Advancing the mechanistic understanding of an enantioselective palladium-catalyzed alkene difunctionalization reaction

Article abstract of DOI:10.1021/ja108106h

The mechanism of an enantioselective palladium-catalyzed alkene difunctionalization reaction has been investigated. Kinetic analysis provides evidence of turnover-limiting attack of a proposed quinone methide intermediate with MeOH and suggests that copper is involved in productive product formation, not just catalyst turnover. Through examination of substrate electronic effects, a Jaffe relationship was observed correlating rate to electronic perturbation at two positions of the substrate. Ligand effects were evaluated to provide evidence of rapid ligand exchange between palladium and copper as well as a correlation between ligand electronic nature and enantioselectivity.

Full text of DOI:10.1021/ja108106h

Published on Web 11/17/2010
Advancing the Mechanistic Understanding of an
Enantioselective Palladium-Catalyzed Alkene
Difunctionalization Reaction
Katrina H. Jensen,† Jonathan D. Webb,‡ and Matthew S. Sigman*,†
Departments of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States, and Queen’s UniVersity, 90 Bader Lane, Kingston,
Ontario K7L 3N6, Canada
Received July 12, 2010; E-mail: sigman@chem.utah.edu
Abstract: The mechanism of an enantioselective palladium-catalyzed alkene difunctionalization reaction
has been investigated. Kinetic analysis provides evidence of turnover-limiting attack of a proposed quinone
methide intermediate with MeOH and suggests that copper is involved in productive product formation, not
just catalyst turnover. Through examination of substrate electronic effects, a Jaffe´ relationship was observed
correlating rate to electronic perturbation at two positions of the substrate. Ligand effects were evaluated
to provide evidence of rapid ligand exchange between palladium and copper as well as a correlation between
ligand electronic nature and enantioselectivity.
Introduction
However, due to facile ꢀ-hydride elimination from the resulting
Pd(II)-alkyl intermediate, methods are required to prevent
Alkene difunctionalization, the formation of two new bonds
from an alkene starting material, is a powerful synthetic method
which rapidly increases molecular complexity.1-19 Such a
transformation has the potential to set two new chiral centers,
and thus methods to accomplish highly enantioselective and/or
diastereoselective transformations catalytically are highly desir-
able. Palladium has become a popular metal of choice for alkene
difunctionalization, likely due to its propensity to coordinate
and activate alkene substrates for nucleophilic attack.3,4,20,21
ꢀ-hydride elimination in order to allow for the second func-
tionalization process. There are several classic strategies em-
ployed to circumvent this issue, including using conjugated
alkenes to form stabilized intermediates (such as π-allyl4,22-28
or π-benzyl complexes14,29) or trapping the Pd(II) intermediate
by insertion of a second alkene.30-33 More recently, Pd(II)-alkyl
intermediates have been oxidized to achieve alkene difunc-
tionalization.10,11,34-41 While many of these approaches are
(21) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem.
ReV. 2007, 107, 5318.
† University of Utah.
‡ Queen’s University.
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A R T I C L E S
Jensen et al.
Scheme 1. Pd-Catalyzed Difunctionalization of Alkenes with an
Adjacent ortho-Phenol and Tethered Nucleophile
without a detrimental effect on enantioselectivity when a
sufficient amount chiral ligand is used. The ability to add two
distinct nucleophiles across alkenes in a regio-, diastereo-, and
enantioselective manner makes this contribution an important
step in the advancement of alkene difunctionalization reactions.
Therefore, in order to understand the precise details of this
successful process, we have evaluated the mechanistic details,
which are presented herein.
Preliminary Mechanistic Hypothesis
We have previously reported the palladium-catalyzed di-
alkoxylation of alkenes with an adjacent ortho-phenol (Scheme
2). This work provided the initial evidence for the dual role of
the ortho-phenol, preventing ꢀ-hydride elimination and allowing
for the intermediacy of an ortho-quinone methide (Scheme
2A).52 Support for these proposals includes the requirement of
an ortho-phenol in the alkene substrate, as para-phenol sub-
strates fail to provide product, presumably due to their inability
to prevent ꢀ-hydride elimination. Further, use of a protected
phenol which should slow ortho-quinine methide formation
(analogue 3) in the intermolecular alkene dialkoxylation reaction
also did not result in product formation (Scheme 2B). Addition-
ally, when a deuterated substrate (d4-2) was submitted to the
reaction, no scrambling of the deuterium labels was observed,
indicating that ꢀ-hydride elimination from D does not occur
(Scheme 2C).33
highly diaseteroselective, few have been rendered enantiose-
lective while also being able to introduce broad classes of
nucleophiles.27,31,42-50
In general, quinone methides are considered to be reactive
intermediates.54 They are inherently electrophilic because of the
disruption to aromaticity; consequently, they react rapidly with
most nucleophiles and dienophiles. The typical decomposition
route for these species is homodimer- or -trimerization. Quinone
methides can be stabilized by steric bulk54 or by coordination
to electron-rich transition metal complexes.55-58
An enantioselective variant of the dialkoxylation reaction was
developed where it was found that the use of chiral quinoline
oxazoline ligands provide products in high enantioselectivity
(eq 1).45 Interestingly, a significant detrimental effect of added
copper on enantioselectivity was observed (Table 1). Therefore,
despite slightly diminished yields, the reaction was performed
in the absence of copper. The limitations of this reaction were
the use of the solvent as the nucleophile and the inability to
add two distinct nucleophiles in a regioselective manner.
Recently, we reported the successful development of an
enantioselective Pd-catalyzed alkene difunctionalization reaction
wherein two distinct nucleophiles were added across an alkene
in a stereo- and regioselective manner (Scheme 1).51 This
reaction involves the use of substrates containing an alkene with
an adjacent ortho-phenol and a linked nucleophile. As has been
discussed elsewhere and will be addressed in detail herein, the
ortho-phenol is crucial:52 not only can it coordinate to the Pd(II)
intermediate, preventing ꢀ-hydride elimination, but it also is
proposed to allow for the in situ formation of an electrophilic
quinone methide species, necessary for the second functional-
ization to occur. Thus, our approach contrasts with others
because oxidation of the substrate, not the Pd center, promotes
the addition of the second nucleophile. The resulting reaction
has broad scope, as exogenous nucleophiles which form C-O,
C-N, and C-C bonds have been successfully used in this
chemistry.51,53 Furthermore, good to high enantioselectivity and
diastereoselectivity are observed in most cases when a
quinoline-oxazoline chiral ligand (1) is employed. Copper salts
were found to be essential additives to achieve effective catalysis
(41) Park, C. P.; Lee, J. H.; Yoo, K. S.; Jung, K. W. Org. Lett. 2010, 12,
2450.
