Pd(II)-catalyzed conversion of styrene derivatives to acetals: Impact of (-)-sparteine on regioselectivity

Article abstract of DOI:10.1021/ol053110p

Pd[(-)-sparteine]Cl₂ catalyzes the formation of dialkyl acetals from styrene derivatives with Markovnikov regioselectivity. The substrate scope of this reaction has been investigated, and initial mechanistic studies indicate that the reaction proceeds through an enol ether intermediate and a Pd-hydride.

Full text of DOI:10.1021/ol053110p

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1121-1124
Pd(II)-Catalyzed Conversion of Styrene
Derivatives to Acetals: Impact of
(−)-Sparteine on Regioselectivity
Amy M. Balija, Kara J. Stowers, Mitchell J. Schultz, and Matthew S. Sigman*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112-0850
sigman@chem.utah.edu
Received December 22, 2005
ABSTRACT
Pd[(−)-sparteine]Cl2 catalyzes the formation of dialkyl acetals from styrene derivatives with Markovnikov regioselectivity. The substrate scope
of this reaction has been investigated, and initial mechanistic studies indicate that the reaction proceeds through an enol ether intermediate
and a Pd-hydride.
The Wacker oxidation has been widely utilized in target-
orientated synthesis because of its ability to transform
terminal olefins mildly and chemoselectively into methyl
ketones.1 One modification of this reaction involves substi-
tuting an alcohol for water to access the carbonyl as its
acetal.2 For example, Hosokawa and Murahashi3 demon-
strated that R,â-unsaturated carbonyl compounds and styrenes
oxidize to acetals in good yields and with high regioselec-
tivity for the anti-Markovnikov product (eq 1).4,5 While
investigating aerobic oxidative transformations of styrene
derivatives using Pd[(-)-sparteine]Cl2 (1) in methanol, we
discovered that dimethyl acetals form under mild reaction
conditions (Table 1). Surprisingly, a reversal in product
regioselectivity was observed to yield the Markovnikov acetal
when using (-)-sparteine as a ligand on Pd. Herein, we report
the substrate scope and a preliminary mechanistic study to
elucidate the salient features of this process.
(1) For a review of Wacker oxidation, see: Takacs, J. M.; Jiang, X.-T.
Curr. Org. Chem. 2003, 7, 369-396 and references therein.
(2) (a) Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Y. K. Dokl. Akad. Nauk
SSSR 1960, 133, 377-380. (b) Lloyd, W. G.; Luberoff, B. J. J. Org. Chem.
1969, 34, 3949-3952.
(3) (a) Hosokawa, T.; Ohta, T.; Murahashi, S.-I. J. Chem. Soc., Chem.
Commun. 1983, 848-849. (b) Hosokawa, T.; Ohta, T.; Kanayama, S.;
Murahashi, S.-I. J. Org. Chem. 1987, 52, 1758-1764. (c) Hosokawa, T.;
Ataka, Y.; Murahashi, S.-I. Bull. Chem. Soc. Jpn. 1990, 63, 166-169. (d)
Hosokawa, T.; Shinohara, T.; Ooka, Y.; Murahashi, S.-I. Chem. Lett. 1989,
2001-2004. (e) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S.-
I. J. Org. Chem. 1995, 60, 6159-6167.
Optimized conditions allowed styrene derivatives 2a-e
to be oxidized to the Markovnikov acetals using 4 mol % 1,
5 mol % CuCl2, and 3 Å molecular sieves in methanol
under an O2 atmosphere at room temperature in 24 h (Table
1). Removal of CuCl2 or O2 results in rapid decomposi-
tion of the Pd catalyst, and molecular sieves were required
to achieve complete conversion.6 In entries 1-5, the
Markovnikov acetal was produced in excellent yields with
little anti-Markovnikov product observed. Methyl ketone was
(4) For examples of acetal formation used in synthesis, see: (a)
Hosokawa, T.; Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49-54. (b)
Lai, J.-Y.; Shi, X.-X.; Dai, L.-X. J. Org. Chem. 1992, 57, 3485-3487. (c)
Byrom, N. T.; Grigg, R.; Kongkathip, B.; Reimer, G.; Wade, A. R. J. Chem.
Soc., Perkin Trans. 1 1984, 1643-1653. (d) Kasahara, A.; Izumi, T.;
Murakami, S.; Miyamoto, K.; Hino, T. J. Heterocycl. Chem. 1989, 26,
1405-1413.
(6) Without molecular sieves the reaction is considerably slower and the
primary product is methyl ketone. However, the role of molecular sieves
may not be as simple as a dehydrating agent; see: Steinhoff, B. A.; King,
A. E.; Stahl, S. S. J. Org. Chem. 2006, ASAP.
(5) For acetal formation with alkynes, see: Scheffknecht, C.; Peringer,
P. J. Organomet. Chem. 1997, 535, 77-79.
10.1021/ol053110p CCC: $33.50
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Published on Web 02/22/2006

