An exceptional palladium-catalyzed alkenylation of silyl enol ether in the absence of a fluoride additive

Article abstract of DOI:10.1016/j.tetlet.2008.04.104

An exceptional intramolecular palladium-catalyzed alkenylation of silyl enol ether in the absence of a fluoride additive was developed, and this reaction led to the construction of bicyclo[3.3.1]nonane ring system in reasonable yield. In this type of reactions, trialkylamines were employed as additives instead of previously indispensable fluoride additives.

Full text of DOI:10.1016/j.tetlet.2008.04.104

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Tetrahedron Letters 49 (2008) 3983–3986
An exceptional palladium-catalyzed alkenylation of silyl
enol ether in the absence of a fluoride additive
Hiroki Shigehisa, Takaaki Jikihara, Osamu Takizawa, Hiromasa Nagase, Toshio Honda *
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
Received 21 March 2008; revised 11 April 2008; accepted 17 April 2008
Available online 22 April 2008
Abstract
An exceptional intramolecular palladium-catalyzed alkenylation of silyl enol ether in the absence of a fluoride additive was developed,
and this reaction led to the construction of bicyclo[3.3.1]nonane ring system in reasonable yield. In this type of reactions, trialkylamines
were employed as additives instead of previously indispensable fluoride additives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Palladium-catalyzed alkenylation; Intramolecular C–C bond formation; Silyl enol ether; Bicyclo[3.3.1]nonane; Trialkylamine
Palladium-catalyzed direct arylation or alkenylation of
ketones in the presence of a strong base, such as a metal
alkoxide, has been well established and widely used in the
past decade for the synthesis of polycyclic compounds,
including natural products.1–4 On the other hand, the
chemistry of a similar carbon–carbon bond formation for
silyl enol ether or ketene silyl acetal instead of a carbonyl
compound under mild basic conditions is still in the devel-
opment stage,5 and is a challenging subject in synthetic
organic chemistry. Since the report by Kuwajima and
Urabe of palladium-catalyzed arylation of silyl enol ether
in 1982,6 several groups have been interested in this chem-
istry, especially for arylation, and have developed the gen-
erality of this protocol.7,8 Despite the great utility of this
type of reaction, there have been few applications of this
approach to alkenylation.9,10 Palladium-catalyzed aryla-
tion or alkenylation for silyl enol ether or ketene silyl acetal
is generally conducted with silicon activators such as a fluo-
ride additive. We report herein a remarkable example of
palladium-catalyzed intramolecular alkenylation of silyl
enol ether in the absence of a fluoride additive. It should
be noted that trialkylamines were employed in this new
type of reaction as additives instead of previously indis-
pensable fluoride additives.
Compounds 8 and 9, readily prepared from commer-
cially available 1,4-cyclohexanedione monoethylene acetal
(1), were chosen as the key precursors for the palladium-
catalyzed carbon–carbon bond formation. Ester 2, pre-
pared in two steps from 1 based on the known procedure,11
was transformed into diethyl malonate derivative 3. The
requisite ketone 6 was provided from 3 by allylation with
2,3-dibromopropene and subsequent hydrolysis of acetal
of 4. Ketone 7 was also synthesized from 3 using 3,4-
dibromo-2-methyl-2-butene4d instead of 2,3-dibromopro-
pene in the same manner. Finally, treatment of 6 or 7 with
TESOTf–iPr2NEt gave the corresponding triethylsilyl enol
ether 8 or 9, respectively (Scheme 1).
With the requisite starting materials available, a study
was carried out to find the best conditions for palladium-
catalyzed alkenylation of 9 by changing the reaction
parameters, such as additive, ligand, solvent, concentration
and temperature, since the product of 9 should have higher
stability than that of the product of 8 (Table 1). In all
attempted reactions, the desired product 10 together with
11 and uncyclized diene 12 were obtained in various ratios
depending on the reaction conditions. To try to improve
*
Corresponding author. Tel.: +81 3 5498 5791; fax: +81 3 3787 0036.
E-mail address: honda@hoshi.ac.jp (T. Honda).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.104

