Planar-Chiral Cyclopentadienyl-Ruthenium-Catalyzed Regio- and Enantioselective Asymmetric Allylic Alkylation of Silyl Enolates under Unusually Mild Conditions

Article abstract of DOI:10.1002/adsc.201500970

We report the asymmetric allylic alkylation of allylic chlorides with silyl enolates as a carbon nucleophile using a planar-chiral cyclopentadienyl-ruthenium (Cp′Ru) catalyst. The reaction proceeds under unusually mild conditions to give the desired branched products with complete regioselectivity and high enantioselectivity, and reactive functional groups, such as aldehyde, can be tolerated. In this reaction system, Cp′Ru plays an important role in activating both silyl enolate and allylic chloride.

Full text of DOI:10.1002/adsc.201500970

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DOI: 10.1002/adsc.201500970
Planar-Chiral Cyclopentadienyl-Ruthenium-Catalyzed Regio- and
Enantioselective Asymmetric Allylic Alkylation of Silyl Enolates
under Unusually Mild Conditions
a,
a
a
a
Naoya Kanbayashi, * Arisa Yamazawa, Koichiro Takii, Taka-aki Okamura,
a,
and Kiyotaka Onitsuka *
Department of Macromolecular Science Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
E-mail: naokou@chem.sci.osaka-u.ac.jp or onitsuka@chem.sci.osaka-u.ac.jp
a
Received: October 19, 2015; Revised: November 26, 2015; Published online: January 25, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500970.
Abstract: We report the asymmetric allylic alkyla-
tion of allylic chlorides with silyl enolates as
a carbon nucleophile using a planar-chiral cyclopen-
tadienyl-ruthenium (Cp’Ru) catalyst. The reaction
proceeds under unusually mild conditions to give
the desired branched products with complete regio-
selectivity and high enantioselectivity, and reactive
functional groups, such as aldehyde, can be tolerat-
ed. In this reaction system, Cp’Ru plays an impor-
tant role in activating both silyl enolate and allylic
chloride.
desired side reactions. For instance, carbonyl groups,
which are sensitive with enolates, will interfere with
the reaction. Therefore, it is necessary to develop
other types of asymmetric allylic alkylation that can
[6]
be achieved under milder reaction conditions.
Silyl enolates are valuable nucleophiles in organic
synthesis, because silyl enolates are stable enough to
be isolated and can be easily handled in comparison
with other metal enolates. Therefore silyl enolates are
capable of forming carbon-carbon bonds under mild
[7]
conditions, such as in the Mukaiyama aldol reac-
[8]
tion. As silyl enolates are much less reactive than
other metal enolates, Lewis acids or bases are needed
to activate silyl enolates to react. In the aldol reac-
tions, with the less reactive silyl enolates, Lewis acids
are usually used to increase the positive charge on the
carbonyl carbon atom enough to be attacked nucleo-
philically. For asymmetric allylic substitutions, an effi-
cient Ir-catalyzed system using silyl enolates as the
Keywords: asymmetric allylic substitution; cyclo-
pentadienyl-ruthenium; enantioselective catalysis;
planar chirality; silyl enolates
Enantioselective allylic alkylation catalyzed by transi- nucleophile under mild conditions has been reported
[9]
tion metal complexes has become a convenient syn- by Hartwig and co-workers. In this reaction system,
thetic method for the asymmetric formation of the carbonate anion, which was generated from the
[
1]
carbon-carbon bonds. In fact, reactions between oxidative addition of an allylic carbonate to the Ir
[9e]
monosubstituted allylic substrates and various carbon complex, serves as an activator of silyl enol ether.
nucleophiles have been reported, affording the corre- The cyclopentadienyl(Cp)-ruthenium complex is an
sponding products in good yields and high regio- and effective catalyst for stereoselective allylic substitu-
[10]
enantioselectivities, leading to their widespread appli- tions,
and several types of reaction using simple
cation in organic synthesis. In such systems, stabilized non-stabilized ketone enolates have been reported.
[
2]
enolates such as b-carbonyl compounds have been For example, Tunge and Lacour have reported a ste-
mainly used. On the other hand, simple non-stabilized reoselective allylic alkylation using the decarboxyla-
ketone enolates are the most important class of nucle- tive Carroll rearrangement to give homoallylic ke-
[
10e–g]
ophiles for the formation of carbon-carbon bonds in tones under mild conditions.
On the other hand,
[3]
[4]
[5]
allylic alkylation. Trost and Hou have demon- we have already shown that planar-chiral ruthenium
strated the palladium-catalyzed asymmetric allylic al- (Cp’Ru) complexes [(S)-1, see Table 1]
[11]
are profi-
kylation using unstable alkali metal enolates as the cient catalysts for regio- and enantioselective allylic
[12]
ꢀ
hardꢁ carbanion to give a-allylic ketones with high se- substitutions of monosubstituted allylic halides. In
lectivity. In contrast, the nucleophilicity and basicity this catalytic system, the Cp’Ru catalyst exhibited
of the alkali metal enolates are liable to result in un- characteristic reactivity towards less-reactive nucleo-
Adv. Synth. Catal. 2016, 358, 555 – 560
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555

