Reversal of stereoselectivity in the Cu-catalyzed conjugate addition reaction of dialkylzinc to cyclic enone in the presence of a chiral azolium compound

Article abstract of DOI:10.1021/jo101147p

Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et₂Zn catalyzed by

Full text of DOI:10.1021/jo101147p

pubs.acs.org/joc
Reversal of Stereoselectivity in the Cu-Catalyzed Conjugate Addition
Reaction of Dialkylzinc to Cyclic Enone in the Presence of a Chiral
Azolium Compound
Naoatsu Shibata, Masaki Okamoto, Yuko Yamamoto, and Satoshi Sakaguchi*
Department of Chemistry and Materials Engineering & High Technology Research Center,
Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
satoshi@ipcku.kansai-u.ac.jp
Received June 11, 2010
Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to
cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-
one (30) withEt2Zn catalyzed by Cu(OTf )2 in the presence of an azolium salt derived from a chiral β-amino
alcohol gave (S)-3-ethylcyclohexanone (31) in good enantioselectivity. Among a series of chiral azolium
compounds examined, the benzimidazolium salt (10) having both a tert-butyl group at the stereogenic
center and a benzyl substituent at the azolium ring was found to be the best choice of ligand in the
Cu(OTf)2-catalyzed reaction. Good enantioselectivity was observed when the reaction was conducted by
employing a benzimidazolium derivative rather than an imidazolium derivative. The influence of the
substituent at the azolium ring on the stereoselectivity of the reaction was also examined. In addition, from
the results of the reaction catalyzed by Cu(OTf )2 combined with an azolium compound derived from (S)-
leucine methyl ester, it was found that the hydroxy side chain in the chiral ligand is probably crucial for the
enantiocontrol of the conjugate addition reaction. On the other hand, it was discovered from a screening test
of copper species that the reversal of enantioselectivity was realized by allowing 30 to react with Et2Zn in the
presence of Cu(acac)2 combined with the same ligand precursor to afford (R)-31 as a major product. The
influence of the stereodirecting group at the chiral ligand on the stereoselectivity in the Cu(acac)2-catalyzed
reaction differed completely from that observed in the Cu(OTf )2-catalyzed reaction. Reaction with a cyclic
enone consisting of a seven-membered ring such as 2-cyclohepten-1-one (40) resulted in increasing the
enantioselectivity of the reaction. Thus, treatment of 40 with Et2Zn catalyzed by Cu(OTf )2 combined with a
benzimidazolium salt produced the corresponding (S)-conjugate adduct in a 92:8 enantiomer ratio (er),
while the Cu(acac)2-catalyzed reaction with the same ligand afforded (R)-product in a 9:91 er.
Introduction
synthesis and medical and bioorganic chemistry.1 This pre-
paration is typically achieved in asymmetric catalysis by
using chiral ligands with different configuration. However,
several of the chiral ligands derived from natural pro-
ducts such as amino acids are available in only one enan-
tiomeric form. The reversal of enantioselectivity of a reac-
tion without employing the antipode of the chiral source
has been achieved by design and control of the ligand
The preparation of both enantiomers of a chiral com-
pound with high enantioselectivity is an important challenge
because both enantiomers are increasingly needed in organic
(1) (a) Tanaka, T.; Hayashi, M. Synthesis 2008, 3361–3376. (b) Zanoni,
G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Chem. Soc. Rev.
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DOI: 10.1021/jo101147p
r
Published on Web 07/22/2010
J. Org. Chem. 2010, 75, 5707–5715 5707
2010 American Chemical Society

Shibata et al.
