Mechanism of the palladium-catalyzed intramolecular hydroalkylation of 7-octene-2,4-dione

Article abstract of DOI:10.1021/ja0293002

Cyclization of (E)-7,8-dideuterio-7-octene-2,4-dione [(E)-1-7,8-d₂] catalyzed by PdCl₂(CH₃CN)₂ (2) formed cis-2-acyl-3,4-dideuteriocyclohexanone (cis-3-3,4-d₂) in 64% yield as the exclusive isotopomer. This experiment, in conjunction with additional deuterium labeling experiments, was in accord with a mechanism for the conversion of 1 to 3 catalyzed by 2 involving attack of the enol carbon atom on a palladium-complexed olefin followed by palladium migration and protonolysis from a palladium enolate complex. Copyright

Full text of DOI:10.1021/ja0293002

Published on Web 01/30/2003
Mechanism of the Palladium-Catalyzed Intramolecular Hydroalkylation of
7-Octene-2,4-dione
Hua Qian and Ross A. Widenhoefer*
P. M. Gross Chemical Laboratory, Duke UniVersity, Durham, North Carolina 27708-0346
Received November 11, 2002 ; E-mail: rwidenho@chem.duke.edu
Scheme 1
The Michael addition is one of the most important C-C bond-
forming processes employed in organic synthesis, but it is restricted
to olefins that bear an electron-withdrawing group.1 In response to
this limitation, we recently reported the palladium-catalyzed intra-
molecular hydroalkylation of alkenyl â-dicarbonyl compounds.2,3
For example, treatment of 7-octene-2,4-dione (1) with a catalytic
amount of PdCl2(CH3CN)2 (2) formed 2-acetylcyclohexanone (3)
in 81% yield via net addition of the enolic C-H bond across the
olefinic CdC bond (eq 1).2 These transformations represent the
first examples of the transition metal-catalyzed hydroalkylation of
an unactivated olefin with a stabilized carbon nucleophile4 and may
provide a general solution to the problems associated with the
alkylation of unactivated olefins. However, further development
of these transformations will require an understanding of the
mechanisms of these processes, in particular, the mechanisms of
C-C bond formation and proton transfer. Here we report a
deuterium-labeling study that provides insight into the mechanism
of C-C bond formation and proton transfer in the conversion of 1
to 3 catalyzed by 2.
dium methoxide (eq 2).11 In a separate set of experiments,
cyclization of (Z)-1-7,8-d2 catalyzed by 2 formed trans-3-3,4-d2 in
67% yield,9 which was converted to syn-4-4,5-d2 in 28% yield.11
The stereochemistry of syn-4-4,5-d2 was established by the 6.0 Hz
coupling constant of the H(4) and H(5) protons of the pentanoate
chain.10
Both inner-sphere and outer-sphere mechanisms have been
established for the palladium-catalyzed addition of oxygen5 and
nitrogen6 nucleophiles to olefins and for the palladium-mediated
addition of carbon nucleophiles to olefins.7 We therefore considered
both inner-sphere and outer-sphere mechanisms for the palladium-
catalyzed hydroalkylation of 1. These pathways can be potentially
distinguished via cyclization of (E)-7,8-dideuterio-7-octene-2,4-
dione [(E)-1-7,8-d2] (Scheme 1). In the inner-sphere pathway, attack
of the enol carbon atom of (E)-1-7,8-d2 on 2 coupled with loss of
HCl could form the palladium alkyl olefin chelate complex I-d2,
which could undergo intramolecular carbometalation followed by
protonolysis of the Pd-C bond of trans-II-3,4-d2 with retention of
configuration8 to form trans-3-3,4-d2 (Scheme 1, path a). In the
outer-sphere pathway, attack of the enolic carbon on the palladium-
complexed olefin of III-d2 coupled with loss of HCl could form
palladium cyclohexyl intermediate cis-II-3,4-d2. Protonolysis of the
Pd-C bond of cis-II-3,4-d2 with retention of configuration would
form cis-3-3,4-d2 (Scheme 1, path b).
Stereospecific conversion of (E)- and (Z)-1-7,8-d2 to cis- and
trans-3-3,4-d2, respectively, is consistent with outer-sphere C-C
bond formation, provided that conversion of II-3,4-d2 to 3-3,4-d2
occurs with retention of configuration (Scheme 1 path b).8 To gain
insight into the nature of the protonolysis step in the cyclization of
