Platinum(II)/europium(III)-catalyzed intramolecular hydroalkylation of 4-pentenyl β-dicarbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2004.11.060

A mixture of [PtCl₂(CH₂CH₂)]₂ (1 mol %), and EuCl₃ (2 mol %) catalyzes the hydroalkylation of 4-pentenyl β-dicarbonyl compounds to form substituted cyclohexanones in moderate to excellent yield with e

Full text of DOI:10.1016/j.tetlet.2004.11.060

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 285–287
Platinum(II)/europium(III)-catalyzed intramolecular
hydroalkylation of 4-pentenyl b-dicarbonyl compounds
Cong Liu and Ross A. Widenhoefer*
P. M. Gross Chemical Laboratory, Duke University, Durham, NC 27708–0346, USA
Received 11 October 2004; revised 9 November 2004; accepted 10 November 2004
Available online 26 November 2004
Dedicated to Professor Iwao Ojima on the occasion of his 60th birthday in honor of his contributions to synthetic organic,
organometallic, and medicinal chemistry
Abstract—Reaction of 5,5-dimethyl-8-nonene-2,4-dione with a catalytic mixture of [PtCl2(CH2@CH2)]2 (2) (1mol%), and EuCl3
(2mol%) in dioxane that contained HCl (1.0equiv) at 90°C for 18h led to the isolation of 2-acetyl-3,6,6-trimethyl-2-cyclohexanone
in 85% yield. A number of 4-pentenyl b-dicarbonyl compounds underwent intramolecular hydroalkylation to form cyclohexanones
in moderate to excellent yield.
Ó 2004 Elsevier Ltd. All rights reserved.
We recently reported the Pd(II)-catalyzed intramolecu-
lar hydroalkylation of 3-butenyl b-dicarbonyl com-
pounds and related substrates (Eq. 1), which represent
the first examples of the catalytic hydroalkylation of
an unactivated olefin with a stabilized carbon nucleo-
phile.1–3 However, efforts to extend this protocol to
ð2Þ
the hydroalkylation of 4-pentenyl b-dicarbonyl com-
pounds have not been successful as 4-pentenyl b-dicar-
bonyl compounds instead tend to undergo oxidative
For the reasons noted above, we sought to identify a
transition metal complex that would catalyze the hydro-
alkylation of alkenyl b-dicarbonyl compounds through
a pathway involving nucleophilic attack on a metal–ole-
fin complex followed by protonolysis of the resulting
metal-alkyl species prior to b-hydride elimination. The
olefin ligand of Pt(II)–olefin complexes are readily at-
tacked by carbon5 and heteroatom6 nucleophiles to
form Pt(II)–alkyl complexes that, in sharp contrast to
a Pd(II)–alkyl complex, are stable with respect to b-hy-
dride elimination but reactive toward protonolysis. On
the basis of this reactivity, we began to investigate the
application of simple Pt(II) complexes as catalysts for
the addition of carbon and heteroatom nucleophiles to
unactivated olefins. These efforts have led to the devel-
opment of effective Pt(II)-catalyzed protocols for the
intermolecular hydroalkylation7 and hydroamination8
of ethylene with b-diketones and carboxamides, respec-
tively, the intramolecular hydroarylation of alkenyl in-
doles,9 and the intramolecular hydroalkoxylation of
hydroxy olefins.10 These results, in particular the hydro-
alkylation of ethylene with b-diketones, suggested that
alkylation in the presence of Pd(II) to form cyclohex-
enones (Eq. 2).3,4 The difficulty in extending palla-
dium-catalyzed hydroalkylation to 4-pentenyl b-
dicarbonyl compounds can be traced to the mechanism
of hydroalkylation. Specifically, the initially formed pal-
ladium alkyl complex I does not react with HCl to re-
lease the cyclohexanone but instead undergoes
isomerization via iterative b-hydride elimination/addi-
tion to form palladium enolate complex II that under-
goes protonolysis (Scheme 1).2,3 Therefore, palladium-
catalyzed olefin hydroalkylation can be achieved only
when the requisite palladium enolate complex is formed
prior to olefin displacement from a palladium olefin
intermediate.
ð1Þ
*
Corresponding author. Tel.: +1 9196601533; fax:+1 9196601605;
e-mail: rwidenho@chem.duke.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.060