JOCArticle
structure.2 However, the development of effective catalytic
asymmetric methods to induce a switch in the enantioselec-
tivity of a reaction with the same chiral ligand is an attractive
possibility.3
The Cu-catalyzed enantioselective conjugate addition (ECA)
reaction has received increasing interest during the past few
years. A great number of successful chiral phosphorus donor
ligands have been developed so far.4 In addition, several chiral N-
heterocyclic carbenes (NHCs) that have emerged as a new family
of ancillary ligands have been introduced for the ECA reaction
of cyclic enones with dialkylzincs.5,6 The monodentate Arduengo-
type diaminocarbene ligands afforded moderate enantios-
electivity in the 1,4-addition of Et2Zn to 2-cyclohexen-1-one,
whereas the bidentate chelating NHC ligands were clearly
superior in the ECA reaction.7
The first example of enantioselective Cu-catalyzed conjugate
addition with a chiral anionic tethered bidentate NHC ligand
was reported by Arnold et al. in 2004.8 Hoveyda et al. have
developed anionic phenoxy- or sulfonate-bearing chiral biden-
tate NHC ligands. These ligands were successfully used not only
in asymmetric catalytic allylic alkylation, but also in ECA
reactions.9,10 Mauduit et al. introduced a second coordination
site at the NHC ligand, provided by an alcohol moiety, to
achieve higher stereoselectivity.11 By using the same ligand, an
efficient 1,4-addition of Grignard reagents to β-substituted cyc-
lic enones, generating all-carbon chiral quaternary centers, has
been developed. As a result, anionic tethered polydentate NHC
chemistry has received attention.12,13
Recently, we designed and synthesized a new chiral tridentate
NHC ligand, which is composed of benzimidazole and a chiral
amino alcohol. The tridentate anionic amidate/alkoxy/NHC
palladium(II) complex successfully catalyzed oxidative Heck-
type reactions of arylboronic acids with alkenes to offer high
enantioselectivities unprecedented in intermolecular Heck-type
couplings.14a,b An important feature of our NHC ligand is that
it bears both a chiral center and hard chelating sites such as
anionic amidate and alkoxy groups. Furthermore, easy tuning
of both the N-anionic functional groups and the N-alkyl groups
of the ligand allowed the development of various tridentate
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SCHEME 1. Reversal of Stereoselectivity with the Same Ligand
TABLE 1. ECA Reaction of 30 with Et2Zn Catalyzed by Cu(OTf)2
Combined with Benzimidazolium Salta
erb
entry
azolium salt
yieldb (%)
S
R
1
2c
3d
4
5
6
7
8
9
10
11
12
13
14e
15 f
16
4
4
4
1
2
3
5
6
7
8
9
10
11
9
9
12
>99
63
85
>99
>99
>99
>99
>99
89
>99
>99
>99
>99
84
87
80.5
85
82
84.5
86
88.5
87
67
76
90.5
91
78.5
90.5
88
13
19.5
15
18
15.5
14
11.5
13
33
24
9.5
9
21.5
9.5
12
CHART 1. Chiral Azolium Salts
>99
>99
14
86
a30 (1 mmol), Et2Zn (3 mmol), Cu(OTf)2 (6 mol %), benzimidazolium
salt (4.5 mol %), THF (9 mL), rt, 3 h. bYield and enantiomer ratio
(er) were determined by GLC analysis. Average of two runs. cEt2Zn
(1.5 mmol), Cu(OTf)2 (2 mol %), 4 (3 mol %), THF (3 mL). dCu(OTf)2
(4 mol %), 4 (3 mol %). e0 °C. f45 °C.
salt 1-12 was examined (Table 1). The reaction catalyzed by
Cu(OTf)2 (6 mol %) and 4 (R1=iBu, R2=Me) (4.5 mol %) de-
rived from (S)-leucinol afforded (S)-31 in preference to (R)-31 in
an 87:13 er (74% ee) with quantitative yield (entry 1), although
decreasing the amount of catalysts resulted in somewhat lower
conversion of 30 (entries 1-3). To investigate the effect of the
stereodirecting group of the chiral ligand, we screened several
benzimidazolium chlorides 1-8 for the Cu(OTf)2-catalyzed
ECA reaction (entries 4-10). It was found that a sterically hin-
dered substituent such as a tert-butyl group proved efficient to
produce (S)-31 in an 88.5:11.5 er (entry 7).
