliminations to form benzylamines and
benzyl ether are similar, but the rates of the elementary steps
of the process differ such that reductive eliminations to form
ethers are less sensitive to the electronic properties of the
heteroatom ligand and to the solvent polarity. Finally, the
reductive elimination to form ethers is much more strongly
dependent on the concentration of free phenol than is the
elimination of amine on the presence of free amine, presum-
ably due to differences in self-association of the anions and
conjugate acids. Studies to delineate the origins of these
differences further and to extend these reactions to reductive
eliminations from purely alkyl complexes are in progress.
Finally, the difference between the propensity of benzyl-
palladium complexes 1–9 to undergo reductive elimination
and the reluctance of methylpalladium aryloxide complex 10
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Experimental Section
Typical procedure for the synthesis of bisphosphine benzylpalladium
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[19] E. V. Salo, Z. Guan, Organometallics 2003, 22, 5033.
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aryloxide complexes (Scheme 1): In
a 20 mL scintillation vial,
[(cod)Pd(Bn)Cl] (110 mg, 0.323 mmol) was dissolved in THF
(5 mL). In another vial dppf (179 mg, 0.323 mmol) was dissolved in
THF (5 mL) and added to the stirred solution of [(cod)Pd(Bn)Cl] in a
nitrogen-filled glovebox resulting in an orange solution. After 10 min
KOAr (0.33 mmol) dissolved in THF (5 mL) was added to the orange
solution, and the resulting mixture was stirred for a further 10 min.
The THF was evaporated in vacuo, and the residue was dissolved in
benzene. The benzene solution was filtered through a plug of Celite,
which was then rinsed with benzene until the color has dissipated. The
filtrate was concentrated in vacuo to a volume of about 3 mL, and
then pentane (15 mL) was added. The mixture was cooled to À358C
for 12 h to complete precipitation. The solid was filtered from the
solution and washed with pentane (3 ꢀ 10 mL) and then dried in
vacuo.
[21] The thermolysis of complex 11 with dppf formed [Pd(dppf)2] as
the only product observable by 31P{1H}.
[22] J. J. Warren, J. M. Mayer, Proc. Natl. Acad. Sci. USA 2010, 107,
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[27] The substitution pattern of the aryloxide group had a minor
impact on the rate of the reductive elimination reaction.
Complex 4 and 5 underwent reductive elimination with rates
that were identical to each other. However, complex 6, contain-
ing 3,5-dimethyl substitution on the phenoxide reacted more
Received: February 13, 2011
Published online: June 17, 2011
Keywords: aryloxides · benzyl complexes · nucleophilic attack ·
slowly than the analogous complex 5 containing 3,5-bistrifluoro-
.
3
palladium · reductive elimination
À
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