Naoya Kanbayashi et al.
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Table 1. Optimization of the Cp’Ru-catalyzed asymmetric al- acetophenone (5a) by fluoride. Other fluoride addi-
[a]
lylic alkylation using silyl enolates.
tives, e.g., LiF, NaF and KF, provided similar results
Figure S1, see the Supporting Information). As the
(
polarities of 4a and 5a are quite similar, the complete
isolation of 4a using silica gel chromatography was
difficult in the presence of 5a. Thus, preventing the
decomposition of 4a was crucial. When metal carbo-
nates, such as KHCO , NaHCO and Na CO , were
3
3
2
3
used as additive, the production of 5a was reduced
(
entries 2, 4 and 5). The reaction in the presence of
KHCO proceeded in 67% yield with 79% ee, and
3
only a slight amount of 5a was observed (entry 2).
Entry Cat. Additive
Temp. 4a
ee
[%]
5a
[%]
[b]
[c]
[b]
When NaHCO and Na CO were used as base, the
3
2
3
[
8C]
[%]
reaction proceeded in 95% yield with high enantiose-
lectivity (entries 4 and 5). In contrast, when K CO
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
CsF
KHCO3
30
30
30
30
30
30
30
10
67
71
95
95
9
N.D.
79
78
78
78
N.D.
N.D.
–
80
80
86
3
20
5
5
9
99
0
3
3
3
2
3
was used as base, the reaction also proceeded, but
0% of 5a was formed (entry 3). In addition, the reac-
tions with KHCO and K CO formed small amounts
K CO3
2
2
NaHCO3
3
2
3
Na CO3
2
of the diallylation product 6a. The reactions with
other metal carbonates such as Li CO and Cs CO
3
Li CO3
2
Cs CO3
0
2
3
2
2
gave only trace amounts of the desired product (en-
tries 6 and 7). When a tertiary amine was used as the
additive, the reaction did not proceed at all (entry 8).
Next, various reaction temperatures were screened
(i-Pr) EtN 30
0
2
NaHCO3
NaHCO3
NaHCO3
35
40
45
20
35
35
35
97
97
97
65
99
99
96
0
1
2
3
4
5
75
72
79
70
NaHCO3
7
1
1
>0
with NaHCO as additive. When the reaction temper-
3
NaHCO3
ature was increased to 35–408C, the enantioselectivity
improved (80% ee, entries 9 and 10). Meanwhile,
lower reactivity and enantioselectivity were observed
NaHCO3
NaHCO3
78
[a]
Reaction conditions: 2a (0.6 mmol), 3a (0.4 mmol), cat. at a lower temperature (entry 12). We previously re-
(
3 mol%), additive (1.2 mmol), THF 2.0 mL for 24 h.
ported that the aryl group on the phosphine ligand in
the Cp’Ru complex plays an important role in achiev-
ing high enantioselectivity in allylic substitution.
However, when the reactions were conducted using
[
[
b]
1
Determined by H NMR based on 3a.
Determined by HPLC analysis on a chiral stationary
phase.
c]
(
S)-1b–d as catalysts (entries 13–15), the enantioselec-
and N- tivities of the resulting products were slightly lower
Most recently, when a b-dike- than those observed for the reaction with (S)-1a. The
[
12b]
[12c]
philes such as metal carboxylates,
alkoxybenzamides.
water
[
12d]
tone was used as the nucleophile, the reaction in the reactions of cinnamyl bromide and cinnamyl carbon-
presence of NaHCO as base, proceeded with quanti- ate were not suitable for the present reaction owing
3
tative conversion despite the latter being a weak to low reactivity (Figure S2, see the Supporting Infor-
[
12e]
base.
Herein, we describe the Cp’Ru-catalyzed mation).
Next, we tested the scope of the asymmetric allylic
asymmetric allylic alkylation of monosubstituted allyl-
ic chlorides with silyl enolates which proceeds to give alkylation under optimized conditions; the results are
good yield with high regio- and enantioselectivities. summarized in Table 2. In all the reactions, as de-
Because activator reagents to generate the free eno- scribed below, regioselectivity was high because linear
late anion are not used, the concentration of free eno- products were not formed at all. The reactions of 3a
late anion in the reaction system is extremely low and with substituted cinnamyl chloride possessing elec-
reactive functional groups can be tolerated. The tron-rich and electron-deficient groups produced the
Cp’Ru complex plays an important role in activating corresponding branched products (4ba–4ea) in a high
both the silyl enolate and the allylic chloride.
yield with moderate enantioselectivities (entries 2–5).
We initially examined the use of the Cp’Ru com- Because the reaction conditions are mild, carbonyl
plex (1a: Ar=Ph, 3 mol%) to catalyze the reaction of groups such as aldehydes can be tolerated in this reac-
cinnamyl chloride (2a: R=Ph) with the silyl enolate tion. The present reaction also proceeded with alkyl-
(3a) that was derived from acetophenone and trime- substituted allylic chlorides 2f–2h to give 4fa–4ha, re-
thylsilyl chloride (Table 1). First, CsF was used to spectively (entries 6–8). Particularly, the reaction of
cleave the SiÀO bond (entry 1). Unfortunately, the 2g proceeded with high enantioselectivity (93% ee,
desired allylic product (4a) was generated in only entry 7).
10% yield, and the majority of 3a was decomposed to
5
56
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Adv. Synth. Catal. 2016, 358, 555 – 560