Moreover, we found that replacement of the methyl by a
benzyl substituent at the azolium ring led to a marked in-
crease in enantioselectivity. Thus, the use of 9 (R1=iBu, R2 =
Bn) in place of 4 (R1=iBu, R2=Me) gave (S)-31 in an 90.5:9.5
er (entry 11). Similar results were obtained with 10 or 11 in-
stead of 5 or 8, respectively (entries 7 and 10 vs entries 12 and
13). The ee of 31 increased to 82% with 10 (entry 12). The
influence of the R2 group at the azolium ring on enantioselec-
tivity will be discussed later (see Table 3). Raising the reaction
temperature to 45 °C or decreasing it to 0 °C did not have a
drastic effect on the outcome (entries 14 and 15).
At this stage of the study, it was necessary to verify whe-
ther the absolute configuration of the stereogenic center in
the ligand showed a significant influence on the enantiocon-
trol of the conjugate addition. Thus, by using the β-amino
alcohol derived from unnatural d-leucine, the enantiomer of
benzimidazolium chloride 12 ((ent)-4) was prepared. Almost
the same enantioselectivity was observed with 12 in the ECA
reaction (entry 1 vs entry 16).
dialkylzincs to cyclic enones. Interestingly, we discovered that
reversal of enantioselectivity with the same ligand was achieved
by changing the Cu precatalyst from Cu(OTf )2 to Cu(acac)2
(Scheme 1).15a For example, reaction of 2-cyclohepten-1-one
with Et2Zn catalyzed by Cu(OTf )2 combined with benzimida-
zolium salt derived from (S)-leucinol gave the corresponding
(S)-adduct in a 92:8 enantiomer ratio (er), while the (R)-adduct
was obtained as a major product in a 9:91 er by using Cu(acac)2
in combination with the same azolium compound. To the best
of our knowledge, this is the first example of the dual enantio-
selective control on the Cu-catalyzed ECA reaction.
Now, we have prepared a huge variety of azolium com-
pounds 1-29 having both the N-hydroxyamide functional
groups and the N-alkyl groups (Chart 1), and studied the
influence of the structure of the ligand and the copper
precatalyst on the stereoselective induction for optimization
of the ECA reaction. Herein, we report the entire results of
the dual enantioselective control in the NHC-Cu-catalyzed
1,4-addition by simply changing the copper catalyst precur-
sor from Cu(OTf )2 to Cu(acac)2 with the same ligand.
It was reported that the azolium moiety plays a critical role in
the NHC-Ir-catalyzed asymmetric transfer hydrogenation of
ketones.16 Therefore, next we investigated the ECA reaction
Results and Discussion
(15) (a) Okamoto, M.; Yamamoto, Y.; Sakaguchi, S. Chem. Commun.
2009, 7363–7365. (b) The same NHC precursor also could be used as an
organocatalyst: Shimakawa, Y.; Morikawa, T.; Sakaguchi, S. Tetrahedron
Lett. 2010, 51, 1786–1789.
(16) Seo, H.; Kim, B. Y.; Lee, J. H.; Park, H.-J.; Son, S. U.; Chung, Y. K.
Organometallics 2003, 22, 4783–4791.
1. Cu(OTf )2-Catalyzed ECA Reaction. The reaction of
2-cyclohexen-1-one (30) with Et2Zn yielding 3-ethylcyclohexa-
none (31) was selected as a model reaction, and the Cu(OTf )2-
catalyzed ECA reaction in the presence of benzimidazolium
J. Org. Chem. Vol. 75, No. 16, 2010 5709

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JOCArticle
TABLE 2. ECA Reaction of 30 with Et2Zn Catalyzed by Cu(OTf)2 Com-
bined with Imidazolium Salta
erb
azolium
salt
entry
yieldb
S
R
1c
2c
3c
4
5
6
7
8
9
10
13
17
18
18
14
15
16
17
19
21
38
61
88
>99
81
87
91
84
68
72
82.5
82
62.5
66
73.5
73.5
74.5
52
32
28
17.5
18
37.5
34
26.5
26.5
25.5
48
92
86
a30 (1 mmol), Et2Zn (3 mmol), Cu(OTf)2 (2 mol %), imidazolium salt
c
(3 mol %), THF (3 mL), rt, 3 h. bSee Table 1, footnote b. Reaction
condition: see Table 1, footnote a.
