Driving catalyst reoxidation in wacker cyclizations with acetal-based metal-hydride abstractors

Article abstract of DOI:10.1021/om2001958

In traditional Wacker processes, Pd(II) becomes reduced to Pd(0) after C-O bond formation and β-H elimination and must be reoxidized to the electrophilic Pd(II) state via a stoichiometric oxidant such as benzoquinone, CuCl₂, or O₂. We report herein a Pt-catalyzed Wacker-type process that regenerates the electrophilic Pt²⁺ state by H ^- abstraction from a [Pt]-H using an oxocarbenium ion generated from an acetal or ketal under acidic conditions.

Full text of DOI:10.1021/om2001958

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Driving Catalyst Reoxidation in Wacker Cyclizations with Acetal-Based
Metal-Hydride Abstractors
Nikki A. Cochrane, Maurice S. Brookhart,* and Michel R. Gagnꢀe*
Department of Chemistry, University of North Carolina at Chapel Hill, CB # 3290, Chapel Hill, North Carolina 27599, United States
S Supporting Information
b
ABSTRACT: In traditional Wacker processes, Pd(II) becomes reduced to
Pd(0) after CꢀO bond formation and β-H elimination and must be reoxidized
to the electrophilic Pd(II) state via a stoichiometric oxidant such as benzoqui-
none, CuCl2, or O2. We report herein a Pt-catalyzed Wacker-type process that
regenerates the electrophilic Pt2þ state by Hꢀ abstraction from a [Pt]-H using
an oxocarbenium ion generated from an acetal or ketal under acidic conditions.
acker-like oxidative cyclization reactions have provided
net-dehydrogenative routes to a broad variety of hetero-
ultimately enabled the development of catalytic, enantio- and
regioselective oxidative cascade cyclizations.
W
cyles.1 The sequence of elementary steps leading to these
products typically involves activation of an alkene by an electro-
philic metal center, attack of a carbon or heteronucleophile (e.g.,
H2O, H2NAr), and β-H elimination of the resulting alkyl
complex to yield a metal hydride and product alkene. The
challenge in rendering these processes catalytic has been to
return the catalyst to its electrophilic state. In the case of Pd(II)
catalysts, the resulting [Pd]-H typically undergoes reductive
elimination (deprotonation) to generate Pd(0), which is reox-
idized to Pd(II).1,2 Early variants of these catalysts relied on
oxidants such as CuCl2 or benzoquinone, although recent
advances have shown that O2 may also be used.1e,2
One disadvantage of this approach, however, was the conse-
quent generation of a full equivalent of Ph3CH, which, combined
with unreacted Ph3COMe, makes workup cumbersome. Resin-
bound variants of the Ph3COMe were effective, but batch-to-
batch variability was observed along with some reduction in
activity. To circumvent these issues, we sought alternative
“oxidants” that could similarly abstract Hꢀ, but were more atom
economical and conveniently removed from products. To this
end, we considered the possibility that acetals, ketals, and ortho-
esters might be capable of hydride abstraction under acidic
conditions (Scheme 1). Supporting this hypothesis were data
reported by Bullock demonstrating that acetals in combination
with strong acids could abstract hydrides from [Mo]-H complexes.8
Since most P2Pt2þ-catalyzed polyene cyclization reactions are
buffered with Ph2NH, we first tested whether its conjugate acid,
Ph2NH2þ, could generate the putative oxocarbenium ion. Ben-
zaldehyde dimethyl acetal was therefore combined with CD3OD,
and in <5 min complete exchange gives PhCH(OCD3)2, which
was observed by 1H NMR spectroscopy (eq 1). This suggested
that the putative oxocarbenium ion, 1, was readily accessible
under conditions known to be compatible with the substrates for
P2Pt2þ-catalyzed cyclizations.