(42) Xu, L.; Shi, Y. J. Org. Chem. 2008, 73, 749.
(43) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001,
123, 2907.
In contrast, in the development of the regioselective alkene
difunctionalization reaction, it was found that copper was
required for efficient catalysis.51 We hypothesized that the reason
for the detrimental effect of copper on enantioselectivity was
that copper and palladium compete for the chiral ligand, thus
allowing for an achiral palladium species to catalyze the reaction,
leading to nearly racemic product.45 In order to prevent this
(44) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem.
Soc. 2006, 128, 3130.
(45) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076.
(46) He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 5626.
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Lett. 2007, 36, 1328.
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Lett. 2003, 44, 711.
(49) Sperrle, M.; Consiglio, G. J. Mol. Catal. A: Chem. 1999, 143, 263.
(50) Wang, C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118.
(51) Jensen, K. H.; Pathak, T. P.; Zhang, Y.; Sigman, M. S. J. Am. Chem.
Soc. 2009, 131, 17074.
(54) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367.
(55) Vigalok, A.; Milstein, D. Acc. Chem. Res. 2001, 34, 798.
(56) Amouri, H.; Le Bras, J. Acc. Chem. Res. 2002, 35, 501.
(57) Stokes, S. M.; Ding, F.; Smith, P. L.; Keane, J. M.; Kopach, M. E.;
Jervis, R.; Sabat, M.; Harman, W. D. Organometallics 2003, 22, 4170.
(58) Poverenov, E.; Shimon, L. J. W.; Milstein, D. Organometallics 2007,
26, 2178.
(52) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 1460.
(53) Pathak, T. P.; Gligorich, K. M.; Welm, B. E.; Sigman, M. S. J. Am.
Chem. Soc. 2010, 132, 7870.
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Enantioselective Pd-Catalyzed Alkene Difunctionalization
A R T I C L E S
Scheme 2. Initial Discovery of Pd-Catalyzed Alkene Dialkoxylation and Evidence for a Quinone Methide Intermediate
Table 1. Detrimental Effect of Copper on Enantioselectivity in
mediate under the standard alkene difunctionalization conditions
(eq 4).54 The major diastereomer is consistent with an inverse
electron demand Diels-Alder reaction proceeding via an endo
transition state with an E-quinone methide.54,59 The E-isomer
of the quinone methide is assumed on the basis of the steric
interactions likely in the Z-isomer (Figure 1). The relative
stereochemistry between the carbons R and ꢀ to the aromatic
ring (originating from the alkene) matches that observed from
the alkene dialkoxylation process, indicating that the dienophile
approaches the quinone methide from the same face as an
alcohol nucleophile.51 This facial selectivity is controlled either
by the stereocenter on the tetrahydrofuran ring or potentially
by the ligand on the metal(s), if bound.
Pd-Catalyzed Alkene Dialkoxylation Reaction
X
GC yield (%)
ee (%)
er
0
2.5
5
10
20
67
80
78
81
88
82
72
59
26
10
91:9
86:14
80:20
63:37
55:45
When a lower Z:E ratio of propenyl ether 7 is used, the major
diastereomer of 8 remains (R,S,R,R), but the relative amount of
the diastereomer arising from the E-enol ether (S,S,R,R)
increases (Table 2). Note that the ratio of (R,S,R,R) to (S,R,S,R),
which arises from the facial selectivity in the approach of the
enol ether to the quinone methide, is nearly constant. These
observations provide evidence for a concerted, albeit asynchro-
nous, reaction, where the E-isomer of the enol ether reacts more
slowly than the Z-isomer. Such a finding supports the existence
of a quinone methide intermediate, as opposed to a stepwise
mechanism involving insertion into the Pd-alkyl bond, followed
by oxocarbenium formation and attack by the phenol intermedi-
ate, as such a mechanism would not be expected to result in
different diastereomers from each enol ether isomer.
from occurring, copper and palladium complexes with (S)-
quinox-iPr were prepared, making any ligand exchange incon-
sequential.51 Using 10 mol % Pd[(S)-quinox-iPr]Cl2 and 20 mol
% Cu[(S)-quinox-iPr]Cl2 in the alkene difunctionalization reac-
tion with substrate 5, product 6 was obtained with no decrease
in enantioselectivity, but in substantially higher yield in a shorter
reaction time (eq 2 vs 3).
We realize that the requirement of an alkene conjugated to
an ortho-phenol is a limitation to this methodology, notwith-
Further evidence in support of the proposed mechanism was
provided by the isolation of 8, formed via a formal Diels-Alder
reaction of propenyl ether 7 with the quinone methide inter-
Figure 1. Stereochemical model for diastereoselectivity.
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Jensen et al.
2A).64 GC analysis was used to confirm that O2 consumption
corresponds to product yield, with 0.5 mmol of O2 consumed
per mmol of product formed. No O2 consumption was observed
in the absence of substrate. Further, when the reaction was
performed under an N2 atmosphere, no product was formed,
confirming the requirement of O2 as an oxidant. Oxidation of
MeOH to formaldehyde was not expected under the reaction
conditions.52,65 Nevertheless, a control for this possibility was
integrated into our experimental design: prior to each run, the
pressure was allowed to equilibrate over the 4:1 toluene:MeOH
solvent mixture containing catalysts and base (Figure 2B). Once
equilibrated, O2 consumption initiated immediately on addition
of substrate (Figure 2A,C). The small pressure increase during
the equilibration period was the result of added vapor pressure
from toluene and MeOH because of atmospheric cycling. A
pseudo-order treatment of the O2 data (Figure 2C,D) did not
provide a straight line across the reaction profile; however, there
could be many reasons for this observation, considering the
complexity of this system. Nonetheless, the reaction was
sufficiently well behaved up to ∼50% conversion to warrant
initial rate analysis of the O2 uptake data. Initial rates were
typically measured up to 5-10% conversion based on O2
consumption data, and each plot contained more than 100
individual pressure measurements. This kinetic method was used
to determine the dependence on the concentration of each
component of the system.