FIGURE 1. Influence of R1 group at benzimidazolium salt (1-8,
front) and imidazolium salt (14-21, back) on enantioselectivity in
the Cu(OTf)2-catalyzed ECA reaction.
TABLE 3. Influence of the R2 Group at Imidazolium Salt on Enantios-
obtained when benzimidazolium compounds are used as
compared to the imidazolium salts, and that the increase in
the steric demand of the alkyl substituent at the ligand led to
improved product ee.
electivity in the Cu(OTf)2-Catalyzed ECA Reaction of 30 with Et2Zna
erb
entry
azolium salt
yieldb (%)
S
R
Note that our catalytic system does not require an additional
base to generate the NHC species from azolium compounds
by deprotonation. This is in contrast with the Mauduit and
Williams reaction systems that need an appropriate base such as
tBuOK or BuLi.11e,13c Recently, Alexakis and Tomioka demon-
strated independently that the Cu-catalyzed conjugate addition
of EtMgBr to an enone under the influence of an azolium salt
takes place in the absence of a base.11d,13b In addition, Hoveyda
et al. reported excellent results from the preparation of a NHC-
Zn complex by allowing an azolium compound to react with
Et2Zn, where Et2Zn acts as a base to generate the NHC species.9b
Therefore, Et2Zn possibly serves as a base to generate the NHC
species as well as an alkylating reagent in our catalytic system.
On the other hand, as mentioned above, a slightly better result
was obtained upon changing the R2 substituent, which is far
from the stereogenic center of the chiral ligand, from a methyl to
a benzyl group (Table 2, entries 1 and 2). We were interested in
the influence of the R2 substituent at the imidazolium compound
on the stereoselectivity in the Cu(OTf )2-catalyzed ECA reaction
of 30 with Et2Zn. A series of imidazolium derivatives 22-29
were synthesized from (S)-tert-leucinol and the asymmetric con-
jugate addition reaction was examined (Table 3).
1
2
3
4
5
6
7
8
9
22
23
24
18
25
26
27
28
29
90
80
42
>99
89
98
>99
96
97
77.5
76.5
76
22.5
23.5
24
82
18
81.5
81.5
80.5
80.5
81.5
18.5
18.5
19.5
19.5
18.5
aReaction condition: see Table 2, footnote a. bSee Table 1, footnote b.
catalyzed by Cu(OTf )2 combined with various chiral imidazo-
lium compounds (Table 2). Treatment of 30 with Et2Zn in
the presence of catalytic amounts of Cu(OTf )2 (6 mol %) and
13 (R1=iBu, R2=Me) (4.5 mol %) derived from (S)-leucinol
afforded the adduct 31 in 38% yield and 68:32 er (entry 1). In a
manner similar to that found in the ECA reaction with benzi-
midazolium derivatives, changing the N-methyl unit in 13 to a
benzyl group improved the stereoselectivity and the product
yield (entry 2). Using these results, we selected the benzyl group
at the azolium ring for further studies of the catalyst perfor-
mance.
The imidazolium salt 18 (R1 = tBu, R2 = Bn) derived from
(S)-tert-leucinol led to slightly better enantioselectivity (entry 3).
