A dinuclear palladium catalyst for α-Hydroxylation of carbonyls with O2

Article abstract of DOI:10.1021/ja108396k

A chemo- and regioselective α-hydroxylation reaction of carbonyl compounds with molecular oxygen as oxidant is reported. The hydroxylation reaction is catalyzed by a dinuclear Pd(II) complex, which functions as an oxygen transfer catalyst, reminiscent of an oxygenase. The development of this oxidation reaction was inspired by discovery and mechanism evaluation of previously unknown Pd(III)-Pd(III) complexes.

Full text of DOI:10.1021/ja108396k

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pubs.acs.org/JACS
A Dinuclear Palladium Catalyst for r-Hydroxylation of
Carbonyls with O2
Gary Jing Chuang, Weike Wang, Eunsung Lee, and Tobias Ritter*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
S Supporting Information
b
paddlewheel complex 1, originally developed by Cotton,7 which
ABSTRACT: A chemo- and regioselective R-hydroxylation
reaction of carbonyl compounds with molecular oxygen as
oxidant is reported. The hydroxylation reaction is catalyzed
by a dinuclear Pd(II) complex, which functions as an oxygen
transfer catalyst, reminiscent of an oxygenase. The devel-
opment of this oxidation reaction was inspired by discovery
and mechanism evaluation of previously unknown Pd-
(III)-Pd(III) complexes.
features four bridging hexahydro-2H-pyrimido[1,2-a]pyrimidine
ligands (hppH, 2), and its use for chemo- and regioselective R-
hydroxylation of carbonyl compounds to form tertiary alcohols
with O2 as the only oxidant (eq 1).
Oxidation of R-methyl-β-tetralone (3) under one atmosphere
of O2 in the presence of 5 mol % 1 produced R-hydroxy-R-
methyl-β-tetralone (4) in 77% isolated yield in the absence of any
other reagent or additive except solvent. R-Hydroxylation reac-
tions of carbonyl compounds are typically performed by oxida-
tion of the corresponding enolates or silyl enol ethers with an
oxygen transfer reagent, such as m-CPBA, dimethyldioxirane
(DMDO), or N-sulfonyl oxaziridines.8 During deprotonation,
silyl enol ether formation, and oxidation, a stoichiometric amount of
waste is generated in each operation. Other metal-mediated
R-hydroxylation reactions of carbonyls with dioxygen typically
afford hydroperoxides and require subsequent reduction, or have
significantly smaller demonstrated substrate scope.9
Hydroxylation proceeded smoothly between 0 and 6 °C in
THF or toluene (for results in toluene and benzene, see Supporting
Information). When the reaction was performed under 1 atm of
air instead of O2, isolated yields of hydroxylated products were
20-30% lower. The reaction could be applied to a variety of
carbonyl compounds, similar or higher in acidity than tetralone,
such as 5, with as little as 2.5 mol % catalyst 1 as shown in Table 1.
Addition of substoichiometric amounts of the commercially
available guanidine derivative hppH (2) enabled hydroxylation
of carbonyl compounds less acidic than tetralone (see for example
reaction to 19). The additive hppH likely does not function solely as
a base for enolate formation; other strong amine bases such as
hppMe and DBU did not have a beneficial effect. Hydroxylation
of R-allyl cyclohexanone proceeded in less than 40% yield, even
with 10 mol % catalyst, likely due to lower acidity, with starting
material being the remainder of the isolated material. Carbonyl
substitutions that favor enol formation by either hydrogen bonding
(11) or conjugation (10) are advantageous for the hydroxylation
reaction.
imetallic catalysis, as we defined it in our previous work, is
B
catalysis with synergistic redox cooperation between two
metal centers.1 Several dinuclear complexes are known to
catalyze redox transformations in organic chemistry and Nature,2
but the design of new dinuclear complexes for bimetallic redox
catalysis is rare.3 While in monometallic redox transformations
only one metal participates in redox chemistry, two metals share
the redox work in bimetallic catalysis and can therefore lower
activation barriers compared to mononuclear catalysts.1 In 2009,
we reported the first reactions from organometallic Pd(III)
compounds and implicated dinuclear Pd(III) complexes with
metal-metal bonds in bimetallic directed oxidation catalysis.4
Subsequently, we sought to evaluate dinuclear Pd catalysts with
potential for metal-metal redox cooperation for other challen-
ging redox transformations. Here, we report a chemo- and
regioselective R-hydroxylation reaction of carbonyl compounds
with molecular oxygen or air as oxidant, catalyzed by the
dinuclear Pd(II) complex 1 (eq 1).
The hydroxylation reaction is regioselective and forms tertiary
alcohols, even when more than one acidic C-H group is present
such as in R-benzylcyclohexanone (reaction to 19). Oxidation of
C-H acidic methylene groups to afford secondary alcohols was
not observed due in part to overoxidation to the corresponding
R-diketo compounds (see Supporting Information). The hydro-
xylation reaction catalyzed by 1 is chemoselective; double bonds
(7, 15, 21, and 22) and sulfides (23), known to react with other
Dioxygen (O2) is a readily available, inexpensive oxidant.
Catalysts that use O2 to reoxidize a reduced catalyst but do not
transfer either oxygen atom from O2 to the product are called
oxidases. Pd complexes with oxidase reactivity have a successful
history in synthesis, as exemplified by the Wacker oxidation and
work by Sigman, Stahl, and Stoltz.5 Oxygenases incorporate one
(monooxygenase) or both oxygen atoms (dioxygenase) from O2
into a substrate and are less common in organic synthesis.6 Here,
we report the first dinuclear Pd(II) oxygen transfer catalyst,
which functions as a dioxygenase. We identified the dipalladium
Received: September 16, 2010
Published: January 19, 2011
r
2011 American Chemical Society
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|