First-order dependence in [palladium] was observed (Figure
3), which points to a single palladium atom involved in catalysis.
Saturation in [substrate] was observed (Figure 4A), indicating
that at low [substrate], substrate binding affects the overall rate
of the reaction, but as [substrate] approaches a certain concen-
tration palladium becomes saturated with substrate, and at this
point increasing [substrate] does not increase reaction rate. This
is consistent with substrate binding prior to the turnover-limiting
step. Nonetheless, many possibilities for the turnover-limiting
step remain, including nucleopalladation, quinone methide
formation, attack of the quinone methide, and Pd0 oxidation.
Saturation in [Cu] was observed under conditions of substrate
saturation (Figure 4C), indicating a step prior to the turnover-
limiting step involves copper. This is evidence that copper is
involved in a step other than just catalyst turnover. To determine
if the saturation behavior in copper and substrate is independent,
[substrate] and [Cu] dependence measurements were repeated
at different conditions, such that [substrate] dependence was
determined at both low and high [Cu] (Figure 4A,B) and [Cu]
dependence was determined at low and high [substrate] (Figure
4C,D). It is interesting that in all four cases saturation is
observed, suggesting that they are independent and thus occur
in distinct steps. If both [copper] and [substrate] saturation occur
in the same step, such as copper-assisted substrate binding via
the formation of a Cu-phenoxide (Figure 5), saturation behavior
would depend on the total concentration of such a species
([substrate-Cu], eq 7), and thus [copper] and [substrate]
saturation would not be independent.
Table 2. Effect of Enol Ether Isomeric Ratio on
Diastereoselectivity
standing prospects for further functionalization. Nonetheless,
we hypothesized that the proposed quinone methide intermediate
could be utilized to develop other reactions and, therefore,
thought it would be beneficial to have a better understanding
of the lifetime of this intermediate. Additionally, we suspected
that the ortho-phenol may be influencing the stereochemical
outcome of the reaction. Furthermore, the distinct effect of
copper in this reaction pointed to the potential involvement of
copper in steps other than simply palladium reoxidation.60 Given
the widespread use of copper as a cocatalyst in palladium
oxidase catalysis, we felt that evaluation of this possibility was
warranted.31,61-63 We were interested in investigating the details
of this transformation in order to develop a deeper understanding
of the mechanism which will aid the future development of
related palladium-catalyzed alkene difunctionalization reactions.
Below we report mechanistic investigations undertaken, includ-
ing kinetic analysis, evaluation of substrate electronic effects,
and investigation of ligand perturbation on selectivity.
Kinetic Experiments
To probe both the lifetime of a proposed quinone methide
intermediate and the role of copper in the reaction, a kinetic
analysis was undertaken. The model substrate 5 was used with
MeOH as the exogenous nucleophile (eq 5) to determine the
dependence of reaction rate on various reaction components and
the turnover-limiting step of the reaction. Preformed complexes
of Pd[(S)-quinox-iPr]Cl2 and Cu[(S)-quinox-iPr]Cl2 were used
for all kinetic experiments for greater accuracy in weighing, as
standard solutions could not be prepared at the desired concen-
trations due to low solubility. Note, however, that the solution
becomes homogeneous upon addition of the substrate and
remains homogeneous over the course of the reaction.
Kinetic measurements were obtained using an oxygen uptake
instrument to monitor the rate of oxygen consumption (Figure
Because we were concerned that some of these saturation
effects might reflect a mass-transport-limited process, the
dependence on molecular oxygen uptake was evaluated by
changing the partial pressure of O2 and N2 with a constant total
system pressure. A zero-order dependence in O2 partial pressure
(59) Arduini, A.; Bosi, A.; Pochini, A.; Ungaro, R. Tetrahedron 1985, 41,
3095.
(60) Tsuji, J. Oxidative Reactions with Pd(II) Compounds. Palladium
Reagents and Catalysts: New PerspectiVes for the 21st Century; John
Wiley & Sons: New York, 2004; p 27.
(61) Takacs, J. M.; Jiang, X.-T. Curr. Org. Chem. 2003, 7, 369.
(62) Hosokawa, T.; Takano, M.; Murahashi, S.-I. J. Am. Chem. Soc. 1996,
118, 3990.
(64) Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348.
(65) Gligorich, K. M.; Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc.
2006, 128, 2794.
(63) Hosokawa, T.; Nomura, T.; Murahashi, S.-I. J. Organomet. Chem.
1998, 551, 387.
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Enantioselective Pd-Catalyzed Alkene Difunctionalization
A R T I C L E S
Figure 2. Typical reaction profiles as measured by O2 uptake. (A) Full O2 uptake profile (including system evaculation and refill with O2). (B) Equilibration
time. (C) Pseudo-zero-order reaction profile. (D) Pseudo-first-order reaction profile.
The effect of base on reaction rate is complex (Figure 7).
There appears to be a positive order in [KHCO3] at low
[KHCO3] and inhibition at high [KHCO3]. However, based on
the observation that reaction yield also decreases as the [KHCO3]
is increased beyond 0.02 M, it is possible that this is a reflection
of catalyst decomposition. In support of this conclusion, Pd-
black precipitation is pronounced at higher base concentrations,
and O2 uptake was negligible.
Finally, dependence on [MeOH] was determined at low
[KHCO3], where the reaction is well behaved, and at high
[substrate], where saturation is assumed. As discussed above,
this experiment was performed under conditions where the
system was not saturated in [Cu] because increasing [MeOH]
at high [substrate] and high [Cu] eventually results in a system
Figure 3. First-order dependence on [Pd]. Conditions: [substrate] ) 0.16
M, [Cu] ) 0.0017 M [KHCO3] ) 0.026 M, 1:4 MeOH:toluene, O2, 25 °C.
that is limited by the rate of mass transport of molecular
oxygen.66 A positive order in [MeOH] was observed (Figure
was observed under conditions where the reaction was not
saturated in [Cu]. This indicates that O2 involvement in the
reaction is subsequent to the turnover-limiting step (Figure 6).