After optimization of the reaction conditions, product 31 was
obtained in quantitative yield and an 82:18 er (entry 4, and Table
S1, Supporting Information). The effect of the choice of the
solvent on the catalyst selectivity was investigated for the Cu-
(OTf)2-catalyzed ECA reaction by using 18 (Table S2, Support-
ing Information). This study showed that THF, DMA, and
AcOEt afford high levels of enantioselectivity. On the basis of
these results, we screened several imidazolium chlorides 14-21
(Table 2, entries 5-10). Because of the highly hydroscopic char-
acter of compound 20 (R1=Ph, R2=Bn) that was prepared
from (S)-2-phenylglycinol, we did not perform the ECA reac-
tion using 20.
i
Ligands 22-24 bearing Me, Bu, and Pr groups at the R2
position, respectively, resulted in almost the same product ratio
(76-77.5:24-22.5 er), though the yield decreased with the use of
a sterically hindered ligand such as 24 (entries 1-3). The stereo-
selectivity in the ECA reaction with ligand 25 was similar to that
observed with ligand 18 (entries 4 and 5). The substituent on the
benzene ring in ligands 26-28 did not show a significant influ-
ence on the enantiocontrol of the conjugate addition (entries
6-8). These results strongly suggest that the stereoselectivity
was not affected by either steric factors or the electronic proper-
ties of the R2 substituent. In addition, we were surprised that the
product ratio obtained with 29 (R2 = allyl) was very compar-
able to that obtained with 18 (R2 = benzyl) (entry 9).
Figure 1 represents the influence of the R1 group at the
azolium salt on enantioselectivity in the Cu(OTf )2-catalyzed
ECA reaction of 30 with Et2Zn giving (S)-31 as a major
product. These data have already been shown in Tables 1 and
2. It was clear that a relatively higher stereoselectivity was
Although the role of the R2 substituent is unclear at this
stage, it may be assumed that a benzyl or an allyl moiety
coordinates with a NHC-Cu during the catalytic cycle as
shown in Scheme 2. The intermediate A, where the substrate
coordinates with the Cu species, undergoes the ECA reaction
5710 J. Org. Chem. Vol. 75, No. 16, 2010

Shibata et al.
JOCArticle
SCHEME 2. Tentative Catalytic Cycle
TABLE 5. Screening of Cu Salts for ECA Reaction of 30 with Et2Zn in
the Presence of 9a
erb
entry
Cu salt
Cu(OTf)2
[Cu(OTf)]2(C6H6)
[Cu(CH3CN)]4OTf
[Cu(CH3CN)]4BF4
Cu(NO2)3
yieldb (%)
S
R
1
2
3
4
5
6
7
8
9
>99
90
89
91
15
84
31
33
84
69
21
9
90.5
88
89
80
72
54
54
53
39
29.5
31
32
50
9.5
12
11
20
28
46
46
47
61
70.5
69
68
50
Cu(OAc)2
Cu(I) saltc
Cu(II) saltd
Cu(acac)2
Cu(acac)2
10e
11e
12
13
Cu(II) oxinate f
CuCl2
none
<5
TABLE 4. ECA Reaction of 30 with Et2Zn Catalyzed by Cu(OTf)2
Combined with Several Chiral Ligands
a30 (1 mmol), Et2Zn (3 mmol), Cu salt (6 mol %), 9 (4.5 mol %), THF
(9 mL), rt, 3 h. bSee Table 1, footnote b. c[Bis(trimethylsilyl)acetylene](hexa-
fluoroacetylacetonato)copper(I). dBis(hexafluoroacetylacetonato)copper-
(II). eCs2CO3 (8 mol %) was added. fBis(8-hydroxyquinolinato)copper(II).
presence of Cu(OTf )2 and 2-chloro-N-[(1S)-1-(hydroxymethyl)-
3-methylbutyl]acetamide (36) produced a racemic mixture of 31
in <5% yield (entry 6). This suggests that the complexation of
the Cu species with the 2-hydroxyamide moiety of the azo-
lium salt to form the catalytic active species is not essential.
2. Cu(acac)2-Catalyzed ECA Reaction. Alexakis et al.
reported the systematic study of the ECA reaction of 30 with
Et2Zn using Cu precursors and a chiral phosphoramidite
ligand.18 Mauduit et al. also examined several copper pre-
catalysts in combination with a bidentate NHC ligand.11e
The reactions in their copper species screening tests always
yielded the conjugate adduct, possessing the same absolute
configuration. In contrast, we achieved a dual enantioselec-
tive control of the product on screening tests of copper
species combined with a chiral azolium salt (Table 5).
