Tandem palladium(0) and palladium(II)-catalyzed allylic alkylation through complementary redox cycles

Article abstract of DOI:10.1002/anie.201204251

Here it goes again: A tandem catalytic process effects sequential Pd ⁰-catalyzed allylic alkylations through leaving group ionization and Pd^II-catalyzed allylic alkylations by C-H activation. By employing an oxidative trigger to convert the catalytic species from Pd⁰ into Pd^II, both transformations can be conducted in a single reaction vessel using the same precatalyst. This allows for the selective introduction of otherwise indistinguishable allyl groups. Copyright

Full text of DOI:10.1002/anie.201204251

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DOI: 10.1002/anie.201204251
Assisted Tandem Catalysis
Tandem Palladium(0) and Palladium(II)-Catalyzed Allylic Alkylation
Through Complementary Redox Cycles**
Barry M. Trost,* David A. Thaisrivongs, and Max M. Hansmann
Among the strategies that seek to address the challenges
inherent to performing chemical synthesis in our increasingly
resource-conscious world, catalysis has provided the most
significant contribution to conducting synthetic transforma-
tions in an atom-economical way, defining a paradigm in
which starting materials are used efficiently and waste is
minimized.[1] In the interest of further enhancing the effi-
ciency and sustainability of the production of fine chemicals,
there has been a recent focus on performing sequential
catalytic operations in a single reaction vessel.[2] The appli-
cation of such tandem processes has the potential to deliver
important practical advantages, both with respect to the
increase in material throughput and the concomitant decrease
in the cost, labor, and time associated with the workup and
isolation of intermediates.[3] Just as importantly, such an
approach also provides an opportunity to develop new
methods that orchestrate the performance of several con-
current catalytic events, allowing for the discovery of new
types of reactivity and selectivity for the direct construction of
molecular complexity.
Of the many types of tandem catalysis, those that employ
one precatalyst to perform two mechanistically distinct bond-
forming events in the presence of a reagent that triggers this
change in mechanism are called “assisted tandem catalysis”.[4]
Strategically, these methods offer advantages over other
tandem processes because they obviate the need to either
begin with or subsequently add a second catalyst, making
efficient use of the typically valuable precatalyst, and they
eliminate the possibility for deleterious interactions between
two different catalytic species.
a RuII-catalyzed ring-closing metathesis of hepta-1,6-dien
-4-one to afford cyclopent-3-enone; addition of H2 under high
pressure generates a different RuII species that hydrogenates
the newly formed alkene (Scheme 1a).[7] Similarly, Rawal and
co-workers have demonstrated that a PdII catalyst which
Scheme 1. a) Ring-closing metathesis followed by hydrogenation using
tandem RuII catalysis. b) Bromoallylation followed by Wacker oxidation
using tandem PdII catalysis. DCE=1,2-dichloroethane, DME=dime-
thoxyethane, Mes=mesityl.
performs a bromoallylation of alkynes can also be used to
conduct a subsequent PdII-catalyzed Wacker oxidation of the
newly formed alkene (Scheme 1b).[8] These examples, among
other analogous reports, share the requirement that each step
of the tandem process be conducted with the same oxidation
state of the catalyst. Reports of assisted tandem catalysis in
which different catalyst oxidation states are used to effect
each stage are rare,[9] and there are no known examples that
Despite these attractive qualities, reports of assisted
tandem catalysis are uncommon and the number of known
chemical triggers is small.[5] A significant fraction of such
processes involve a Ru–carbene-catalyzed alkene metathesis
event followed by a Ru-catalyzed non-metathetic transfor-
mation.[6] For example, Grubbs and co-workers have reported
that their second generation metathesis catalyst can perform
À
employ palladium, or that form C C bonds in both catalytic
steps.