The rate of reaction was also found to be independent of stir
rate under these conditions (see Supporting Information). These
observations coupled with the observation of a first-order
dependence in [catalyst] pointed to a reaction that was not mass-
transport-limited in O2 under low [Cu] conditions. This inter-
pretation of mass transport effects in palladium-catalyzed
reactions is similar to that used by Steinhoff and Stahl in regard
to aerobic alcohol oxidation.64 For these reasons, low [Cu]
conditions were considered to be kinetically well behaved and
were used for subsequent reagent dependencies. It should be
noted that it is possible to observe modest mass transport effects
at high concentrations of [Cu] and high total O2 pressure (see
Supporting Information).
8A). This suggests that MeOH is involved in the turnover-
limiting step. The relationship of ln(rate) vs ln([MeOH]) has a
slope less than 1 (0.66) (Figure 8B), likely due to the fact that
this experiment was performed under conditions where the
system is not saturated in [Cu], which may result in a situation
where more than one step is influencing the overall measured
rate. While changing [MeOH] also has an effect on solution
polarity, which may affect reaction rate, one would not expect
to see a strong correlation from a polarity effect alone.
Dependence on [MeOH] also suggests that Pd is still bound
when the quinone methide is attacked (Scheme 3, top), as attack
by MeOH of a dissociated quinone methide (Scheme 3, bottom),
(66) A dependence on stir rate was observed at high [Cu], indicative of a
system that is limited by mass transport of oxygen. See Supporting
Information for details.
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A R T I C L E S
Jensen et al.
Figure 4. Saturation in [substrate] and [Cu]. Conditions: [Pd] ) 0.0026 M, [KHCO3] ) 0.026 M, 1:4 MeOH:toluene, O2, 25 °C, (A) [Cu] ) 0.0053 M, (B)
[Cu] ) 0.0017 M, (C) [substrate] ) 0.16 M, (D) [substrate] ) 0.026 M.
With the kinetic data in hand, we needed to adjust our initially
proposed mechanism to account for the observed kinetic results.
Most significantly, our original mechanism needed to be
modified to account for the observation of independent [Cu]
and [substrate] saturation. In particular, these results require a
flexible pathway where turnover-significant steps can change
depending on the reaction conditions. Two distinct mechanisms
involving copper in steps besides catalyst turnover or substrate
binding were postulated (Scheme 4).67 The first three steps,
which do not differ between the mechanisms, are the disas-
Figure 5. Formation of substrate-copper complex. Does not account for
observed independent saturation in [substrate] and [Cu].
sociation of an anionic ligand from intermediate A to provide
an open coordination site on B, substrate binding to form C,
and intramolecular nucleopalladation to reach Pd-alkyl species
D. This portion of the mechanism invokes a substrate-binding
pathway which is similar to that observed in related systems68
and satisfactorily describes the observed saturation effect. In
fact, K1 for the interconversion of species of types A and B has
been calculated from electrochemical studies when (-)-sparteine
is the ligand.68,69 Note that bidentate substrate binding is
assumed (Vide infra); however, analogous mechanisms invoking
monodentate substrate binding would also be consistent with
the kinetic data. From the common intermediate D, the two
proposed mechanisms differ. Recall that intermediate D is
insufficiently electrophilic and incorrectly structured to account
for the observed reactivity toward the nucleophiles and dieno-
Figure 6. Zero-order dependence on partial pressure of O2 (with N2).
philes. In mechanism A, D undergoes quinone methide forma-
Conditions: [Pd] ) 0.0026 M, [Cu] ) 0.0017 M, [substrate] ) 0.16 M,
tion via electron transfer from the electron-rich organic frame-
[KHCO3] ) 0.026 M, 1:4 MeOH:toluene, 25 °C, total pressure ) 850 Torr.
work to palladium.70 Copper is invoked as a Lewis acid to form
the activated quinone methide species E, which undergoes
nucleophilic attack by MeOH. Pd0 is oxidized to regenerate the
active catalyst, a process most likely involving CuII, although
direct O2 oxidation is possible in the absence of copper.45,71,72
In contrast, mechanism B accounts for the possibility of copper-
assisted quinone methide formation. A possible redox mecha-
nism to account for copper mediation involves coordination of
copper to D to form a heterobimetallic species H, followed by
oxidation to a PdII-quinone methide intermediate I, likely
(67) Catalyst saturation can imply reversible formation of higher order metal
complexes in situ. However, such saturation curves are often marked
by large x-intercepts and/or pronounced slopes reflective of the binding
constants which are not observed here.
(68) Anderson, B. J.; Keith, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2010,
Figure 7. Dependence of rate and yield on [KHCO3]. Conditions: [Pd] )
0.0026 M, [Cu] ) 0.0017 M, [substrate] ) 0.16 M, 1:4 MeOH:toluene,
O2, 25 °C.
132, 11872.
(69) Mueller, J. A.; Cowell, A.; Chandler, B. D.; Sigman, M. S. J. Am.
Chem. Soc. 2005, 127, 14817.
(70) Alternatively, D and E could be interpreted as resonance structures.
However, it is unclear whether Pd remains coordinated to both the
oxygen atom and the benzylic carbon in the Pd-quinone methide
intermediate. Therefore, we have chosen to depict D and E as distinct
intermediates to allow for the possibility of atom movement. These
two interpretations result in the same derived rate law.
(71) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221.
(72) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400.
even if rate-limiting in terms of product formation, would allow
palladium to reenter the catalytic cycle, and thus should not
affect the rate of O2 consumption. Additionally, if Pd was not
bound, an accumulation of quinone methide in the reaction
mixture would be expected, and this was not observed.
9
17476 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Enantioselective Pd-Catalyzed Alkene Difunctionalization
A R T I C L E S
Figure 8. Positive dependence on [MeOH]. Conditions: [Pd] ) 0.0026 M, [Cu] ) 0.0017 M, [substrate] ) 0.16 M, [KHCO3] ) 0.010 M, O2, 25 °C.