While Pt complexes display many of the same reactivity
profiles as Pd complexes, they have typically not been used for
Wacker-type transformations.3 The reasons include a lower
acidity of the platinum hydride and the higher binding strength
of Pt(II) to counterions such as Clꢀ, which poison its electro-
philic character. Previous efforts in our group on electrophilic
dicationic Pt(II) complexes demonstrated that Wacker-like
activity could be achieved with polyene substrates that propagate
via cationꢀolefin pathways.4 A terminating regioselective β-H
elimination subsequently gave polycyclic structures with control of
elimination regiochemistry.3a,5b,5c Returning the resulting [Pt]-H
cations to the electrophilic Pt-dicationic state, however, was not
achievable using conventional oxidants. Fortunately, trityl cation
[Ph3Cþ][BF4ꢀ] was found to efficiently abstract the hydride to
form Ph3CH and regenerate Pt2þ free of coordinating anions.5b,c,6
Use of Ph3Cþ thus provides an approach to Pt(II) Wacker-
type catalysts and access to new transformations not available to
Pd variants.3a,5b,5c,7 Most convenient in this first-generation
approach was the use of Ph3COMe, which, upon reacting with
Hþ (the byproduct of the electrophilic activation), liberated
MeOH and the active Ph3Cþ. This served to keep the concen-
tration of the reactive species at relatively low levels and
The ability of reactive intermediate 1 to abstract hydride from
a catalytic [P2Pt-H]þ intermediate was examined using a close
mimic of this intermediate in our reaction mechanism, [(xylyl-
phanephos)Pt(H)(NCC(CH3)3)][BF4], 2. Complex 2 could be
generated in situ from the corresponding P2PtI(H) by iodide
abstraction with AgBF4 in the presence of 2 equiv of
Received: March 2, 2011
Published: April 06, 2011
r
2011 American Chemical Society
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Scheme 1. Hydride Abstraction Reactions with [Pt-H]þ
Table 1. Stoichiometric Pt-H Abstractor Candidatesa
Scheme 2. Predicted Pathway for Hydride Abstraction with
Benzaldehyde Dimethyl Acetal
NCC(CH3)3. P2PtI(H) was obtained from the reaction of P2PtI2
with polystyrene-bound triacetoxyborohydride (see Supporting
Information).
To look for hydride abstraction activity, a stoichiometric
amount of 2 was added to a premixed solution of a 1:1 ratio of
benzaldehyde dimethyl acetal and [Ph2NH2][BF4] in CD3NO2,
the solvent of choice for catalysis (Scheme 2). Over the course of
5 h, 2 cleanly converted to [(xylyl-phanephos)Pt(NCC-
1
(CH3)3)2][(BF4)2], 3; no intermediates were observed by H
a Acetal added to [Ph2NH2][BF4] in 0.1 mL of CD3NO2 for 5 min at
RT; subsequently [Pt] in 0.2 mL CD2Cl2/0.3 mL CD3NO2 was added.
b Percent conversion to 3 after 24 h as determined by 31P NMR
spectroscopy.
and 31P NMR spectroscopy. The predicted byproducts of
hydride abstraction, benzyl methyl ether and MeOH, were
1
confirmed by H NMR spectroscopy and GC-MS (BnOMe),
consistent with Scheme 1. Under identical conditions, reactions
of Ph3COMe with a stoichiometric amount of [Ph2NH2][BF4]
and 2 resulted in >95% conversion to 3, and as expected, Ph3CH
was observed as the only byproduct (1H NMR and GC-MS).
These baseline experiments were slightly faster than the acetal
abstraction experiments.
With a reliable protocol in hand for testing the viability of
acetal-based hydride abstraction, other convenient commercially
available aromatic, cyclic, and aliphatic acetals and ketals were
tested. As shown in Table 1, the most successful aromatic hydride
abstractor candidates included benzaldehyde dimethyl acetal and
4-methoxy benzaldehyde dimethyl acetal, each giving >95%
conversion to 3 within 24 h. Noteworthy is the observation that
benzaldehyde itself was equally effective and presumably paral-
leled the protonated carbonyl reactivity reported by Bullock,
Tilset, Norton, and others.8a,b,d,9ꢀ11
oxocarbenium ion (entry 7). By contrast, the doubly stabilized
dioxocarbenium ion derived from trimethylorthoformate likely
suffers from a slow abstraction rate (entry 8). Encouraging were
results obtained from the acetals derived from formaldehyde and
acetaldehyde, especially dimethoxymethane, which generated 3
in high yields. Since both the reaction products and dimethoxy-
methane are volatile, workup using this reoxidant is particularly
attractive.