Table 1. Pd(II)-Catalyzed Acetalization of Styrenes in Various
Table 2. Pd(II)-Catalyzed Acetalization of Styrenes Containing
Alcohols
Electron-Withdrawing Functional Groups
a Average isolated yield over two reactions. b Measured by 1H NMR; 3
includes ∼5% ketone.
During acetalization, a hydrogen atom is added to the
â-carbon of the styrene. To elucidate the origin of this
hydrogen atom, isotopic labeling experiments were per-
formed.9 Substrate 2c was submitted to the reaction condi-
tions in d4-MeOH (eq 2). No deuterium atoms were
incorporated in the methyl group of the product, indicating
that the hydrogen atom does not originate from the solvent.10
To investigate the origin of the hydrogen atom incorporated
further, R-deuteriostyrene was subjected to the reaction
conditions (eq 3). The resulting acetal retained >93% of the
deuterium atom at the â-position in 7, providing support for
a hydride shift.
a Average isolated yield over two reactions. b Measured by 1H NMR.
c Reaction performed at 0.1 M with 20 mol % CuCl2.
found to be a minor contaminant due to acetal hydrolysis
during purification.7 Additionally, the regioselectivity does
not change as the reaction progresses. Switching the solvent
to ethylene glycol or ethanol similarly provided the Mark-
ovnikov acetals in good yields (entries 6 and 7). However,
an increased amount of CuCl2 was required when using
ethylene glycol, potentially due to low O2 solubility.
Unfortunately, larger nucleophiles such as 2-propanol did
not react with styrenes under these conditions.
Formation of methyl acetals using electron-poor styrenes
(2f, 2g, and 2h) required elevated temperatures and higher
catalyst loadings (Table 2). In these examples, a mixture of
Markovnikov and anti-Markovnikov acetals was obtained,
with the most electron-poor substrate 2h leading to a nearly
equal mixture of the two regioisomers. Furthermore, a direct
correlation between Hammett σ values and the log of the
ratio of regioisomers is observed (F ≈ -2.0).8
These experiments provide insight into a possible mech-
anism for acetalization that involves a palladium-assisted 1,2-
hydride migration (Scheme 1). Following formation of the
Pd-bound sytrene A, nucleopalladation of methanol can
proceed with Markovnikov or anti-Markovnikov regioselec-
tivity. In the presence of (-)-sparteine, it is believed a
kinetically favored pathway is preferred to minimize steric
interactions between substrate and catalyst.11 Upon nu-
The above results contrast Hosokawa and Murahashi’s
observations in which styrene derivatives under similar
conditions are converted preferentially to anti-Markovnikov
acetals.3 This ligand-dependent regioselectivity led us to ask
the following questions: (1) what is a reasonable reaction
mechanism and (2) what factors dictate regioselectivity?
(9) For a review of previous isotopic labeling studies, see: Henry, P.
M. Palladium Catalyzed Oxidation of Hydrocarbons; Reidel Publishing
Company: Dordrecht, Holland, 1980.
(10) These results are consistent with previous isotope labeling experi-
ments performed by Hosokawa and Murahashi on an R,â-unsaturated
carbonyl substrate. See ref 3b for additional information.
(7) It has also been shown that the methyl ketone could result from
a Wacker coupled alcohol oxidation; see: Nishimura, T.; Kakiuchi, N.;
Onoue, T.; Ohe, K.; Uemura, S. J. Chem. Soc., Perkin Trans. 1 2000, 1915-
1918.
(8) See Supporting Information for details.
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Org. Lett., Vol. 8, No. 6, 2006