3984
H. Shigehisa et al. / Tetrahedron Letters 49 (2008) 3983–3986
Table 1
Optimization of palladium-catalyzed alkenylation of silyl enol ether 9
OTES
O
O
1) Pd2dba3 (5 mol %)
OTES
rac - BINAP (10 mol %)
Br
+
+
Me
DMA - NPr3 (2 : 1)
concentration = 0.1 M
140 °C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C CO2Et
EtO2C CO2Et
Me
Me
10
11
12
9
2) TBAF
TBAF
Entry
Changed factor from standard conditions
Yield of 10 + 12a (%)
Ratio (10:12)
1
2
3
4
5
6
7
8
a
Solvent = DMA–NPr3 (19:1)
Solvent = DMA–NPr3 (9:1)
Solvent = DMA–NPr3 (2:1)
Solvent = DMA–NPr3 (1:2)
Solvent = DMF–NPr3 (2:1)
LIGAND = DPPF
92
93
99
99
99
87
90
NR
2:1
4:1
8.3:1
10:1
3.3:1
4.4:1
8:1b
Temperature = 120 °C
Temperature = 100 °C
ratios and yields were obtained based on NMR analysis.
10% of ketone 7 was observed in its NMR spectrum.
b
the ratio of cyclized product 10 to uncyclized product 12,
the reaction mixture was treated with TBAF (1 equiv),
after the disappearance of the starting material 9 on
TLC, to convert 11 to 10. Since difficulties were encoun-
tered in isolation of 10 and 12 from the reaction mixture
as pure forms, the ratio of 10 and 12 was obtained on
the basis of NMR analysis as shown in Table 1.
was decreased, and the starting material remained
unchanged, even after longer reaction time, when tert-
butyldimethylsilyl enol ether was used.
Under the optimum reaction conditions described
above,12 a similar reaction was carried out without treat-
ment of the crude products with TBAF in order to isolate
the corresponding silyl enol ether. The reaction of 9 under
the same reaction conditions as those for entry 3 provided
46% (isolated yield) of 11 as the major product together
with 26% of 10 and 15% of 12.
The structure of 10 was unambiguously determined by
X-ray crystallographic analysis of the corresponding p-
nitrobenzoate 14 (recrystallized from AcOEt–hexane),
derived from 10 via reduction with NaBH4 in EtOH and
subsequent benzoylation of alcohol 13 with p-nitrobenzoyl
chloride. An ORTEP drawing of 14 is shown in Scheme
2.13
By investigation of a suitable base for this conversion,
we found that an amine additive is essential for this reac-
tion. Significant enhancement of the 10/12 ratio was
achieved by increasing the volume ratio of NPr3. Although
the best result was obtained in entry 4 in terms of yield and
products ratio, removal of the amine used was found to be
troublesome. Thus, we decided to employ the reaction con-
ditions of entry 3 for the following experiments. The use of
NEt3 and iPr2NEt exhibited lack of reproducibility, proba-
bly due to their low boiling points. The products (10–12)
were not obtained without the presence of amine bases
Application of the palladium-catalyzed alkenylation to
silyl enol ether 8 gave the desired cyclized product 15
i
such as NPr3, NEt3 and Pr2NEt. Other amine bases (pyr-
idine, lutidine, DBU, DABCO) and an inorganic base
(K2CO3) examined did not give 10–12. By screening of
readily available ligands, BINAP was selected as the opti-
mum ligand for the desired reaction. Other phosphine
ligands (DPPM, DPPE, DPPP, DPPB, PPh3) did not give
the desired product 10 or 11. Using the suitable ligand
and additive, a systematic screening of other reaction
parameters was undertaken. Among the common solvents
usually used for this type of reaction, it was revealed that
only N,N-dimethylacetamide (DMA) and N,N-dimethyl-
formamide (DMF) afforded the desired product 10. It
was also revealed that the optimum temperature was
140 °C. In general, improvement of yields for the desired
product is observed at a low substrate concentration; how-
ever, we used 0.1 M solution for this reaction by reason of
its easy handling. Regarding the silyl group on enol ether, a
triethylsilyl group gave the best results. When this reaction
was applied to trimethylsilyl enol ether, the ratio of 10/12
LDA
ethyl chloro-
formate
2 steps
[Ref. 11]
O
O
O
O
O
O
THF
(quant.)
O
EtO2C
EtO2C CO2Et
1
2
3
NaH, 2,3-dibromo-
propene for 4
or
NaH, 3,4-dibromo-
2-methyl-2-butene for 5
THF
OTES
TESCl
O
iPr2NEt
O
O
3N HCl
Br
Br
Br
CH2Cl2
THF
R
R
R
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
R
R
R
8 R = H (93%)
9 R = Me (89%)
6 R = H (qunt.)
7 R = Me (93%)
4 R = H (96%)
5 R = Me (80%)
Scheme 1. Synthesis of 8 and 9.

