Palladium(II)-catalyzed aerobic hydroalkoxylation of styrenes containing a phenol

Article abstract of DOI:10.1021/ja0585533

An intermolecular Pd-catalyzed hydroalkoxylation of styrenes that contain a phenol is presented. The reaction can be performed on terminal, disubstituted, and trisubstituted olefins in a variety of alcoholic solvents. Initial mechanistic data suggest a mechanism that involves oxidation of the alcoholic solvent to provide a Pd-hydride that inserts into an olefin. This is followed by formation of a quinone methide and subsequent addition of an alcohol to yield the hydroalkoxylated product. Copyright

Full text of DOI:10.1021/ja0585533

Published on Web 02/14/2006
Palladium(II)-Catalyzed Aerobic Hydroalkoxylation of Styrenes Containing a
Phenol
Keith M. Gligorich, Mitchell J. Schultz, and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850
Received December 16, 2005; E-mail: sigman@chem.utah.edu
Table 1. Scope of Pd-Catalyzed Hydroalkoxylation
Considering the ubiquitous nature of carbon-oxygen bonds in
biologically interesting compounds, developing new catalytic
methods for the efficient construction of such bonds is desirable.
One approach is metal-catalyzed addition of an alcohol across an
olefin, which offers considerably enhanced synthetic versatility
compared to the related Brønsted acid variants.1 Recently, there
have been several reports of catalytic olefin hydroalkoxylation
processes,2 which are thought to proceed via nucleophilic attack
on a metal-coordinated olefin followed by protonation of the M-C
bond.3,4 In light of this and as expected, Pd(II) complexes5 have
not been reported to catalyze olefin hydroalkoxylation due to facile
â-hydride elimination.6 Herein, we disclose a mild new Pd(II)-
catalyzed aerobic hydroalkoxylation reaction of styrene derivatives
containing a phenol. In contrast to previous methods, the initial
mechanistic studies support a process in which alcohol oxidation
is coupled to the functionalization of the olefin.
While exploring the scope of a recently discovered PdCl2-
catalyzed dialkoxylation reaction of propenyl phenol 1a,7 we found
that the complex Pd[(-)-sparteine]Cl28 catalyzed the transformation
in MeOH, resulting in a 70% yield with a 4.5:1 syn-to-anti ratio in
<5% ee (eq 1). Interestingly, switching the solvent to EtOH led to
an unanticipated change in reaction outcome providing a 64% yield
of the hydroalkoxylation product 3a in <5% ee (eq 2).9 Notably,
without (-)-sparteine as a ligand, dialkoxylation was the major
product.7
a Average isolated yield of two reactions. b Ratio measured by 1H NMR.
c Reaction carried out at 35 °C.
2-propanol as a nucleophile is noteworthy in that secondary alcohols
are typically not viable in related nucleopalladation reactions.11
After exploring the initial scope of the Pd-catalyzed hy-
droalkoxylation, we were interested in elucidating the mechanistic
features of the reaction. Specifically, we wanted to address three
questions: (1) What is the source of the incorporated proton? (2)
What is the role of the phenol, considering simple styrenes produce
the acetal under the same conditions?12 (3) What is the role of the
solvent on reaction outcome?
Initially, it was thought that the reaction was proceeding through
a nucleopalladation/protonation process similar to that proposed by
both Widenhoefer and co-workers3 and Yang and He.4 Therefore,
the use of CH3CH2OD as the solvent should result in a single
deuterium incorporation at the site of Pd-C protonation. However,
submitting 5 to the hydroalkoxylation conditions in CH3CH2OD
resulted in no deuterium incorporation into the product (eq 3).9 In
Optimization for hydroalkoxylation of 1a led to the use of 5
mol % Pd[(-)sparteine]Cl2, 20 mol % CuCl2, and 3 Å molecular
sieves at 35 °C under an O2 atmosphere in ethanol (Table 1, entry
1). Removal of catalytic CuCl2 or molecular oxygen resulted in
significant catalyst decomposition and low yields. Expansion of
the scope to include o-vinylphenols revealed these substrates are
significantly more reactive and allowed the use of lower catalyst
loadings (entries 3-5). The main byproduct of the reaction with
o-vinylphenols is the ketone, which is inseparable by chromatog-
raphy.10 Unexpectedly, the hydroalkoxylation of 1f led to low mass
recovery, presumably due to polymerization of the substrate (entry
6). A trisubstituted styrene derivative 1g undergoes hydroalkoxy-
lation in 48% yield at a longer reaction time (entry 7).
Both ethylene glycol and 2-propanol were successful nucleophiles
for hydroalkoxylation (entries 8 and 9), while benzyl alcohol and
acetic acid did not lead to appreciable product formation. Use of
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C O M M U N I C A T I O N S
and co-workers10b and Lloyd16 have shown that methanol is not
easily oxidized by Pd(II). On the basis of the proposed mechanism,
we can attribute the change in reaction outcome from dialkoxylation
in methanol to hydroalkoxylation in ethanol to the ability of the
catalyst to oxidize the solvent to form the requisite Pd-hydride.
