Regio- and enantioselective O-allylation of phenol and alcohol catalyzed by a planar-chiral cyclopentadienyl ruthenium complex

Article abstract of DOI:10.1002/anie.200704457

(Chemical Equation Presented) Design of an asymmetric catalyst: The planar-chiral cyclopentadienyl ruthenium complex shown in the scheme effectively catalyzes the reactions of unsymmetrically substituted allyl halides with phenol and alcohol to give the corresponding branched allyl ethers with high regio- and enantioselectivity.

Full text of DOI:10.1002/anie.200704457

Communications
DOI: 10.1002/anie.200704457
Asymmetric Catalysis
Regio- and Enantioselective O-Allylation of Phenol and Alcohol
Catalyzed by a Planar-Chiral Cyclopentadienyl Ruthenium Complex**
Kiyotaka Onitsuka,* Haruki Okuda, and Hiroaki Sasai
Optically active allylic aryl ethers have high potential for use
as precursors of biologically active organic molecules.[1,2]
Whereas stereospecific allylation of phenol derivatives has
been demonstrated with transition-metal catalysts,[3] the
enantioselective version catalyzed by chiral palladium com-
plexes has been successfully applied to the synthesis of natural
products.[4] However, compared to the myriad reports on
enantioselective allylic alkylation and amination, there has
been little research on enantioselective allylic substitutions
with alcohol and phenol.[5] Recently, an efficient Ir-catalyzed
system has been reported to give allyl aryl ethers as well as
Table 1: Reaction of cinnamyl derivatives 2 with o-cresol (3a).
allyl silyl ethers with high regio- and enantioselectivities.[6,7]
Entry
Cat.
2, LG
Yield [%] 4a/5a[a]
ee [%][b]
Although Ru complexes with chiral bisoxazoline ligands also
show catalytic activity towards asymmetric allylic substitution
with oxygen nucleophiles, the regio- and enantioselectivities
are not very high.[8]
We have been investigating the syntheses and stereo-
selective reactions of planar-chiral cyclopentadienyl (Cp’; see
Eq. (1) for ligand) ruthenium complexes.[9] Previously, we
reported the first example of Ru-catalyzed asymmetric allylic
amination and alkylation of symmetrically substituted allyl
carbonates using planar-chiral Cp’Ru complexes 1.[10] We
describe herein the Ru-catalyzed reaction of unsymmetrically
substituted allyl halides with phenol and alcohol to give ethers
with high regio- and enantioselectivities.
1
2
3
4
5
6
7
1a
1b
1c
1a
1a
1a
1a
2a, Cl
2a, Cl
2a, Cl
2b, Br
2c, OP(O)(OEt)2
2d OC(O)OtBu
2e, OAc
92 (>20:1)
78 (>20:1)
95 (>20:1)
91 (20:1)
99 (12:8)
85 (7:13)
95 (R)
3 (R)
52 (S)
84 (R)
22 (R)
28 (S)
5 (S)
10 (9:11)
[a] Yields and ratios of branched and linear ethers were determined from
1
the H NMR spectra using hydroquinone dimethyl ether as a standard.
[b] Determined by HPLC analysis using a chiral stationary phase.
[c] Configuration based on the sign of specific rotation is given in
parentheses.
To optimize the conditions, we chose the reaction of
cinnamyl chloride (2a, LG = Cl) with o-cresol (3a) [Eq. (1)].
After careful examination, we found that the reaction of 2a
(2.0 equiv) with 3a was effectively catalyzed by 3 mol% (S)-
1a in THF at 38C in the presence of K2CO3 (3.0 equiv) to give
the branched ether 4a with R configuration in 92% yield and
95% ee, along with a trace amount of the linear ether 5a. The
proper selection of cinnamyl derivatives and Ru catalyst was
essential to achieve high selectivity (Table 1). Although
methyl- and phenyl-substituted planar-chiral Cp’Ru com-
plexes (S)-1b and (S)-1c also catalyzed the reaction with high
regioselectivity, the enantioselectivities were lower than that
obtained with (S)-1a (Table 1, entries 1–3). The substituent at
the 4-position on the Cp’ ring has a similarly large effect on
the enantioselectivity in the allylic aminations and alkyl-
ations.[10] The reaction of cinnamyl bromide (2b) also
produced 4a in good yield, albeit with slightly lower
enantioselectivity than the reaction of 2a (Table 1, entry 4).