We became interested in the possibility of applying our
À
recently disclosed palladium-catalyzed allylic C H alkylation
of 1,4-dienes[10] to a new assisted tandem catalytic process. In
that report we demonstrated that PPh3, a ligand that has long
been employed in a wide variety of palladium-mediated
allylic alkylations that proceed through leaving group ioniza-
[*] Prof. B. M. Trost, D. A. Thaisrivongs, M. M. Hansmann
Department of Chemistry, Stanford University
Stanford CA 94305-5080 (USA)
tion,[11] could also promote allylic alkylation by C H activa-
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost
À
tion. Despite the mechanistic dichotomy between these two
processes, the fact that they could both be promoted by the
same phosphine ligand encouraged us to consider whether it
might be feasible to conduct both types of reactions in one pot
with a single precatalyst. The hypothesis was that an oxidant
could be used to trigger the necessary change in mechanism,
thus converting a Pd0 catalyst capable of performing allylic
alkylation through leaving group ionization into a PdII
[**] We thank the NSF (CHE 0948222) for their generous support of our
programs. D.A.T. acknowledges support from a Stanford Graduate
Fellowship (The William K. Bowes, Jr. Foundation) and an Eli Lilly
and Company Graduate Fellowship; M.M.H. acknowledges support
from the Studienstiftung des deutschen Volkes and the DAAD—
PROMOS scholarship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204251.
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methyl carbonate, only 2 is observed, with no trace of 3
[Eq. (2)]. This result demonstrates that the acetate generated
by allylic ionization is necessary for the subsequent allylic
À
C H alkylation, a finding which is consistent with mechanistic
0
II
À
Scheme 2. Pd -catalyzed allylic alkylation and Pd -catalyzed allylic C H
alkylation performed in tandem with the use of an oxidative trigger.
Ac=acetyl, L=ligand, Nu=nucleophile.
work that suggests carboxylate ligands on PdII are responsible
À
for C H activations that proceed through concerted metal-
ation–deprotonation pathways.[12] Indeed, when acetic acid is
added to a reaction that otherwise lacks acetate, the desired
À
À
catalyst capable of performing allylic alkylation by C H
allylic C H alkylation event is restored [Eq. (3)].
activation (Scheme 2). This approach might provide the first
means of chemoselectively achieving two different allylic
alkylations simultaneously by differentiating each event using
the oxidation state of both the electrophile and the metal.
Since each partner would only react in a matched sense (for
example, in Scheme 2, allyl acetate with Pd0 or 1,4-pentadiene
with PdII), such a strategy would govern the introduction of
otherwise indistinguishable allyl groups through complemen-
tary catalytic redox cycles. As this method accepts substrates
for both Pd0 and PdII-catalyzed allylic alkylations, it provides
greater flexibility in terms of the choice of electrophile than
either reaction alone. When considering the commercial
availability of a desired starting material or the kind of
substrate that would best fit into a synthetic sequence, an allyl
group may be more efficiently installed using either the
corresponding allyl acetate or the corresponding alkene; both
options become available with this tandem catalysis method.
When ethyl nitroacetate (1) is treated with allyl acetate
(1.0 equiv) in the presence of Et3N (1.0 equiv) and Pd(PPh3)4
(7.0 mol%) in toluene at room temperature, ethyl 2-nitro-
pent-4-enoate (2) is generated. In line with our hypothesis, if
to this reaction 1,4-pentadiene (1.2 equiv), Et3N (1.1 equiv),
and 2,6-dimethylbenzoquinone (2,6-DMBQ; 1.1 equiv) are
subsequently added, (E)-ethyl 2-allyl-2-nitrohepta-4,6-dien-
oate (3) can be isolated in 78% yield [Eq. (1)]. The success of
We established the scope of this tandem catalytic process
by systematically varying the nucleophile, the allylic acetate,
À
and the electrophile undergoing C H activation. When
reacted with allyl acetate and 1,4-pentadiene, ethyl nitro
acetate gives desired product 3 in 78% yield with a 7.2:1 E/Z
selectivity (Scheme 3). With the corresponding methyl ester,
Scheme 3. Tandem Pd0 and PdII-catalyzed allylic alkylations with stabi-
lized nucleophiles. All yields shown are of isolated products; E/Z
ratios obtained by 1H NMR spectroscopy.