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Planar-Chiral Cyclopentadienyl-Ruthenium-Catalyzed Regio- and
[
a]
[a]
Table 2. Effect of the substituent on the allylic chlorides.
Table 3. Effect of the substituent on the silyl enolate.
[
a]
Reaction conditions: 2a (0.60 mmol), 3 (0.40 mmol), cat.
1
a (0.012 mmol, 3 mol%) at 358C, NaHCO (1.2 mmol),
3
THF (2.0 mL) for 24 h. Yield of isolated product after
column chromatography. Enantiomeric excesses were de-
termined by HPLC analysis on a chiral stationary phase.
[a]
Reaction conditions: 2 (0.60 mmol), 3a (0.40 mmol), cat.
a (0.012 mmol, 3 mol%) at 358C, NaHCO (1.2 mmol),
1
3
THF (2.0 mL) for 24 h. Yield of isolated product after
column chromatography. Enantiomeric excesses were de- ated by oxidative addition of allylic chloride with high
termined by HPLC analysis on a chiral stationary phase.
diastereoselectivity. From mechanistic studies, the re-
action is thought to occur by an inner-sphere mecha-
nism, in which the nucleophilic anion coordinates to
The scope of this reaction was also tested using var- the ruthenium with high diastereoselectivity at the
ious silyl enolates 3 (Table 3). Substituents on the metal center prior to the attack of the p-allyl group.
phenyl moiety of the silyl enolate, such as OMe, The reaction proceeds by an inside attack of the coor-
COOMe, Br and SiMe , and even its replacement dinated nucleophile at the substituted allylic carbon
3
with 2-naphthyl, were well tolerated and the corre- atom of the p-allyl group (Scheme 1). Because the ab-
sponding branched product 4 was obtained in 69–90% solute configuration of the resulting branched product
yield with 76–85% ee (entries 1–5). The reaction 4 is in agreement with the conventional reaction
[15]
system tolerated the presence of the trimethylsilyl mechanism, it is likely that the present asymmetric
group, because a metal fluoride to cleave the SiÀO allylic alkylation catalyzed by 1 using silyl enolates
bond was not used (entry 4). The mild conditions al- proceeds through the inner-sphere pathway via
[14]
lowed us to use the nucleophiles of 3g and 3h that a ruthenium enolate complex. However, the step of
were derived from unsaturated ketones, the reactions cleaving the SiÀO bond is unclear in the present
proceeded in a good yield without any side reactions,
such as aldol condensation or Michael additions (en-
tries 6 and 7), because of the mild reaction conditions.
Additionally, the reaction can be applied to ketene
silyl acetals (entry 8). When 3i was used as the ketene
silyl acetal, the product containing a trisubstituted a-
[13]
carbon was formed in a good yield with 81% ee.
In recent years, we have reported the reaction
mechanism of asymmetric allylic substitutions cata-
[
12a]
lyzed by 1.
Thus, the reaction proceeds via the for- Scheme 1. Proposed reaction mechanism for asymmetric al-
mation of a p-allyl intermediate (S)-7, which is gener- lylic substitution catalyzed by (S)-1.
Adv. Synth. Catal. 2016, 358, 555 – 560
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Naoya Kanbayashi et al.
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Scheme 2. Reaction for investigation of the reaction mecha-
nism.
mechanism. Additionally, the reaction proceeds under
unusually mild conditions in comparison with other
[
3e,g,4,5]
methods
for allylic substitution using enolates as
nucleophile; substituents bearing carbonyl groups sen-
sitive to enolate ions, such as aldehydes and esters,
can be used in this reaction. These facts demonstrate
that the concentration of free enolate anion in the re-
action system must be extremely low.