When cinnamyl phosphate (2c) or cinnamyl carbonate (2d)
was used as a substrate, a mixture of 4a with low enantiose-
lectivities and 5a was obtained in good yield (Table 1,
entries 5 and 6). Cinnamyl acetate (2e) was not suitable for
the present reaction owing to its low reactivity (Table 1,
entry 7).
The scope of the present O-allylation catalyzed by (S)-1a
under the optimized conditions was examined [Eq. (2)], and
the results are summarized in Table 2. The reactions of 2a
with various phenol derivatives 3 selectively produced the
corresponding branched ethers 4 in good yields with more
than 90% ee even when the phenol has a bulky substituent at
[*] Prof. K. Onitsuka, H. Okuda, Prof. H. Sasai
The Institute of Scientific and Industrial Research
Osaka University
Mihogaoka, Ibaraki, Osaka 567-0047 (Japan)
Fax: (+81)6-6879-8469
E-mail: onitsuka@sanken.osaka-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Priority Area (No. 19028037, Chemistry of Concerto Catalysis) from
the Ministry of Education, Culture, Sports, Science and Technology
(Japan). We thank the technical staffs of the Materials Analysis
Center, ISIR, Osaka University, for their support of instrumental
analyses.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 2: Reaction of substituted allyl chlorides 2 with phenol and primary alcohols 3.
tive formation of (R)-4a in 54%
yield with > 99% ee, suggesting
that (SCp,RRu,Rallyl)-6 is a reason-
able intermediate.[12]
The plausible reaction mecha-
nism is illustrated in Scheme 1.
Oxidative addition of 2 to (S)-1a
produces (SCp,RRu,Rallyl)-6a selec-
tively. Then, nucleophilic attack of
phenol derivatives takes place to
Entry
2, R1
3, R2
Yield [%][a]
Regioselectivity[b]
ee [%][c]
1
2
3
4
5
6
7
8
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
3a, o-MeC6H4
3b, Ph
91
99
91
95
86
85
99
98
88
69
90
96
63
98
36
4a/5a >20:1
4b/5b >20:1
4c/5c >20:1
4d/5d >20:1
4e/5e >20:1
4 f/5 f >20:1
4g/5g >20:1
4h/5h >20:1
4i/5i >20:1
4j/5j >20:1
4k/5k >20:1
4l/5l=20:1
95 (R)
92
93
93
93
91
91 (R)
93
87 (R)
83
94
3c, m-MeC6H4
3d, p-MeC6H4
3e, o-tBuC6H4
3 f, o-PhC6H4
3g, p-CF3C6H4
3h, p-ClC6H4
3i, PhCH2
3j, Me
3b, Ph
3b, Ph
3b, Ph
3b, Ph
9
2a, Ph
2a, Ph
give
4 and regenerate (S)-1a.
10
11
12
13
14
15
There are two possible pathways
for this step: One is the direct
attack on the h3-cinnamyl group
from outside, and the other pro-
ceeds by substitution of chloride
with phenoxide on the Ru atom
and subsequent reductive elimina-
tion (inside attack). Judging from
the retention of stereochemistry
2 f, p-CF3C6H4
2g, p-ClC6H4
2h, o-MeOC6H4
2i, 1-naphthyl
2j, Me
86
95
82
80
4m/5m >20:1
4n/5n >20:1
4o/5o >20:1
3b, Ph
[a] Yields of isolated products. [b] Ratio of branched and linear ethers was determined from the 1H NMR
spectrum. [c] Determined by HPLC analysis using a chiral stationary phase. Configuration based on the
sign of specific rotation is given in parentheses.
the ortho position (Table 2, entries 2–8). This system was
successfully applied to the reaction of alcohol to give allyl
alkyl ethers with high enantioselectivities (Table 2, entries 9
and 10). The reactions of substituted cinnamyl chlorides
proceeded smoothly giving the branched ethers in good yields
with high enantioselectivities (Table 2, entries 11–14), while
the reaction of crotyl chloride produced the branched ether in
36% yield with 80% ee (Table 2, entry 15).
To obtain information on the reaction mechanism, we
examined the stoichiometric reactions [Eq. (3)]. Treatment of
Figure 1. X-ray crystal structurÀe of (S*Cp,R*Ru,R*allyl)-6a. Ellipsoids at
the 50% probability level; PF6 and hydrogen atoms are omitted for
clarity.