Scheme 3. Evidence for Attack of Palladium-Bound Quinone
Methide Intermediate
Furthermore, the proposal of turnover-limiting attack of the
quinone methide intermediate results in derived rate laws
consistent with kinetic measurements.
Linear Free Energy Relationships
To probe the effect of substrate electronic perturbation on
the reaction, a series of substrates with substitution at the
4-position were synthesized and evaluated. Initial rates were
measured under conditions where saturation in [Cu] and
[substrate] could be assumed in order to examine the proposed
turnover-limiting step. Because such a substitution has the
potential to influence two reactive sites, either the phenol or
the alkene, Hammett plots were constructed using both σp and
σm values (Figure 9). Neither plot shows a linear correlation,
suggesting electronic perturbation does not occur at just one
through single-electron transfer.73 Both mechanisms account for
site.
a turnover-limiting nucleophilic attack of the quinone methide
Considering the Hammett equation (Table 4), a Hammett plot
intermediate by MeOH to form the product and release
should result in a linear relationship only if one position has a
palladium when the system is saturated in [substrate] and/or
much more significant effect than the other (i.e., if σm . σp or
[Cu]. It should be pointed out that the precise location of metals
within a given intermediate cannot be deduced kinetically, and
the structures merely represent a reasonable binding mode.
σp . σm). This is the case when a reactant has only one reactive
site on an aromatic ring. However, in this reaction, both meta
and para sites are potentially involved during the reaction. The
In mechanism A, [Cu] operates as a Lewis acid; in mechanism
Jaffe´ equation simply takes the Hammett equation and divides
B, [Cu] has a redox role in the formation of the quinone methide.
by one of the σ-values.75,76 This operation results in an equation
To determine if the role of [Cu] in the two mechanisms could
which allows for a linear relationship even when two sites are
be distinguished kinetically, a rate law was derived for each
perturbed. Depending on which σ-value is in the denominator,
using the King-Altman method74 (Table 3; see Supporting
the slope of the resulting plot gives one F-value, and the
Information for full derivation). Each derived rate law is rather
y-intercept gives the other F-value.
complex. Therefore, to investigate whether each is consistent
Two plots were constructed with the initial rate data measured
with empirical observations made under certain conditions, the
in the alkene difunctionalization reaction (Figure 10). A linear
rate laws were simplified by making assumptions specific to
free energy relationship is observed in both cases. The y-
different sets of reaction conditions. In doing so, we observed
intercept from plot A is similar (within error) to the slope of
that the simplified rate laws are relatively similar for both
plot B. This is crucial, as both represent Fp. The same is true
mechanisms and are consistent with kinetic data. Specifically,
for Fm, thus validating the linear free energy relationship.
when [Cu] is high, the simplified rate laws predict saturation in
Evaluation of the Jaffe´ plots reveals that Fp ≈ +2.3 and Fm
[substrate], as was observed. Likewise, when [substrate] is high,
≈ -1.2. The resonance structure shown in Figure 11, which
there is saturation in [Cu]. Finally, when both [substrate] and
places a negative charge on the oxygen and a positive charge
[Cu] are high, the rate laws reflect a first-order dependence on
on the benzylic carbon, is often invoked to explain the reactivity
[PdT] and [MeOH].
of quinone methides.54 Such a species has a buildup of negative
charge para to the R substituent and positive charge meta to
Neither of the proposed mechanisms can be ruled out, as they
are essentially indistinguishable kinetically; thus, the specific
the R substituent. If this species is involved in the transition
role of copper remains ambiguous. We can, however, rule out
state of the turnover-limiting step, one would expect electron-
a mechanism involving turnover-limiting Pd0-to-PdII oxidation
by copper, as the rate law derived for this mechanism is
inconsistent with empirically observed saturation in [Cu].
withdrawing groups to destabilize the positive charge at the meta
position, leading to a negative Fm value. Likewise, electron-
(75) Jaffe´, H. H. J. Am. Chem. Soc. 1954, 76, 4261.
(73) Balla, J.; Kiss, T.; Jameson, R. F. Inorg. Chem. 1992, 31, 58.
(74) King, E. L.; Altman, C. J. Phys. Chem. 1956, 60, 1375.
(76) Edwards, D. R.; Neverov, A. A.; Brown, R. S. J. Am. Chem. Soc.
2009, 131, 368.
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A R T I C L E S
Jensen et al.
Scheme 4. Proposed Mechanisms To Account for Potential Role of Copper
Table 3. Derived and Simplified Rate Laws for Proposed Mechanisms
Derived Rate Laws
Mechanism A
k1k2k3k4k5k6[PdT][sub][Cu][MeOH][Ox][base]2
d[P]
dt
)
k2k3k4k5k6[sub][Cu][MeOH][Ox][base]2 + k-1k3k4k5k6[Cu][MeOH][X-][Ox][base] +
k-1k-2k4k5k6[Cu][MeOH][X-]2[Ox] + k1k3k4k5k6[Cu][MeOH][Ox][base] +
k1k-2k4k5k6[Cu][MeOH][Ox-][X-] + k1k2k4k5k6[sub][Cu][MeOH][Ox][base] +
k1k2k3k5k6[sub][MeOH][Ox][base]2 + k1k2k3k-4k6[sub][X-][Ox][base] +
k1k2k3k4k6[sub][Cu][Ox][base] + k1k2k3k4k5[sub][Cu][MeOH][base]2
(
)
Mechanism B
k1k2k3k7k8k9[PdT][sub][Cu][MeOH][Ox][base]2
d[P]
)
k-1k3k7k8k9[Cu][MeOH][X-][Ox][base] + k-1k-2k7k8k9[Cu][MeOH][X-]2[Ox] +
k1k3k7k8k9[Cu][MeOH][Ox][base] + k1k-2k7k8k9[Cu][MeOH][X-][Ox] +
k1k2k7k8k9[sub][Cu][MeOH][Ox][base] + k1k2k3k8k9[sub][MeOH][Ox][base]2 +
k k k k-7k9[sub][MeOH][X-][base]2 + k1k2k3k7k9[sub][Cu][MeOH][base]2 +
dt
(
)
1
2 3
k1k2k3k8k9[sub][Cu][Ox][base]
Simplified Rate Laws
at high [Cu]
at high [sub]
at high [Cu] and high [sub]
A
K1k2k5[PdT][sub][MeOH][base]
K1k2[sub] + k5[MeOH]([X-] + K1)
k4k5[PdT][Cu][MeOH][base]
k4[Cu] + k5[MeOH] + k-4[X-]
d[P]
d[P]
d[P]
dt
) k5[PdT][MeOH][base]
dt
)
)
dt
B
K1k2k5[PdT][sub][MeOH][base]
K1k2[sub] + k9[MeOH]([X-] + K1)
k7k9[PdT][Cu][MeOH][base]
d[P]
d[P]
dt
d[P]
dt
) k9[PdT][MeOH][base]
dt
)
)
k9[MeOH][base] + k7[Cu]
donating groups para to the oxygen would destabilize the
negative charge and result in a positive Fp value. Thus, the
observed Jaffe´ relationship signifies a substituent effect con-
sistent with turnover-limiting quinone methide attack.