Scheme 4. Proposed reaction mechanism for asymmetric al-
lylic alkylation catalyzed by (S)-1a using silyl enolates
To obtain information on the mechanism of the SiÀ
O bond activation, some experiments were conduct-
ed. In the absence of the additive, the reaction of 2a complex 8a. This process is further promoted by inter-
and 3a proceeded in 36% yield with 74% ee; the action of the hydrogen carbonate ion on the Si atom.
enantioselectivity was similar in the presence of the Subsequently, the resulting complex 8 can immediate-
additive NaHCO (Scheme 2). On the other hand, the ly undergo reductive elimination via an inside attack
3
absence of (S)-1a caused a drastic reduction in con- of the coordinated enolate anion at the p-allyl group
version of 3a (0%, Scheme 2). Therefore, the Cp’Ru to yield the branched chiral product 4aa. Thus, a low
catalyst is needed to activate the SiÀO bond. To fur- concentration of free enolate ion is achieved in this
ther clarify this, an NMR experiment was conducted. system.
3
1
The P NMR spectrum of the cationic Ru(IV) species
In conclusion, we have demonstrated the asymmet-
of 7a (Ar=Ph) showed a peak at 22.1 ppm, which ric allylic alkylation of monosubstituted allylic chlor-
was assigned to the anchoring phosphine moiety. ides with silyl enolates catalyzed by (S)-1a. The mild
Treatment of 7a with 3a in acetone-d resulted in the conditions and broad scope of the allylic chlorides
6
quantitative conversion of 7a and the branched prod- and silyl enolates are the key attributes of this reac-
[
15]
uct 4aa was observed,
which was confirmed by tion system. Furthermore, substrates containing reac-
1
31
H NMR. In the P NMR, the resonance of 1a was tive groups that do not tolerate the presence of free
observed at 33.0 ppm (Scheme 3). These results sup- enolate anion, such as aldehydes, can be used in this
port that 7 is involved in the activation of the SiÀO reaction. We have also shown that the Cp’Ru catalyst
bond.
plays an important role in activating the silyl enolate
A proposed reaction mechanism is shown in for cleavage of the SiÀO bond and formation of
Scheme 4. In this reaction, p-allyl complex 7a is an Cp’Ru enolate complex. Further development of this
important intermediate as in the previous reactions. reaction system using these specific reactivities is now
Additionally, the electron-deficient high-valence cat- in progress.
ionic Ru(IV) species 7a can probably serve as a Lewis
acid to activate the SiÀO bond of 3, which accelerates
the transmetallation of 7a to form the Ru-enolate
Experimental Section
General Procedure
To Cp’Ru catalyst 1 (0.012 mmol, 3 mol%) and NaHCO3
(
(
1.2 mmol) was added a THF (1.0 mL) solution of 2
0.60 mmol) and the mixture was stirred at 358C. After
2
0 min, a THF (1.0 mL) solution of 3 (0.40 mmol) was then
added by a syringe and the reaction mixture was stirred for
4 h at 358C. After dilution with ether, the insoluble parts
2
Scheme 3. Stoichiometric reaction of 7a with 3a in acetone-
d .
6
were filtered off. The filtrate was concentrated under re-
duced pressure, and the residue was purified by SiO2
5
58
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Adv. Synth. Catal. 2016, 358, 555 – 560

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Planar-Chiral Cyclopentadienyl-Ruthenium-Catalyzed Regio- and
column chromatography to give branched allylic compound
4) as colorless oil.
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Acknowledgements
This work was supported by a grant-in-aid for young scien-
tists (B) from JSPS(26870344) and the Ogasawara Founda-
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