Table 5 summarizes the results of 1,4-addition of Et2Zn to 30
catalyzed by several Cu compounds in the presence of benzi-
midazolium salt 9 (R1=iBu, R2=Bn). Cu(I) salts such as [Cu-
(OTf)]2(C6H6), [Cu(CH3CN)4]OTf, and [Cu(CH3CN)4]BF4
could be used in the same manner as Cu(OTf )2 to produce
(S)-31 as a major product (entries 1-4). Cu(NO3)2 afforded (S)-
adduct in low yield, whereas Cu(OAc)2 led to a racemic mixture
of 31 in good yield (entries 5 and 6). We were then surprised to
discover that the combination of Cu(acac)2 with 9 furnished (R)-
31 as the major product (entry 9). The addition of a base such as
Cs2CO3 improved the enantiomer ratio slightly (entry 10).
Reversal of enantioselectivity was also observed in the case of
bis(8-hydroxyquinolinato)Cu(II)/9 and in the CuCl2/9 catalytic
system, but the yield of 31 was very low (entries 11 and 12). The
present ECA reaction did not take place in the absence of a
copper precatalyst (entry 13), although Hoveyda et al. recently
demonstrated enantioselective allylic alkylation of allylic phos-
phates with dialkylzinc catalyzed by chiral bidentate imidazo-
lium salt under Cu-free conditions, where a chiral Zn-based
NHC complex that was formed by the reaction of the imidazo-
lium salt with dialkylzinc promoted enantioselective allylic
alkylation.9b
erb
entry
ligand
conditiona
yieldb (%)
S
R
1
2
3
4
5
6
32
33
34
34
35
36
A
B
A
B
B
A
>99
98
72
98
50
78.5
60
51.5
50.5
35
21.5
40
48.5
49.5
65
<5
50
50
aCondition A: see Table 1, footnote a. Condition B: see Table 2,
footnote a. bSee Table 1, footnote b.
to give B in which the reaction would be facilitated by
coordination of the Cu species with the π-bond. B then reacts
with Et2Zn to form C, followed by coordination of substrate
30 to regenerate A. Similar observations have been reported
in the Ir-catalyzed transfer hydrogenation of ketones, where
the NHC-Ir complex having a hemilabile alkene moiety
generated a vacant site in the iridium coordination sphere
during the reaction.17
In addition, several chiral ligands 32-36 were tested (Table 4).
Azolium compounds 32 and 33 derived from (1R,2R)-2-
amino-1-phenyl-1,3-propanediol, which has an additional hy-
droxy moiety, were not effective for the present ECA reaction
(entries 1 and 2). On the other hand, ligand 34, prepared by the
same procedure as 9 by employing (S)-leucine methyl ester
instead of (S)-leucinol, provided racemic 31 (entries 3 and 4).
This indicates that the hydroxy side chain in the NHC ligand is
probably crucial for the enantiocontrol of the conjugate addi-
tion. Interestingly, the corresponding imidazolium salt 35 pre-
ferred (R)-31 over (S)-31 (entry 5). The use of this new ligand is
currently under investigation. Treatment of 30 with Et2Zn in the
Next, we studied the influence of the stereodirecting group of
several azolium chlorides 1-21 on the Cu(acac)2-catalyzed ECA
ꢁ
(17) (a) Corberan, R.; Sanau, M.; Peris, E. Organometallics 2007, 26,
3492–3498. (b) Corberan, R.; Peris, E. Organometallics 2008, 27, 1954–1958.
ꢁ
(18) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem.
Soc. 2002, 124, 5262–5263.
ꢁ
J. Org. Chem. Vol. 75, No. 16, 2010 5711

Shibata et al.