Tilset has previously demonstrated that hydride abstraction by
triflic acid in acetone is proportional to the steady-state concen-
tration of (CH3)2CdOHþ.10 This observation reasonably sug-
gests that the rate of the reactions described in Table 1 depends
on a combination of factors including the steady-state concen-
tration of the oxocarbenium ion along with its electrophilicity.
More electrophilic ions will be present at lower concentrations
than stabilized ions, but would compensate with higher reactiv-
ities. In the event, the balance of forces tended to favor the more
stabilized oxocarbenium ions (entries 2ꢀ4, 9, and 10). Although
no intermediates were observed during the reaction in Scheme 2,
both Bullock and Tilset have shown that hydride abstraction by
Aliphatic acetals were also examined and found to be viable
(entries 7ꢀ11). Bullock has previously noted that secondary
carbenium ions are more reactive than tertiary ions, a trend
followed by these aliphatic hydride abstractor candidates (see
Table 1).8d,12,13 Trioxane was not particularly effective, perhaps
because fast reclosure results in a low steady concentration of the
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Table 2. Catalytic Results Using Alternative Hydride
Abstractorsa,
Scheme 3. Proposed Catalytic Cycle for Oxocarbenium
Hydride Abstractor
serve as stoichiometric oxidants in Wacker-type catalysis with
concomitant improvements in atom efficiency and ease of use
over alternative oxidants (e.g., benzoquinone and Ph3COMe).
’ ASSOCIATED CONTENT
S
Supporting Information. Synthesis of metal complexes
b
and experimental information are available free of charge via the
Internet at http://pubs.acs.org.
a All reactions performed under standard catalytic conditions with a
13 mM solution of 10 mol % [(R)-(xylyl-MeO-BIPHEP)]Ptl2, 25 mol %
AgBF4, 20 mol % Ph2NH, and 2.1 equiv of acetal in CH3NO2. b Yields
and % ee determined by chiral GC after 24 h. The mass balance was
unreacted 4. c Results after 48 h.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: mgagne@unc.edu.
’ ACKNOWLEDGMENT
protonated ketones proceeds through a pathway wherein oxygen
coordination to the metal immediately follows MꢀH breakage
and yields alcohol adducts as the kinetic product.8a,b,d,9,10,14
On the basis of the reaction profiles displayed in Table 1, the
most efficient hydride abstractor candidates were submitted to
catalytic reaction conditions using a biaryl xylyl-MeO-BIPHEP-
based Pt(II) catalyst (Table 2).5a,b Our working mechanism for
this new protocol is thus shown in Scheme 3; the P2Pt dication
coordinates to the least substituted alkene and initiates the
cyclization of 4 to give an alkyl cation that regioselectively β-H
eliminates to generate 5. Hydride abstraction by transiently
generated oxocarbenium ions thus turns the catalytic cycle over
by regenerating the electrophilic P2Pt2þ initiator.15 Even with
Ph2NH as a buffer, acid buildup can initiate a Brønsted cycliza-
tion to generate 6. As shown in Table 2, the acetals, while
generally more sluggish than Ph3COMe, were also less likely to
generate Brønsted products. Dimethoxymethane was especially
selective, giving a high preponderance of the desired 5 over 6.
Enantioselectivities were unchanged compared to experiments
using Ph3COMe.5b Product isolation of 5 for entry 5 (Table 2)
simply involved running the reaction mixture through a plug
of silica gel to remove the catalyst, followed by removal of
the methanol and dimethyl ether byproducts via vacuum
concentration.
We thank the National Institute of General Medical Sciences
for generous support (Grant GM-60578).
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