this transformation demonstrates that 2,6-DMBQ can not
only be employed as the oxidative trigger to convert a Pd0
catalyst that performs the allylic alkylation with allyl acetate
into a PdII catalyst that performs the allylic alkylation with
1,4-pentadiene, but also as the oxidizing reagent necessary for
converting 2 to 3. Indeed, control experiments verify that no
the yield of 4 moderately decreases to 62%, but the E/Z
selectivity increases to 10:1. Conducting the reaction with
ethyl cyanoacetate provides 5 in 55% yield and with complete
control of the internal double bond geometry. Electron-
withdrawing groups besides esters can also be borne by
nucleophiles for the tandem catalytic reaction. For example,
nitroacetophenone gives 6 in 67% yield with 3.0:1 E/Z
selectivity. The success of the reaction with (nitromethyl)-
À
allylic C H alkylation proceeds in the absence of 2,6-DMBQ.
Unexpectedly, the nature of the leaving group in the first half
of this tandem process is critical for the success of the second
half. For example, when allyl acetate is replaced with allyl
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benzene to generate 7 in 85% yield with 15:1 E/Z selectivity
demonstrates that, in the absence of a second strongly
electron-withdrawing functionality, the nitro group alone
can serve as the main nucleophilic activating group.
A variety of allylic acetates effectively undergo reaction
with ethyl nitroacetate in concert with 1,4-pentadiene
(Scheme 4). With but-3-en-2-yl acetate, which is substituted
Scheme 5. Tandem Pd0 and PdII-catalyzed allylic alkylations with elec-
trophiles. All yields shown are of isolated products; E/Z ratios
obtained by 1H NMR spectroscopy. [a] Reaction conducted with a 1:1
E/Z mixture of 1,4-hexadiene. [b] The second half of the tandem
catalysis was performed at 508C; see the Supporting Information for
details. BDMS=benzyl(dimethyl)silyl, S of others=sum of all other
configurations.
with a phenyl group, the corresponding triene (15) can be
obtained in 79% yield with almost complete stereoselectivity.
The corresponding benzyl(dimethyl)silyl containing 1,4-diene
gives 16 in 97% yield, but with less control over the double
Scheme 4. Tandem Pd0 and PdII-catalyzed allylic alkylations with allylic
acetates. All yields shown are of isolated products; E/Z ratios obtained
by 1H NMR spectroscopy. [a] Reaction conducted with but-3-en-2-yl
acetate. S of others=sum of all other configurations.
À
bond geometries. In addition to activating C H bonds
belonging to methylene groups, the catalyst can also react
À
with methine C H bonds. For example, when 3-methyl-1,4-
pentadiene is employed as an electrophile, 17 can be obtained
in 49% yield, with a slight excess of the Z configuration.
on the carbon bearing the leaving group, 8 is isolated in 52%
yield with a predominantly E,E configuration. When the
electrophile is methallyl acetate, in which there is substitution
on the central carbon of the p-allylpalladium intermediate,
desired product 9 can be obtained in 52% yield with an 8.1:1
E/Z selectivity. In general, cinammyl-based substrates pro-
vide excellent control of the double bond geometry set in the
À
The allylic C H alkylation event is not limited to 1,4-
dienes. It can also be performed with 1,4-enynes, as a phenyl-
substituted 1,4-enyne is smoothly converted to 18 in 74%
yield and with complete control of double bond geometry.
Allylbenzene, in which the adjacent p system is a phenyl
group instead of a double or triple bond, reacts efficiently to
give 19 in 66% yield and with > 19:1 E/Z selectivity.
À
subsequent allylic C H alkylation. For example, reaction with
cinnamyl acetate gives 10 in 62% yield with > 19:1 E/Z
selectivity. The corresponding electron-deficient para-nitro
electrophile provides 11, also in 62% yield and > 19:1 E/Z
selectivity, and the corresponding electron-rich para-methoxy
electrophile gives 12 in 59% yield and > 19:1 E/Z selectivity.
When benzyl 2-(acetoxymethyl)acrylate is employed as the
allylic acetate, 13 is isolated in 48% yield and with 9.0:1 E/Z
selectivity.