JOCArticle
TABLE 6. Screening of Azolium Salts for ECA Reaction of 30 with Et2Zn
in the Presence of Cu(acac)2 and Cs2CO3
TABLE 7. Reversal of Enantioselectivity by Changing the Cu Saltsa
a
erb
entry
azolium salt
yieldb (%)
S
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1
2
3
4
5
6
7
8
>99
>99
78
>99
30
73
97
83
69
73
45.5
41
33
38
57.5
32
44
25
29.5
63
40
44
36.5
40.5
35.5
70
35.5
46
54.5
59
67
62
42.5
68
56
75
70.5
37
60
56
63.5
59.5
64.5
30
64.5
54
enone R22Zn
erc
azolium
salt
yieldb
(%)
entry
n
R1
R2
Cu salt
S
R
1
2
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Bu Cu(OTf)2
Bu Cu(OTf)2
Bu Cu(acac)2
Bu Cu(acac)2
Et
Et
Et
Et
Et
Et
Et
Et
9
10
9
8
9
10
9
8
9
10
9
8
9
10
9
8
92
>99
82
63
49
84
44
35
>99
>99
>99
>99
>99
>99
>99
55
92
94
26
19
14
8
6
74
81
86
3
4d
5
Cu(OTf)2
Cu(OTf)2
Cu(acac)2
Cu(acac)2
Cu(OTf)2
Cu(OTf)2
Cu(acac)2
Cu(acac)2
9
6
<0.5 >99.5
10
11
14
15
16
17
18
19
21
7
85
73
92
95.5
9
15
27
8
93
8d
9
>99
>99
94
91
78
10
11
12d
13
14
15
16d
4.5
91
93
12
2
89
90
7
Bu Cu(OTf)2
Bu Cu(OTf)2
Bu Cu(acac)2
Bu Cu(acac)2
88
98
11
10
95
90
aReaction condition: see Table 5, footnotes a and e. bSee Table 1,
footnote b.
aReaction condition: see Table 1, footnote a. bIsolated yield. cEnantiomer
ratio (er) was determined by GLC analysis. dReaction condition: see Table 5,
footnotes a and e, and also text (the improved experimental procedure).
Before the study on a scope of cyclic enones with our catalytic
system, we reexamined the experimental procedure to improve
the ee in the ECA reaction catalyzed by Cu(acac)2 combined
with 8. The above-mentioned reaction was conducted by
adding first the enone and then Et2Zn to a THF solution
containing catalytic amounts of Cu(acac)2 and 8 to give (R)-31
in a 25:75 er (Table 6, entry 8). This is the same procedure used
for the Cu(OTf)2-catalyzed ECA reaction shown above. Addi-
tional optimization revealed that (R)-31 could be obtained in a
15.5:84.5 er by adding enone 30 to the mixture of Cu(acac)2, 8,
and Et2Zn (see the Experimental Section).
Finally, on the basis of these results, we examined the ECA
reaction of several cyclic enones with dialkylzinc reagents cata-
lyzed by Cu(OTf )2 or Cu(acac)2 in the presence of the appro-
priate azolium compound as a chiral ligand (Table 7). Replace-
ment of Et2Zn by Bu2Zn resulted in a slight improvement of the
reversal of enantioselectivity (entries 1-4). For example, the
reaction of 30 with Bu2Zn, catalyzed by Cu(OTf )2, combined
with 9 gave (S)-3-butylcyclohexanone (37) as a major product in
a 92:8 er (entry 1), while the use of Cu(acac)2 with the same
ligand induced a reversed enantioselectivity to afford (R)-37 in a
26:74 er (entry 3). The dual enantioselective control was also
observed in the reaction of 4,4-dimethyl-2-cyclohexen-1-one (38)
with Et2Zn producing 3-ethyl-4,4-dimethylcyclohexanone (39)
(entries 5-8). An excellent ee value of >99.5% was obtained in
the ECA reaction, which was catalyzed by the Cu(OTf )2/10
system (entry 6). Although the reversed isomer of adduct 39 was
the main product in both the Cu(acac)2/9 and Cu(acac)2/8
catalytic systems, the yields were lower (entries 7 and 8).