additional insight into the reaction mechanism in terms of the
role of copper. If copper is acting as a Lewis acid, the ligand
on copper may affect the selectivity of addition to the quinone
methide intermediate. To probe this possibility, we chose to
evaluate ligand effects on the diastereoselective outcome of the
reaction. In order to perform such analysis, however, we needed
to increase our understanding of ligand exchange. On the basis
Probing the Role of Copper
Buoyed by the mechanistic insight gained from kinetic
analysis, we were interested in exploring experiments to gain
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17478 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010

Enantioselective Pd-Catalyzed Alkene Difunctionalization
A R T I C L E S
Figure 9. Evaluation of substrate electronic effect on rate. Hammett plots:
log(kX/kH) vs σp (A) and σm (B).
Figure 10. Jaffe´ plots showing a linear free energy relationship between
substrate electronics and reaction rate. Fp and Fm values from each plot are
within error.
Table 4. Hammett and Jaffe´ Equations
Hammett equation
Jaffe´ equation
kX
kX
log
) Fmσm + Fpσp
log
( )
( )
kH
kH
Fpσp
σm
)
)
+ Fm
σm
Figure 11. Quinone methide resonance structures.
or
tiomers of the ligand are employed in the reaction. A change
in diastereoselectivity, either an increase or a decrease, would
indicate that copper is involved in the turnover-limiting step
and that the ligand on copper influences stereoinduction. A
decrease in enantiomeric excess will indicate a loss of catalyst
enantiopurity resulting from rapid ligand exchange. The use of
Pd[(R)-quinox-iPr]Cl2 and Cu[(S)-quinox-iPr]Cl2 under the
standard reaction conditions resulted in complete conversion
to nearly racemic product (eq 10, 4% ee (S,S) and 7:1 dr, as
compared to 93% ee (R,R) and 7:1 dr with Pd[(S)-quinox-iPr]Cl2
and Cu[(S)-quinox-iPr]Cl2). This points to rapid ligand exchange
on the time scale of this reaction; thus, no insight into ligand
influence on diastereoselectivity was gained.
kX
log
( )
kH
Fmσm
σp
+ Fp
σp
of the detrimental effect of unligated copper on enantioselectivity
in the intermolecular alkene dialkoxylation reaction,45 we
hypothesized that the ligand preferentially coordinates to copper,
i.e., that the equilibrium of eq 8 lies to the right. If there is
sufficient ligand, both metals are coordinated.
However, if we start with preformed complexes of both
metals, how rapid is ligand exchange between the two metals
(eq 9)? To answer this question, an experiment was designed
wherein palladium and copper complexes with opposite enan-
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A R T I C L E S
Jensen et al.
Table 5. Evaluation of Copper Complexes with Achiral Ligands
entry
copper complex
time
conv (%)
yield (%)
ee (%)
dr
1
Cu(2,2′-bipyridine)Cl2
30 min
2 days
30 min
2 days
5 min
10 min
30 min
2 h
31
99
30
98
27
53
86
100
19
50
96
3
55
7
52
9
22
49
63
1
80
12
81
18
91
91
92
91
5:1
6:1
7:1
6:1
6:1
6:1
6:1
7:1
6:1
5:1
13:1
2
3
Cu(phenanthroline)Cl2
Cu(bathocuproine)Cl2
4
Pd(MeCN)2Cl2, CuCl2 14 mol % bathocuproine
30 min
2 h
17 h
5
27
Table 6. Evaluation of Lewis Acid Additives
It was hypothesized that other ligands may not exchange as
rapidly. Thus, copper complexes with 2,2′-bipyridine, phenan-
throline, and bathocuproine were prepared and evaluated (Table
5). Catalytic systems with Cu(bipyridine)Cl2 (entry 1) and
Cu(phenanthroline)Cl2 (entry 2) were significantly slower, with
only 3% and 7% yields, respectively, at 30 min compared to
complete conversion for the all-(S)-quinox-iPr system. Ad-
ditionally, ligand exchange occurs between copper and pal-
ladium, as the enantiomeric excess of the product decreases as
the reaction progresses (80% ee at 30 min and 12% ee at
completion for Cu(bipyridine)Cl2, entry 1, and 81% ee at 30
min and 18% ee at completion for Cu(phenanthroline)Cl2, entry
2). Interestingly, Cu(bathocuproine)Cl2 behaves differently
(entry 3). The reaction is complete within 2 h, with good yield,
only slightly diminished enantiomeric excess (91% ee), and a
diastereomeric ratio (7:1) similar to that observed with Cu[(S)-
quinox-iPr]Cl2 (93% ee and 7:1 dr). In contrast to the systems
using Cu(bipyridine)Cl2 and Cu(phenanthroline)Cl2, ee is con-
stant over the course of the reaction with Cu(bathocuproine)Cl2,
implying that ligand exchange does not occur. However, another
explanation exists: ligand exchange is rapid, and the resulting
Pd(bathocuproine)X2 catalyst is significantly less active than the
Pd[(S)-quinox-iPr]X2 catalyst. In exploring this possibility, a
control experiment was performed using bathocuproine as the
ligand for both metals (entry 4). This reaction is indeed
significantly slower, with only 5% yield after 2 h and 27% yield
with nearly complete conversion of the substrate at 17 h.