(S)-1a with 10 equiv of 2a in THF at room temperature led to
the quantitative formation of the h3-cinnamyl ruthenium
complex 6a, which was isolated in 80% yield.[9f] Although
chirality was generated not only at the Ru center but also on
the h3-cinnamyl plane, the NMR spectra of the reaction
mixture suggested that 6a was a single diastereomer. The
configuration of 6a was unequivocally determined by X-ray
crystallographic analysis of the racemic sample to be
S*Cp,R*Ru,R*allyl, as shown in Figure 1.[11] It should be noted
that the chloro ligand on the Ru atom is located at a position
close to the phenyl group of the h3-cinnamyl ligand. When the
reaction was conducted in an NMR tube, no 31P NMR signals
other than those of (S)-1a and (SCp,RRu,Rallyl)-6a were
detected; this is consistent with kinetic control of the
configuration around Ru in the reaction of 1 with allyl
chloride.[9f] The reaction of 2a with 3a was also catalyzed by
(SCp,RRu,Rallyl)-6a to give (R)-4a with 92% ee (yield of ether:
98%; 4a/5a > 20:1). Although (SCp,RRu,Rallyl)-6a did not react
with o-cresol even in the presence of K2CO3, the reaction with
2 equiv of lithium o-methylphenoxide led to the regioselec-
Scheme 1. Plausible reaction mechanism for the enantioselective
O-allylation.
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Communications
between (SCp,RRu,Rallyl)-6a and (R)-4a, the latter pathway
forming intermediate 7a seems to be reasonable,[13,14] because
(S)-4a and/or linear ether 5a should be provided by means of
the former mechanism. Moreover, the highly regioselective
formation of 4 can be explained if phenoxide binds to Ru at
the position of the chloride ligand of (SCp,RRu,Rallyl)-6.
However, we cannot completely exclude the possibility of
the mechanism that includes SN2’-type nucleophilic attack on
the h1-cinnamyl complex at this stage.[15]
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which revealed that the configuration at the Ru center and
the coordination plane of the h3-cinnamyl group are opposite
to those of (S*Cp,R*Ru,R*allyl)-6a.[11,16] The reaction of 1c with
2a also produced (S*Cp,S*Ru,S*allyl)-6c quantitatively.[11,16]
When an enantiomerically pure sample of (SCp,SRu,Sallyl)-6c
was treated with lithium o-methylphenoxide, (S)-4a was
selectively formed in 76% yield with 91% ee (4a/5a 20:1).
These results, which support with the reaction mechanism
including inside attack of phenoxide, clearly suggest the
reason why the reaction using (S)-1c as a catalyst does not
produce (R)-4a but (S)-4a as a major enantiomer (Table 1,
entry 3). Because the regioselectivity of the resulting ether is
high, the moderate enantioselectivity may result from partial
isomerization of (SCp,SRu,Sallyl)-6c to (SCp,RRu,Rallyl)-6c during
the catalytic reaction. The lower enantioselectivity of (S)-1b
(Table 1, entry 2) can be explained by assuming that isomer-
ization of (SCp,SRu,Sallyl)-6b to (SCp,RRu,Rallyl)-6b is significantly
faster than that of (SCp,SRu,Sallyl)-6c to (SCp,RRu,Rallyl)-6c.
In conclusion, we have described the highly regio- and
enantioselective O-allylation of phenol and alcohol. The
planar chirality of the Cp’ ligand on the Ru catalyst controls
not only the Ru-centered chirality but also the planar chirality
of the h3-cinnamyl group of the intermediate. Nucleophilic
attack of phenoxide to the h3-cinnamyl ruthenium complex
from the inside is the key to the high regio- and enantiose-
lectivity. Although allylation often takes place at the more
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extension to other allylic substitutions as well as further
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given in the Supporting Information. CCDC 662086, 662087,
and 662088 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
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Received: September 27, 2007
Published online: January 18, 2008
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ˇ
Keywords: allylation · asymmetric synthesis · catalysts ·
phenols · ruthenium
ˇ
´
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Angewandte
Chemie
[16] ORTEP drawings of (S*Cp,S*Ru,S*allyl)-6b and (S*Cp,S*Ru,S*allyl)-
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