286
C. Liu, R. A. Widenhoefer / Tetrahedron Letters 46 (2005) 285–287
O
O
OH
O
HCl
Ac
Ac
Ac
Ac
Pd
HPd
Pd
I
L
L
Pd Cl
Cl
O
O
O
II
Pd
O
Ac
Ac
Ac
Ac
HPd
HCl
Pd
Scheme 1.
Pt(II) complexes might also catalyze the intramolecular
hydroalkylation of 4-pentenyl b-dicarbonyl compounds.
Here we report the Pt(II)/Eu(III)-catalyzed hydroalkyla-
tion of 4-pentenyl b-dicarbonyl compounds to form
substituted cyclohexanones.
lated yield of 3, although longer reaction time was re-
quired (Table 1, entry 4). Platinum(II) was required for
cyclization and treatment of 1 with EuCl3 (2mol%) and
HCl (1equiv) in dioxane at 90°C for 21h formed no
detectable amounts of 3 by GC analysis of the crude reac-
tion mixture (Table 1, entry 5).
In an initial experiment, treatment of 8-nonene-2,4-dione
(1) with a catalytic amount of [PtCl2(CH2@CH2)]2 (2)
(2.5mol%) in dioxane at 90°C for 19h led to 66% conver-
sion to form 3 in 13% GC yield (Table 1, entry 1). On the
assumption that protonolysis of the Pt–C bond of the ini-
tially formed platinum alkyl species was slow under these
conditions, we explored the effect of acid on the plati-
num-catalyzed conversion of 1 to 3. In support of our
hypothesis, treatment of 1 with a catalytic amount of 2
(2.5mol%) in dioxane that contained HCl at 90°C for
22h formed 3 in 63% GC yield and 45% isolated yield
(Table 1, entry 2). Because both lanthanide11 and transi-
tion metal12 Lewis acids catalyze the addition of b-dicar-
bonyl compounds to Michael acceptors, we considered
that a Lewis acid might also facilitate the platinum-cata-
lyzed cyclization of 1.13 We focused on the use of EuCl3
as a Lewis acid co-catalyst for platinum-catalyzed olefin
hydroalkylation because we had previously employed
EuCl3 to good effect in the Pd-catalyzed oxidative alkyl-
ation of propene with b-dicarbonyl compounds.7 Treat-
ment of 1 with a mixture of 2 (2.5mol%) and EuCl3
(5mol%) in dioxane that contained HCl formed 3 in
76% GC yield and 64% isolated yield (Table 1, entry 3).
Employing this procedure, catalyst loading was dropped
to 1% of 2 and 2% of EuCl3 without decrease in the iso-
A number of 4-pentenyl b-diketones underwent Pt/Eu-
catalyzed hydroalkylation to form the corresponding
cyclohexanones in moderate to excellent yield (Table 2).
Table 2. Hydroalkylation of 4-pentenyl b-dicarbonyl compounds
catalyzed by [PtCl2(CH2@CH2)]2 (2) (1mol%), and EuCl3 (2mol%)
in dioxane that contained HCl (1.0equiv) at 90°C for 18–22h
Entry
Substrate
Cyclohexanone
Yield (%)a
O
O
O
O
Me
Me
Me
R
Me
R
CH3
1
2
3
4
5
R = Me
R = Et
85
87
91
55b
89
R = i-Pr
R = t-Bu
R = Cy
O
O
O
O
CH3
CH3
6
7
93
31
CH3
O
O
O
O
Me
Me
Et
CH3
Et
Table 1. Effect of HCl, EuCl3, and catalyst loading on the conversion
of 1 to 3 catalyzed by [PtCl2 (CH2@CH2)]2 (2)
O
O
O
O
Me
Me
Me
O
O
OR
CH3
O
O
Me
OR
2/EuCl3/HCl
CH3
CH3
CH3
dioxane
90 ˚C
8
R = Me
R = Et
R = i-Pr
66
77
80
9
10
3
1
Entry
2
HCl
EuCl3
(mol%) (equiv) (mol%) (h)
Time GC
Isolated
yield(%) yield (%)
O
O
O
O
Me
Me
1
2
3
4
5
2.5
2.5
2.5
1
—
1
—
—
5
19
22
22
41
21
13
63
76
—
0
—
45
64
64
—
OMe
CH3
11
40
OMe
1
1
2
a Isolated yields of >95% purity.
b Reaction run with 2.5mol% of 2 for 63h.
—
1
2

C. Liu, R. A. Widenhoefer / Tetrahedron Letters 46 (2005) 285–287
287
Cl
O
Cl
4-pentenyl b-dicarbonyl compounds to form substituted
cyclohexanones.
Eu
O
O
O
HCl
Me
Me
Acknowledgements
1
3
III
PtCl2
Ac
PtCl2/EuCl3
Acknowledgement is made to the NSF (CHE-03-04994)
for support of this research. R.W. thanks the Camille
and Henry Dreyfus Foundation and GlaxoSmithKline
for additional unrestricted financial assistance.
EuCl3
O
O
OH
Me
PtCl
Me
HCl
IV
Scheme 2.
Supplementary data
4-Pentenyl b-diketones that possessed gem-dimethyl
groups on the alkenyl chain were particularly effective
substrates for Pt/Eu-catalyzed hydroalkylation, presum-
ably due to the Thorpe–Ingold effect on cycliz-
ation (Table 2, entries 1–6).14 4-Pentenyl b-keto esters
also underwent Pt/Eu-catalyzed hydroalkylation to
form the corresponding 2-carboalkoxycyclohexanones
in moderate to good yield (Table 2, entries 8–11). Substi-
tution of DCl for HCl in the Pt/Eu-catalyzed cyclization
of b-diketone 4 led to isolation of 5-CH2D in 65% yield
as the exclusive deuterated isotopomer (Eq. 3).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-
let.2004.11.060. Experimental procedures and spectro-
scopic data for new compounds (4 pages).
References and notes
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ð3Þ
On the basis of the mechanisms of the palladium2,3 and
platinum-catalyzed9 addition of carbon nucleophiles to
unactivated olefins and the mechanisms of the stoichio-
metric addition of carbon and nitrogen nucleophiles to
platinum olefin complexes,5,6 we propose a mechanism
for the Pt/Eu-catalyzed intramolecular hydroalkylation
of 1 involving outer-sphere attack of a europium enolate
on the platinum-complexed olefin of III to form the
platinum cyclohexylmethyl species IV (Scheme 2). Proto-
nolysis of the Pt–C bond of IV with HCl would release
3 and regenerate the Pt(II) catalyst. Direct protonolysis
of the Pt–C bond of IV is supported by the formation of
5 –CH2D as the exclusive deuterated isotopomer in the
Pt/Eu-catalyzed hydroalkylation of 4 (Eq. 3).
In summary, we have developed an effective Pt/Eu-cata-
lyzed protocol for the intramolecular hydroalkylation of