1 catalyzed by 2, we studied the cyclization of 3,3-dideuterio-7-
octene-2,4-dione (1-3,3-d2) (eq 3). If conversion of II to 3 occurred
via direct protonolysis of the Pd-C bond of II, cyclization of 1-3,3-
d2 should form exclusively 3-2,4-d2 via deuteriolysis of the Pd-C
bond of intermediate II-2-d1. However, cyclization of 1-3,3-d2
catalyzed by 2 followed by silica gel chromatography formed none
of the expected C(4)-d1 isotopomer and instead formed 3-6-d1 in
45% isolated yield as the exclusive deuterated isotopomer (eq 3).12
Formation of 3-6-d1 rather than 3-4-d1 in the cyclization of 1-3,3-
d2 points to migration of palladium from the C(4) carbon atom to
the C(6) carbon atom of the 2-acetylcyclohexanone ring prior to
deuteriolysis. Three additional experiments provided insight into
the mechanism of palladium migration. In separate experiments,
cyclization of 1-1,1,1,5,5-d5, 1-6,6-d2, and 1-8,8-d2 catalyzed by 2
formed 3-2,3-d2-6-COCD3, trans-3-4,5-d2, and 3-3,3-d2, respec-
tively, as the exclusive isotopomers (eqs 4-6); the stereochemistry
of trans-3-4,5-d2 was established by the 4.4 Hz coupling constant
of the H(3) and H(4) protons of the pentanoate chain of derivative
syn-4-3,4-d2.
Treatment of (E)-1-7,8-d2 with a catalytic amount of 2 (10 mol
%) in dioxane at room temperature for 12 h formed cis-3-3,4-d2 in
64% isolated yield (eq 2).9 The stereochemistry of cis-3-3,4-d2 was
established indirectly by the 9.2 Hz coupling constant of the H(4)
and H(5) protons of the corresponding pentanoate derivative anti-
4-4,5-d2 (eq 2),10 generated in 18% yield by treatment of cis-3-
3,4-d2 with (E)-2,3-dibromo-1-phenylsulfonylpropene (5) and so-
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C O M M U N I C A T I O N S
chemistry of 3-2,3-d2-6-COCD3 formed in the cyclization of
1-1,1,1,5,5-d5 (eq 4), we presume that intermediate VI is also stable
toward olefin displacement (Scheme 2). The failure to form
detectable amounts of 3-3,4-d2 in the cyclization of 1-8,8-d2 (eq 6)
precludes protonolysis from the palladium â-diketonate complex
VIII, but does not rule out reversible formation of VIII (Scheme
2).
In summary, we have presented a deuterium labeling study that
provides insight into the mechanism of the palladium-catalyzed
intramolecular hydroalkylation of 7-octene-2,4-dione (1). These
experiments are in accord with a mechanism involving attack of
the enol carbon atom on the palladium-complexed olefin of III
followed by palladium migration and protonolysis from the pal-
ladium enolate complex VII (Scheme 2). Further studies in this
area will be directed toward elucidating the structure of palladium
enolate complex VII and toward understanding the potential role
of â-diketonate complex VIII in palladium-catalyzed hydro-
alkylation.
Acknowledgment. R.W. thanks the Camille and Henry Dreyfus
Foundation, the Alfred P. Sloan Foundation, DuPont, and Glaxo-
SmithKline for financial assistance.
Supporting Information Available: Experimental procedures,
spectroscopic data, and copies of spectra for deuterated isotopomers
of 1, 3, and 4 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Conversion of 1-1,1,1,5,5-d5 and 1-6,6-d2 to 3-2,3-d2-6-COCD3
and trans-3-4,5-d2, respectively (eqs 4 and 5), is consistent with
isomerization of II to the palladium enolate complex VII via
successive â-hydride elimination/addition (Scheme 2).13 Isomer-
ization of II to VII prior to protonolysis is not surprising given the
high reactivity of palladium(II) alkyl complexes toward â-hydride
elimination/addition.14 The stereoselective conversion of 1-6,6-d2
to trans-3-4,5-d2 precludes reversible olefin displacement from
intermediate IV (Scheme 2) and also establishes that the stereo-
chemistry generated via initial cyclization of (E)- and (Z)-1-7,8-d2
is retained upon subsequent conversion to cis- and trans-3-3,4-d2,
respectively. Although we were unable to determine the stereo-
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