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Table 1. R-Hydroxylation Reaction of Carbonyl Compounds
with O2
Figure 1. In situ UV-vis spectroscopy of reaction intermediate and
dinuclear Pd(III) benzoate complex 24.
mechanism to afford 6 would require that radical recombination
after hydrogen abstraction were faster than cyclopropane ring-
opening. Moreover, triphenylmethane (HCPh3), with a small
C-H bond dissociation energy, was not oxidized under the
reaction conditions. We therefore think that a hydrogen abstrac-
tion mechanism is less likely, and that the mechanism of the
hydroxylation reaction presented here is distinct from the
mechanism of radical metal-mediated and C-H autoxidation
reactions by O2.
Our original design targeted high-valent Pd oxygen species,
accessible by bimetallic synergistic redox participation, for oxida-
tion chemistry. When the hydroxylation reaction shown in eq 1
was analyzed by in situ UV-vis spectroscopy, an absorption
centered at 650 nm was observed spectroscopically (Figure 1).
Upon discontinued agitation, this absorption disappeared within
a minute, and remaining coloration was observed at the interface
between reaction solution and dioxygen atmosphere. Previously,
we have reported a variety of dinuclear Pd(III) complexes, all
of which display a UV-vis absorption maximum around
600 nm, which was not observed for the corresponding Pd(II)
complexes.1,4 For comparison, we prepared the dinuclear Pd(III)
benzoate complex 24, featuring oxygen ligands on both Pd
centers. As shown in Figure 1, 24 displays a similar UV-vis
absorption centered at 650 nm as observed during the reaction.
Computational analysis predicted that the absorption at 650 nm
is due to a transition from a metal-metal bonding to a metal-
metal antibonding orbital.12 Catalyst 1, substrate 3, and a combina-
tion thereof do not display a similar absorption, and no mono-
nuclear Pd catalyst that was investigated afforded hydroxylation
comparable to 1 (see Supporting Information for details). While
the intermediacy of a dinuclear Pd(III) complex is an enticing
possibility, consistent with our original reaction design, substan-
tiated discussion of mechanism is premature at this stage and
requires additional experimentation.
a A total of 2.5 mol % of 1 was used. b No 2 was added. c A total of
10 mol % of 1, and 60 mol % of 2 were used.
electrophilic and nucleophilic oxygen transfer reagents,10 were
compatible with the Pd-catalyzed oxidation presented here.
Our results indicate that the dinuclear Pd(II) catalyst 1 behaves
as a dioxygenase: Oxygen transfer from O2 to the substrate was
established by hydroxylation in an 18O2 atmosphere, which
afforded the 18O-isotopologue as hydroxylation product in 97%
isotopic purity as determined by mass spectrometry (eq 2). On
the basis of an oxygen uptake experiment, both oxygen atoms
from O2 were incorporated into the product. Hence, the oxida-
tion reported here proceeds without generation of stoichiometric
amounts of waste except solvent.
In conclusion, we report a chemo- and regioselective R-
hydroxylation reaction of carbonyl compounds by oxygen
transfer from O2, catalyzed by a dinuclear Pd(II) complex.
While the hydroxylation reaction presented here is a first
example of reaction development inspired by bimetallic
Pd(III) catalysis, we anticipate that bimetallic Pd(III) cata-
lysis may serve as a concept for synthetically useful reaction
discovery.
The mechanism of the hydroxylation reaction, formally an
oxygen insertion into a C-H bond, is currently unknown.
Because more acidic carbonyl compounds afford higher yields,
we speculate that enol formation is important for hydroxylation.
One role of hppH (2) may be to facilitate enolization. Several
C-H autoxidation reactions by O2 and metal-catalyzed oxida-
tion reactions with O2 proceed by radical mechanisms via
hydrogen abstraction and often afford peroxides or hydroper-
oxides as products.11 No hydroperoxide was observed in the O2
oxidation reactions catalyzed by 1 (see Supporting Information).
Successful hydroxylation via a potential hydrogen abstraction
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
ritter@chemistry.harvard.edu
’ ACKNOWLEDGMENT
We thank NSF (CHE-0952753) and NIH-NIGMS (GM088237)
for financial support, Theodore Betley and David Powers for
discussions, and NSC of Taiwan for a post graduate fellowship
for G.J.C. (NSC-972917I564145). DFT computation was per-
formed using the computer facilities at the Odyssey cluster at
Harvard University.
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