Palladium-catalyzed intramolecular oxidative alkylation of unactivated olefins

Article abstract of DOI:10.1021/ja026317b

Reaction of 5,5-dimethyl-8-nonene-2,4-dione catalyzed by PdCl₂(CH₃CN)₂ (5 mol %) in the presence of CuCl₂ (2.5 equiv) at room temperature for 3 h formed 2-acetyl-3,6,6-trimethyl-2-cyclohexenone in 96% isolated yield. Palladium-catalyzed intramolecular oxidative alkylation tolerated a range of substitution and was applicable to the synthesis of spirobicyclic compounds and to the cyclization of ζ-alkenyl β-keto esters. Copyright

Full text of DOI:10.1021/ja026317b

Published on Web 12/20/2002
Palladium-Catalyzed Intramolecular Oxidative Alkylation of Unactivated
Olefins
Tao Pei, Xiang Wang, and Ross A. Widenhoefer*
Duke UniVersity, P. M. Gross Chemical Laboratory, Durham, North Carolina 27708-0346
Received March 25, 2002 ; E-mail: rwidenho@chem.duke.edu
Scheme 1
The palladium(0)-catalyzed oxidative arylation and alkenylation
of olefins (Heck reaction) is one of the most useful transition metal-
catalyzed transformations utilized in organic synthesis (eq 1).1 In
contrast, oxidative alkylation of olefins via the Heck reaction
remains problematic due to the inefficient oxidative addition of the
alkyl halide or competitive â-hydride elimination of the initially
formed Pd(II) intermediate.1,2 An alternative approach to the
oxidative alkylation of olefins that would also obviate the need for
Scheme 2
the alkyl halide is via the Pd(II)-catalyzed nucleophilic addition of
a carbon nucleophile to an olefin in the presence of an oxidant.
Indeed, Pd(II) complexes catalyze the oxidative amination,3 alkoxyl-
ation,4 and hydroxylation5 of unactivated olefins (eq 2). Unfortu-
nately, Pd(II)-catalyzed oxidative alkylation of olefins remains
problematic due to incompatibility between the carbon nucleophile
and the stoichiometric oxidant.6-8 Here we report the first effective
procedure for the Pd(II)-catalyzed oxidative alkylation of an olefin
with a carbon nucleophile.
mixture of dione 4 and 2 in dioxane at room temperature for 15
min led to isolation of cyclohexenone 5 in 80% yield as the
exclusive product (Scheme 2). In accord with our initial expecta-
tions, diketone 4 tolerated the conditions required for in situ
oxidation of Pd(0) to Pd(II), and in an optimized procedure, slow
addition of 4 to a mixture of 2 (5 mol %) and CuCl2 (2.5 equiv) in
1,2-dichloroethane (DCE) over 3 h at room temperature led to the
isolation of 5 in 96% yield (Scheme 2). Oxidative alkylation of 4
was also achieved by employing a catalytic amount of both 2 (5
mol %) and CuCl2 (10 mol %) under an oxygen atmosphere, albeit
with somewhat diminished yield (Scheme 2).
The oxidative alkylation of ú-alkenyl â-diketones tolerated a
number of terminal acyl groups including propionyl, isobutyryl,
ꢀ-Alkenyl â-diketones were initially targeted as substrates for
Pd(II)-catalyzed oxidative alkylation on the expectation that the
â-diketone would be sufficiently nucleophilic to attack the tethered
olefin in the presence of Pd(II) and yet tolerate the conditions
required for in situ oxidation of Pd(0). However, treatment of the
ꢀ-alkenyl â-diketone 1 with a catalytic amount of PdCl2(CH3CN)2
pivaloyl, and cyclohexanecarbonyl groups (Table 1, entries 1-4).
(2) formed none of the desired cycloalkenone but instead formed
gem-Dimethyl groups at the γ-carbon atom of the ú-alkenyl
cyclohexanone 3 in 81% isolated yield via net addition of the enolic
â-diketone appeared to facilitate cyclization but were not required
C-H bond across the olefinic CdC bond (hydroalkylation) (eq
(Table 1, entries 5-8). Palladium-catalyzed oxidative alkylation
3).9 We have proposed that protonolysis of the Pd-C bond of the
also tolerated allylic substitution (Table 1, entry 9) and was
palladium cyclohexyl intermediate I in preference to â-hydride
elimination leads to formation of 3 rather than the expected
oxidative alkylation product (Scheme 1).9
applicable to the synthesis of spirobicyclic compounds (Table 1,
entry 10) and to the cyclization of ú-alkenyl â-keto esters (Table
1, entry 11). However, efforts to effect the oxidative alkylation of
ꢀ-alkenyl â-diketones or ú-alkenyl â-diketones that possess olefinic
substitution have been unsuccessful.
We have formulated a working mechanism for the oxidative
alkylation of 4 catalyzed by 2 that is based on the proposed
mechanism of the Wacker oxidation.10 Attack of the pendant enolic
carbon atom on the palladium-complexed olefin of II coupled with
loss of HCl could form the palladium cyclohexylmethyl species
III (Scheme 3). Isomerization of III via â-hydride elimination/
addition/elimination followed by olefin displacement from inter-
mediate VI would release 5 and form a palladium hydrochloride
Although attempts to access the oxidative alkylation pathway in
the cyclization of 1 catalyzed by 2 were unsuccessful, we have
now found that ú-alkenyl â-diketones undergo selective oxidative
alkylation in the presence of 2. For example, reaction of a 1:1
9
648
J. AM. CHEM. SOC. 2003, 125, 648-649
10.1021/ja026317b CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Oxidative Alkylation of ú-Alkenyl â-Diketones Catalyzed
by PdCl2(CH3CN)2 (2) (5 mol %) in the Presence of CuCl2 (2.5
equiv) in DCE at Room Temperature for 3-7 h
Scheme 3
Acknowledgment. R.W. thanks the A. P. Sloan Foundation,
the Camille and Henry Dreyfus Foundation, DuPont, and Glaxo-
SmithKline for financial assistance. Academic year support for T.P.
and X.W. has been provided by Duke University in the form of a
Charles R. Hauser Fellowship and Burroughs Wellcome Fellowship,
respectively.
Supporting Information Available: Experimental procedures and
spectroscopic data for new compounds and cyclohexanones (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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b
Reaction run at 70 °C. 10 mol % catalyst employed and 14%
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species,10 which would eliminate HCl and react with CuCl2 to
regenerate the catalytically active Pd(II) species (Scheme 3). Both
the isomerization of III to VI and olefin displacement from VI
must be fast relative to protonolysis of palladium alkyl intermediates
III and V to account for the selective formation of 5. We currently
do not understand the factors that control partitioning between the
oxidative alkylation and hydroalkylation pathways in the Pd(II)-
catalyzed cyclization of alkenyl â-diketones.9
In summary, we have developed the first effective transition
metal-catalyzed protocol for the oxidative alkylation of an unac-
tivated olefin with a carbon nucleophile. Our efforts are currently
directed toward expanding the substrate scope of oxidative alkyl-
ation with respect to tether length and olefinic substitution, toward
elucidating the mechanism of this transformation, and toward
understanding the factors that determine product selectivity in the
Pd(II)-catalyzed cyclization of alkenyl â-diketones and related
substrates.
JA026317B
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J. AM. CHEM. SOC. VOL. 125, NO. 3, 2003 649