Unfortunately, given the potential for ligand exchange, no
evidence was gained to either indicate or rule out copper
involvement in the diastereoselective step. Nevertheless, a highly
enantioselective system using an achiral ligand on copper was
discovered, thus reducing the necessary loading of chiral
material by more than half.
entry Lewis acid
solvent
time
conv (%) yield (%)
er
dr
1
2
3
4
5
6
7
-
1:1 THF:tol 19 h
toluene 30 min
43
97
100
99
62
29
2
75
81
57
22
6
nd
nd
CuCl
97:3 8:1
97:3 11:1
90:10 6:1
92:8 4.5:1
94:6 4:1
95:5 4:1
CuCl2 1:1 THF:tol 30 min
FeCl3
FeCl3
ZnCl2
ZnCl2
toluene
1:1 THF:tol 19 h
toluene 17 h
1:1 THF:tol 19 h
17 h
77
28
attack, which would explain the positive effect with ZnCl2, it
suggests that it is likely serving another purpose as well. Copper
is known to catalyze the oxidation of catechol to quinone with
molecular oxygen,73 and a similar process could occur in this
reaction. Moreover, the observation that FeCl3 improves product
yield, albeit at a significantly slower rate than copper, is in
agreement with this analysis, as iron has also been shown to
facilitate quinone formation.77 Therefore, mechanism B, where
copper acts to facilitate quinone methide formation, is the
favored mechanism.
Origin of Stereoselectivity
A better understanding of the origin of enantioselectivity
would be beneficial for future reaction development. Our
stereochemical analysis invokes initial nucleopalladation at the
ꢀ-position as the enantiodetermining step. When considering
the development of a stereochemical model for this reaction,
many variables affecting selectivity on nucleopalladation need
to be taken into account. Two possible mechanisms for this step
are cis-nucleopalladation, where both the alkene and the
nucleophile are coordinated to palladium and the alkene inserts
into the Pd-Nu bond, and trans-nucleopalladation, where the
nucleophile attacks the alkene from the face opposite palladium.
Unfortunately, because the stereochemical information at the
R-position is lost upon quinone methide formation, it is difficult
to envision a method to directly elucidate the precise mechanistic
nature of this step. Furthermore, because this step is fast, it
To further probe the possibility of copper simply acting as a
Lewis acid, other Lewis acid additives were tested in the reaction
(Table 6; see Supporting Information for complete list of Lewis
acids evaluated). Of all of the Lewis acids tested, only FeCl3
(entries 4 and 5) and ZnCl2 (entries 6 and 7) demonstrated a
positive effect on the product yield compared to the reaction
without an added Lewis acid (entry 1). Even in these cases,
however, the reaction is much slower, with completion occurring
after approximately 24 h, whereas the reactions employing
copper are complete in approximately 30 min (entries 2 and 3).
While this does not rule out the possibility of copper acting as
a Lewis acid to activate the quinone methide intermediate for
(77) Smith, L. I.; Davis, H. R., Jr.; Sogn, A. W. J. Am. Chem. Soc. 1950,
72, 3651.
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Enantioselective Pd-Catalyzed Alkene Difunctionalization
A R T I C L E S
Table 7. Evaluation of Pyrox-tBu Ligand Derivatives
Figure 12. Hammett plot of log(er) vs σ, showing ligand electronic effect
on enantioselectivity.
entry
R
time
conv (%)
yield (%)
ee (%)
er
dr
Scheme 5. Evidence for Initial Oxypalladation at the ꢀ-Position
1
2
3
4
5
CF3
Cl
3 h
3 h
3 h
3 h
3 h
67
67
83
79
79
46
39
56
49
49
68.9
74.2
82.1
81.6
81.7
84.5:15.5
87.1:12.9
91.0:9.0
90.8:9.2
90.9:9.1
15:1
13:1
14:1
13:1
14:1
H
Me
OMe
cannot be probed kinetically. If trans-nucleopalladation is
operative, there is the potential for the substrate to be bound to
palladium in either a monodentate or bidentate mode (through
the alkene and the phenoxide). Further complicating the analysis,
it cannot be determined whether the E- or Z-isomer of the alkene
is the reactive species, since alkene isomerization has been
shown to be rapid.52 Additionally, because the ligand is not C2-
symmetric, the two potential coordination sites are not identical.
In light of these issues, we reasoned that the best way to probe
the enantiodetermining nucleopalladation step is through a
systematic examination of ligand effects.
While (S)-quinox-iPr was found to be the optimal chiral ligand
for this reaction, it was observed that the reaction using (S)-
pyrox-tBu is well behaved and gives relatively high enantiomeric
excess (82%). It was presumed that derivatives of (S)-pyrox-
tBu would be synthetically easier to access than those of (S)-
quinox-iPr. Therefore, a series of 4-substituted pyrox-tBu ligands
was chosen for evaluation of ligand electronic effects. Ligands
17-21 were synthesized in two steps from commercially
available picolinic acid derivatives (see Supporting Information
for details) and tested in the Pd-catalyzed alkene difunctional-
ization reaction under our standard conditions. A subtle ligand
electronic effect on enantioselectivity was revealed (Table 7).
A linear free energy relationship was observed by plotting
log(er) vs Hammett σ values with F ) -0.34 (Figure 12). A
negative F value indicates that more-electron-rich ligands lead
to improved enantioselectivity. However, it should be noted that
the electron-rich ligands have nearly the same enantiomeric ratio,
but their selectivity is better than that of electron-withdrawing
ligands. An unanticipated outcome of this set of experiments
was an observed ligand-modulated enhancement of the diaste-
reoselectivity (compared to 9:1 dr under identical conditions
with (S)-quinox-iPr). This result supports the assertion that the
ligated metal species is intimately involved in the addition of
the exogenous nucleophile.
through a later transition state. Such a transition state is more
product-like, where there should be a greater difference between
the activation energies to reach the two enantiomers.78
Our stereochemical analysis invokes initial nucleopalladation
at the ꢀ-position as the enantiodetermining step. Evidence for
this hypothesis was provided when trisubstituted alkene 22 was
submitted to the intermolecular alkene dialkoxylation reaction
conditions.45 The product 23 was obtained in 0% ee (Scheme
5), indicative of initial oxypalladation at the ꢀ-position. As two
of the substituents are at this position are identical, the
subsequent quinone methide intermediate is achiral, leading to
racemic product. A mechanism involving enantioselective
addition at the R-position would be expected to result in
enantiomerically enriched product 23. Further, as previously
reported, the intermolecular nucleophile employed has an
influence on diastereoselectivity, generally leaving enantiose-
lectivity unperturbed.