conditions in methanol (eq 4). No product was detected after
24 h, indicating that acetal formation does not proceed in
the absence of a Pd-H species.15 To promote Pd-H
formation, an equal mixture of 2a16 and 8 was subjected to
similar reaction conditions (eq 5). After 14 h, only 26% of
the enol ether was converted to 3a, suggesting that 8 becomes
tightly associated with 1 and inhibits the reaction. Interest-
ingly, exposure of ethyl enol ether 917 to the acetalization
conditions in ethanol (eq 6) results in complete conversion
to the diethyl acetal. Under these conditions, ethanol is
proposed to undergo oxidation18 to form a Pd-H species
that can react with 9 to facilitate acetal formation.
Scheme 1. Pd(II)-Catalyzed Acetalization of Styrene under
Proposed Kinetic and Thermodynamic Control
cleopalladation at the R-position, methanol is deprotonated
followed by â-hydride elimination to afford D. Nucleophilic
attack of methanol12 onto D or a related intermediate re-
sults in the formation of the Markovnikov acetal and re-
lease of Pd(0). Several mechanistic pathways have been
proposed to describe addition of the second methanol,
including nucleopalladation of the enol ether or hydride
insertion into the enol ether followed by oxonium forma-
tion.3,8 We are currently unable to differentiate these pos-
sibilities.
Further evidence for an enol ether intermediate was
obtained upon oxidation of the sterically demanding 2,4,6-
trimethyl sytrene 10 (eq 7). Under the optimized acetalization
conditions, a 5:1 mixture of enol ether 11 and dimethyl acetal
12 was observed by H NMR. It is believed that after
â-hydride elimination, 11 disassociates from the Pd, thus
limiting formation of 12.
1
In the absence of ligand, Pd-catalyzed acetalization of 2a
results in the anti-Markovnikov product. To account for this
reversal in regiocontrol, we propose that nucleopalladation
proceeds reversibly. It has been proposed by Stahl in a related
transformation that the thermodynamically favorable inter-
mediate arises from anti-Markovnikov addition. This pro-
posal requires reversable nucleopalladation where F can
be stabilized by a Pd-benzylic species similar to G.13 Con-
sidering that electron-poor substrates require more forc-
ing reaction conditions leading to erosion of regioselectiv-
ity, entry into the proposed thermodynamic pathway is
reasonable. However, an alternative explanation for the
electronic correlation on regioselectivity is a change in
polarization of the Pd-bound olefin affecting kinetic nu-
cleopalladation.
In summary, the Pd(II)-catalyzed oxidation of styrenes in
alcoholic solvents proceeds under mild conditions to afford
the corresponding Markovnikov acetal in excellent yields.
Initial mechanistic studies indicate that the reaction proceeds
through a methyl enol ether intermediate and Pd-H species.
When (-)-sparteine is used as a ligand on Pd, a change in
regioselectivity favoring the Markovnikov product is ob-
served. Elucidating the precise reasons for the control of
To examine whether the methyl enol ether proposed in
Scheme 1 is a viable intermediate for acetalization, 8 was
synthesized14 and exposed to the Pd(II)-catalyzed reaction
(14) Gassman, P. G.; Burns, S. J.; Pfister, K. B. J. Org. Chem. 1993,
58, 1449-1457.
(15) Methanol does not readily oxidize under these conditions. For further
evidence, see: Lloyd, W. G. J. Org. Chem. 1967, 32, 2816-2819.
(16) In the absence of 8, substrate 2a is >95% consumed as observed
by GC.
(17) A 1.3:1 mixture of enol ether 9 and its corresponding diethyl acetal
was used in this experiment.
(18) For alcohol oxidations using Pd[(-)-sparteine]Cl2, see: Mueller,
J. A.; Cowell, A.; Chandler, B. D.; Sigman, M. S. J. Am. Chem. Soc. 2005,
127, 14817-14824 and references therein.
(11) For crystal structure of 1, see: Jensen, D. R.; Pugsley, J. S.; Sigman,
M. S. J. Am. Chem. Soc. 2001, 123, 7475-7476.
(12) Portney, M.; Milstein, D. Organometallics 1994, 13, 600-609.
(13) Similar studies regarding the mechanism of styrene amination were
recently reported; see: Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc.
2005, 127, 17888-17893.
Org. Lett., Vol. 8, No. 6, 2006
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regioselectivity and applying this information to related
transformations is a subject of future research.
a summer research fellowship. We are grateful to Johnson
Matthey for the gift of various Pd salts.
Acknowledgment. This work is supported by the Na-
tional Institute 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. K.J.S. thanks Pfizer GRD for
Supporting Information Available: Experimental pro-
cedures and characterization data for products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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