Because the chemical trigger used to generate the second
catalyst species would interfere with the performance of the
first, every example of assisted tandem catalysis requires
a delay between the start of the reaction and the addition of
the trigger. Although this temporal separation allows each
catalytic transformation to be conducted independently, it
necessitates monitoring the first reaction to determine when
the second can begin, an inconvenience that decreases the
operational practicality of executing multiple bond-forming
steps using this strategy. Given control experiments which
demonstrate that Pd0-catalyzed allylic alkylation is more
facile than the analogous PdII-catalyzed reaction, our hypoth-
esis was that it would be possible to carry out this tandem
À
Many different types of electrophiles undergo C H
activation in this tandem catalytic process (Scheme 5).
When a 1:1 E/Z mixture of 1,4-hexadiene is used as
a substrate, desired product 14 is isolated in 56% yield with
a 10:1 ratio of the E,E configuration to the other double bond
isomers. When one terminus of 1,4-pentadiene is substituted
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catalytic process without delaying the introduction of either
the oxidant or the second electrophile. Even in the presence
of the chemical trigger, the difference in relative rates should
allow the Pd0-catalyzed bond-forming event to proceed to
completion before the PdII-catalyzed one. When ethyl nitro-
acetate, allyl acetate, 1,4-pentadiene, 2,6-DMBQ, Et3N, and
Pd(PPh3)4 are combined at the same time in toluene in
a single reaction vessel and heated to 508C for 24 h, 3 is
obtained in 70% yield and with 11:1 E/Z selectivity
(Scheme 6), an achievement that marks the first example of
In summary, we have demonstrated that two concurrent
Pd-catalyzed allylic alkylation events can be independently
controlled by exploiting the chemoselectivity of the catalyst in
its Pd0 and PdII states. By differentiating substrates using their
oxidation level, it is possible to govern which catalyst species
each engages with. Such an approach may prove to be a more
general strategy for effecting two or more coupling reactions
that, in the absence of another distinguishing feature, would
have to be performed stepwise.
Experimental Section
General procedure for the tandem Pd0- and PdII-catalyzed allylic
alkylations: A reaction vial equipped with a stir bar was charged with
Pd(PPh3)4 (11.6 mg, 0.010 mmol), sealed with a septa, and then
evacuated and filled with Ar three times. PhCH3 (0.7 mL) was added,
followed by the nucleophile (0.200 mmol), the allylic acetate
(0.200 mmol), and Et3N (27.9 mL, 0.200 mmol). A second reaction
vial equipped with a stir bar was charged with 2,6-DMBQ (30.0 mg,
0.220 mmol), sealed with a septa, and then evacuated and filled with
Ar three times. PhCH3 (0.3 mL) was added to the second reaction
vial, and after 4 h this solution was added to the reaction via syringe,
followed by the alkene (0.240 mmol) and Et3N (30.7 mL, 0.220 mmol).
After 20 h, the reaction was concentrated under reduced pressure to
give crude material, which was purified by column chromatography
on silica gel (see the Supporting Information for details).
Scheme 6. Simultaneous tandem Pd0 and PdII-catalyzed allylic alkyla-
tions with stabilized nucleophiles. All yields shown are of isolated
products; E/Z ratios obtained by 1H NMR spectroscopy.
Received: June 1, 2012
Revised: August 6, 2012
Published online: October 10, 2012
assisted tandem catalysis that does not require intervention to
initiate the second catalytic step. Several aspects of this
success merit further comment. First, both Pd0 and PdII
catalytic cycles operate sequentially in the presence of 2,6-
DMBQ, suggesting that this strong oxidant for Pd0 is
effectively out-competed by allyl acetate. Additionally, the
rate of the first Pd0-catalyzed allylation is substantially faster
than the second, as significant quantities of the corresponding
bis-allylated product are not detected. Notably, although
there is a slight decrease in the amount of isolated material,
this process is more stereoselective than the two-stage
protocol (Scheme 3). In analogous reactions with methyl
nitroacetate, ethyl cyanoacetate, benzoylnitromethane, and
(nitromethyl)benzene, the corresponding products (4, 5, 6,
and 7, respectively) can be similarly obtained (Scheme 6).
One of the advantages of employing 1,4-dienes as
Keywords: 1,4-dienes · allylic alkylation · C-H activation ·
.
palladium · tandem catalysis
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