Given the significant number of variables associated with
nucleopalladation, several assumptions need to be made in order
to develop a working stereochemical model. First, it is assumed
that intramolecular nucleopalladation occurs on a Pd-substrate
species which is bidentate, coordinated through the alkene and
the phenoxide. Given the evidence that nucleophilic attack
occurs at the anti-Markovnikov ꢀ-position, it seems necessary
to invoke a reason for this normally electron-rich site to be the
A reasonable explanation to account for this modest effect
was postulated: a palladium-alkene intermediate that is more
electron rich is less electrophilic and thus at a lower energy
than the analogous system with an electron-poor substituent on
the ligand. This suggests that the nucleopalladation reaction is
less exothermic and thus, by the Hammond postulate, goes
(78) Palucki, M.; Finney, N. S.; Pospisil, P. J.; Gueler, M. L.; Ishida, T.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948.
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A R T I C L E S
Jensen et al.
Table 8. Enantiomeric Ratio and Diastereomeric Ratio for Product
Derivatives
entry
R
ee (%)
er
dr
Figure 13. Working stereochemical model.
1
2
3
4
5
F
Cl
H
Me
OMe
97.8
93.9
93.2
93.8
85.2
98.9:1.1
97.0:3.0
96.6:3.4
96.9:3.1
92.6:7.4
2.9:1
4.5:1
8.1:1
6.8:1
9.9:1
presented to explain the observed facial selectivity. While
thermodynamically less stable than the E-isomer, the Z-alkene
may be the more reactive species, in terms of both alkene
binding and ability to access conformers that lead to product
formation. Furthermore, a stereochemical model which involves
coordination of the alkene trans to the pyridine is consistent
with the observed electronic effect of the ligand on enantiose-
lectivity.
more electrophilic site upon coordination. Substrate binding in
a bidentate fashion would require the aromatic ring to rotate
out of conjugation with the alkene and thus inhibit the phenol’s
ability to donate electron density to the alkene. This hypothesis
is supported by the mixture of products obtained with a protected
phenol substrate 3 (Scheme 2B).52 Furthermore, the modest
substrate electronic effects on enantioselectivity (Table 8) are
consistent with the alkene being out of conjugation with the
aromatic ring during nucleopalladation. Interestingly, the dias-
tereoselectivity is loosely related to electron donation to the
phenol, in contrast to the insensitivity observed when ligand
electronics were modified (Table 7). Thus, we make the
assumption that a bidendate substrate-Pd species undergoes
nucleopalladation, as reflected in proposed mechanisms A and
B (Scheme 4). Nevertheless, mechanisms invoking monodendate
substrate binding may be drawn.
The assumption that a bidentate substrate-Pd species un-
dergoes nucleopalladation eliminates the possibility of a cis-
nucleopalladation pathway because all four coordination sites
on the square plane of palladium are occupied. This leaves eight
possible binding geometries to obtain the product (two possible
alkene isomers, two possible faces of each alkene, two possible
sites for the alkene to coordinate). The second assumption is
that, given the bulky nature of the substituent on the oxazoline,
the substrate will coordinate in a manner that orients the alkyl
chain toward the opposite face of the palladium plane. This
eliminates four of the eight possibilities. Two of the remaining
possibilities lead to the minor enantiomer of the product. The
last two possibilities are (1) the E-isomer bound trans to the
oxazoline and (2) the Z-isomer bound trans to the pyridine. In
examination of physical models, the former seems to have slight
steric interactions between the alkyl chain and the pyridine
portion of the ligand, while the latter seems to orient the chain
away from the ligand. Also, the latter possibility orients the
alkene closer in space to the chiral center on the ligand. Further,
this orientation provides for the observed electronic communica-
tion between the ligand and substrate, as described above.
Finally, it would be difficult to envision how asymmetric
induction could be imparted if the alkene was oriented away
from the oxazoline. Thus, the model shown in Figure 13 is
Conclusion
Detailed investigation of a palladium-catalyzed alkene di-
functionalization reaction provided insight into the mechanistic
details. Kinetic evidence for turnover-limiting attack of the
quinone methide was uncovered, supported by the observation
of a linear free energy relationship correlating substrate elec-
tronic nature to the rate of reaction. The Jaffe´ relationship is
used to interpret the complex influence of an aromatic substituent
when there are two potential reactive sites on the aromatic ring,
providing further support for turnover-limiting quinone methide
attack. While the precise function of copper in this reaction was
not elucidated, evidence for copper involvement in more than
just catalyst turnover was discovered. The kinetic data and
results using other Lewis acids support copper-facilitated
quinone methide formation. Ligand exchange between copper
and palladium was found to be rapid in most cases, but an
enantioselective system was developed which uses an achiral
copper complex in conjunction with a chiral palladium complex,
thus reducing the loading of chiral material. Finally, we hope
to take advantage of these findings to design new alkene
functionalization manifolds in which the substrate undergoes
oxidation to a reactive intermediate.
Acknowledgment. This work was supported by the National
Institutes of Health (NIGMS RO1 GM3540). M.S.S. thanks the
Dreyfus Foundation (Teacher-Scholar) and Pfizer for their support.
J.D.W. is grateful for the award of a Queen’s University Dean’s
Travel Grant. We are grateful to Johnson Matthey for the gift of
various Pd-salts.
Supporting Information Available: Experimental procedures,
kinetic data, and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA108106H
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17482 J. AM. CHEM. SOC. VOL. 132, NO. 49, 2010