H. Shigehisa et al. / Tetrahedron Letters 49 (2008) 3983–3986
3985
p-nitrobenzoyl
NO2
O
chloride
O
OH
NEt , DMAP
NaBH
O
3
4
EtOH
59%
CH Cl
2
2
EtO2C CO2Et
EtO2C CO2Et
90%
EtO2C CO2Et
(for 2 steps)
10
13
14
ORTEP drawing of 14.
Scheme 2. Confirmation of relative configuration.
Table 2
Pd(0)
7
12
Palladium-catalyzed alkenylation of 8
OTES
Pd dba (5 mol %)
O
2
3
rac - BINAP (10 mol %)
O
O
Br
DMA - NPr (2 : 1)
3
EtO2C
EtO2C
EtO2C CO2Et
concentration = 0.1 M
PdBr
R
15
X °C
8
EtO2C
EtO2C
EtO2C
EtO2C
R
Yielda (%)
C
D
Entry
Temp. (x °C)
1
2
3
a
80
100
120
NR
54
51
Scheme 4. A plausible mechanism for generation of diene 12.
Isolated yields after chromatography.
was transformed to allene D in the absence of a silyl enol
ether moiety. The allene moiety in D would be subse-
quently isomerized into diene 12. Indeed, when ketone 7
was treated under identical conditions, diene 12 was
obtained as the major product in 78% yield without the
formation of a detectable amount of 10.
In summary, palladium-catalyzed alkenylation of silyl
enol ether was achieved in an intramolecular manner to
furnish a bicyclo[3.3.1]nonane ring system in reasonable
yield. This exceptional reaction was developed using an
amine base instead of a fluoride silicon activator. The scope
and limitation of this methodology are now under investi-
gation in our laboratory.
together with a complex product mixture, although the
yield of 15 was not satisfactory (when 8 was completely
consumed, TBAF was added) (Table 2). The decreased
yield would be due to H–Pd elimination of active hydrogen
on sp2 carbon.
The formation of 10 and 11 is consistent with the mech-
anistic proposal provided for Heck reaction of allylsilane
by Tietze and co-worker as shown in Scheme 3.14,15 The
palladium complex A, generated by oxidative addition of
Pd(0) to alkenyl bromide moiety, would lead to bicyclic
compound B by migratory insertion of a C–Pd bond into
silyl enol ether. The subsequent elimination step of TES-
Pd or H–Pd to afford 10 or 11 would be competitive. In
the case of allylsilane, Tieze and co-workers also reported
analogous competitive elimination depending on the
conditions.
Acknowledgements
This research was supported financially in part by a
grant for The Open Research Center Project and a
Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology of Japan
A plausible mechanism for the generation of 12 is also
shown in Scheme 4. Palladium complex C, generated by
oxidative addition of Pd(0) to the alkenyl bromide moiety,
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Scheme 3. A plausible mechanism for generation of product 10 or 11.

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