rangement to access cyclic ketones, and report our initial
observations herein.
Trost has shown that Pd-enolates do not isomerize on the
time scale of allylic alkylation.9 Moreover, we opted to
prepare E- and Z-allyl ethers to establish whether these
stereoisomers would converge to a single E-olefin substituted
cyclohexanone via rapid syn-:anti-isomerization of the Pd-π-
allyl complex.10
The required phosphonium salts were prepared by using
a protocol originally developed by Ley, and by analogy to
the method reported in our Co-mediated rearrangement study
(Scheme 1).2,11 Specifically, addition of a vinyl aluminum
Surprisingly little precedent for such a catalytic transfor-
mation can be found in the literature. Nonetheless, Trost and
Tsuji independently demonstrated that furan-based enol
ethers can be transformed to cyclopentanones in good yield,
in the presence of a low-valent palladium source.5 This
concept was later used by Langer in an intramolecular variant
in order to access bicyclo[3.2.1]octan-8-ones.6 Notably, all
of these examples exploited the intermediacy of a stabilized
enolate by appending electron-withdrawing substituents on
the enol ether moiety.
We wanted to investigate the rearrangement of nonstabi-
lized pyran enol ethers such as 2 (RE/Z ) aryl, alkyl) into
2,3-substituted cyclohexanones 3 using substoichiometric
quantities of a transition metal catalyst (Figure 1). A key
Scheme 1. Synthesis of Enol Ether Precursors
species generated from DibalH and terminal alkyne12 allowed
us to access E-pyranyl ether substrates. Alternatively, alkyl-
ation with preformed alkynylaluminum species, followed by
hydrogenation provided Z-pyranyl ether substrates. Finally,
a terminal alkene substrate was prepared in three steps
following a literature procedure.13 The Wittig salts 7-9 could
be prepared on multigram scale and in high yield by
treatment of the respective pyranyl ethers with triph-
enylphosphonium tetrafluoroborate.
Figure 1. Pd-catalyzed O-to-C rearrangement.
step in this process is the intramolecular Pd-catalyzed allylic
alkylation (AA) of a ketone enolate, which is generated in
situ. The regio- and diastereoselective Pd-catalyzed AA of
ketone enolates remains a challenging transformation, and
is often restricted to stabilized ketone enolates or substrates
bearing a single point of enolization.7 An alternative approach
employs functional groups that act as a masked enolate.8 In
our approach, we wished to exploit a cyclic enol ether as a
masked ketone enolate that would be generated after Pd-
promoted ionization of an allyl ether. As highlighted in
Figure 1, one would expect the stereochemistry of the enol
ether alkene moieties to play a role in determining the
diastereoselectivity of cyclohexanone product formation, as
The subsequent Wittig reaction was next investigated by
using a range of aromatic and aliphatic aldehydes (Table 1).
Table 1. Scope of the Wittig Reaction
(5) (a) Trost, B. M.; Runge, T. A.; Jungheim, L. N. J. Am. Chem. Soc.
1980, 102, 2840. (b) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981,
103, 2485. (c) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103,
7550. (d) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103, 7559.
(e) Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron Lett.
1980, 21, 1475.
(6) (a) Langer, P.; Holtz, E. Angew. Chem., Int. Ed. 2000, 39, 3086. (b)
Langer, P.; Holtz, E.; Saleh, N. N. R. Chem.sEur. J. 2002, 8, 917.
(7) (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121,
6759. (b) Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000,
39, 3494. (c) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem.,
Int. Ed. 2002, 41, 3492. (d) Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou,
X.-L. J. Am. Chem. Soc. 2007, 129, 7718. (e) Braun, M.; Meier, T.; Laicher,
F.; Meletis, P.; Fidan, M. AdV. Synth. Catal. 2008, 350, 303.
(8) (a) Behenna, D. C.; Stoltz, B. J. Am. Chem. Soc. 2004, 126, 15044.
(b) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. (c) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 17180. (d) Burns, A. C.; Forsyth, C.
Org. Lett. 2008, 10, 97. (e) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org.
Lett. 2009, 11, 293.
a Yield of isolated product. b Refers to enol ether stereochemistry.
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