Without a Pd-hydride, initial nucleopalladation by methanol is
thought to be the first step of the dialkoxylation reaction.7a
In summary, we have discovered a novel intermolecular Pd-
catalyzed hydroalkoxylation of styrene derivatives that contain a
phenol. The hydroalkoxylation reaction can be performed on
terminal, disubstituted, and trisubsituted olefins with several
alcoholic solvents including 2-propanol. Mechanistic experiments
support a pathway wherein the oxidation of an alcohol is coupled
to olefin functionalization via a quinone methide intermediate.
Future work will include further elucidation of the mechanism and
utilizing coupled alcohol oxidations in olefin functionalization
reactions.
Scheme 1. Proposed Mechanism
contrast, the use of CD3CD2OD produced isotopomers 6a and 6b
in a 2.5:1 ratio (eq 4).
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.
M.J.S. thanks the University of Utah for a graduate research
fellowship. We thank Professor Jim Mayer for insightful discus-
sions. We are grateful to Johnson Matthey for the gift of various
Pd salts.
The labeling experiments suggest that the acidic proton from
EtOH is not cleaving the Pd-C bond; rather, the incorporated
hydrogen originates from the alkyl chain of a separate equivalent
of ethanol. With this in mind, we propose a mechanism requiring
the oxidation of ethanol to produce a Pd-hydride B, followed by
coordination of the olefin to produce C (Scheme 1). On the basis
of the isotopic labeling experiments, we propose that hydride
insertion into the olefin yields a mixture of D and E, which
interconvert through C via â-hydride elimination.13 Since the
products arise only from substitution at the R-carbon of the styrene,
E is proposed to proceed to product via formation of an ortho-
quinone methide intermediate F with concomitant reduction of the
catalyst.14,15 Ethanol would subsequently add into the ortho-quinone
methide to form the carbon-oxygen bond.
To further explore the plausibility of intermediate F, both 7 and
10 were submitted to the reaction conditions (eqs 5 and 6). Reaction
of 7, which is able to form a para-quinone methide, resulted in the
formation of a mixture of the hydroalkoxylation product 8 and
ketone 9 in an overall 87% yield. However, reaction of 10, which
is unable to form a quinone methide, did not result in the formation
of the hydroalkoxylation product, but instead generated ketone 11.
These experiments offer support for the formation of a quinone
methide prior to addition of the alcohol. Additionally, a planar
quinone methide intermediate or a weakly associated Pd complex
may account for the lack of enantioselectivity observed.9
Supporting Information Available: Experimental procedures and
characterization data for substances. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For example, see: Larock, R. C. ComprehensiVe Organic Synthesis, 2nd
ed.; Wiley & Sons: New York, 1999; pp 903-904.
(2) Intramolecular hydroalkoxylation of olefins: (a) Grant, V. H.; Liu, B.
Tetrahedron Lett. 2005, 46, 1237-1239. (b) Coulombel, L.; Favier, I.;
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N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553-4556. Intermolecular
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(6) For reviews of Pd-catalyzed oxidation reactions, see: (a) Stahl, S. S.
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(7) (a) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 1460-
1461. (b) For a similar example, see: Chevrin, C.; Bras, J. L.; He´nin, F.;
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(8) For the use of Pd[(-)-sparteine]Cl2 in alcohol oxidations, see: Mueller,
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2005, 127, 14817-14824 and references therein.
(9) See Supporting Information for details.
(10) (a) One possibility to account for the formation of ketone is via acetal
formation, which is hydrolyzed upon workup; for a review see ref 6b. (b)
Another possible pathway is via a Pd-catalyzed aerobic alcohol oxidation
coupled Wacker oxidation. See: Nishimura, T.; Kakiuchi, N.; Onoue, T.;
Ohe, K.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 1915-1918.
(11) For an example of a nucleopalladation with a chiral secondary alcohol,
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Chem. 1987, 52, 1758-1764.
(12) Under identical conditions with 4-methylstyrene in ethanol, the Mark-
ovnikov diethyl acetal is formed.
(13) Only one deuterium atom is incorporated into the olefin, indicating that
the equilibration of D and E does not include dissociation of the olefin.
(14) For an example of a stoichiometric Pd(II)-mediated formation of a quinone
methide, see: Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J.
C. J. Am. Chem. Soc. 1971, 93, 6696-6698.
(15) For a review of quinone methides in synthesis, see: Van De Water, R.
W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367-5405.
(16) Lloyd, W. G. J. Org. Chem. 1967, 32, 2816-2819.
The final mechanistic question outlined above was how the subtle
change in solvent influences the reaction outcome. Both Uemura
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