Reaction of a cyclic enone consisting of a seven-membered
ring such as 2-cyclohepten-1-one (40) was found to increase
the enantioselectivity of the reaction (entries 9-16). A similar
observation was reported in the monodentate NHC-Cu-cat-
alyzed conjugate addition of dialkylzinc to cyclic enone.7b
Treatment of 40 with Et2Zn catalyzed by Cu(OTf )2 combined
with 10 afforded (S)-3-ethylcycloheptanone (41) in a 95.5:4.5 er
(entry 10). On the other hand, (R)-41 was produced as a major
FIGURE 2. Influence of the R1 group at benzimidazolium salt
(1-8, front) and imidazolium salt (14-21, back) on enantioselec-
tivity in the Cu(acac)2-catalyzed ECA reaction.
reaction (Table 6 and Figure 2). These results differed completely
from the observations in the Cu(OTf )2-catalyzed ECA reaction:
(i) ligands 5, 10, and 18 derived from (S)-tert-leucinol produced
(S)-31 as the major product, while (R)-31 was obtained with
other ligands (entries 5, 10, and 16); (ii) an unusual relationship
between the steric factor of the ligand and the enantioselectivity
of the reaction was observed (Figure 2); and (iii) ligand 8 (R1=
Bn, R2=Me) gave a 25:75 er, a slightly better result than otained
with 9 (R1=iBu, R2=Bn) (entries 8 and 9).
In addition, we examined several Cu catalyst precursors in the
presence of ligand 29 having a tBu group (Table S3, Supporting
Information). All of these reactions produced (S)-31 in pre-
ference to the (R)-enantiomer, implying no reversal of stereo-
selectivity was observed in this case. It is difficult to explain why
the ligands having a tBu group at the R1 position, such as 5, 10,
18,and29,affordthe(S)-enantiomer in the Cu(acac)2-catalyzed
ECA reaction in contrast to that provided by other ligands. We
assume that the complex, which is an active catalytic species
derived from Cu(acac)2 and 18, would be structurally different
from the complex derived from 11-21 excuding 18 beause of
the steric hindrance of the tBu moiety.
5712 J. Org. Chem. Vol. 75, No. 16, 2010

Shibata et al.
JOCArticle
product in a 7:93 er by reacting 40 with Et2Zn in the presence of
Cu(acac)2 combined with 8 (entry 12). In the Cu(OTf)2-
catalyzed ECA reaction of 40 with Bu2Zn ligand 9 provided
76% ee, whereas 96% ee was recorded by using 10 leading to
(S)-adduct (entries 13 and 14).
obtain a solid, which was purified by reprecipitation with ethyl
acetate and methanol to afford the corresponding coupling pro-
duct as a white solid. The compounds 3, 4, 5, 7, 9, 12, 13, 16, and 17
were reported in our previous papers.14,15
1-[2-((S)-1-Hydroxy-2-propanylamino)-2-oxoethyl]-3-methyl-
benzimidazolium chloride (1): yield 72%; mp 117.6-117.8 °C; 1H
NMR (DMSO) δ 9.78 (s, 1H), 8.68 (br, 1H), 8.05-7.93 (m, 2H),
7.74-7.66 (m, 2H), 5.31 (s, 2H), 4.87 (t, J = 6.0 Hz, 1H), 4.14 (s,
3H), 3.81-3.77 (m, 1H), 3.39-3.30 (m, 2H), 1.08 (d, J = 6.4 Hz,
3H); 13C NMR δ 163.9, 143.7, 131.5, 131.4, 126.7, 126.4, 113.6,
Conclusions
We conducted systematic studies on the Cu-catalyzed asym-
metric conjugate addition of Et2Zn to cyclic enones using a wide
variety of chiral azolium compounds that are readily accessible,
highly stable, and easily tunable. The most important feature of
our ligands was that almost complete reversal of enantioselec-
tivity with the same ligand was achieved simply by changing the
Cu species employed. Reaction of cyclic enones with dialkylzinc
catalyzed by Cu(OTf )2 combined with an appropriate chiral
benzimidazolium compound afforded the corresponding opti-
cally active conjugate adducts in moderate to excellent yields
and 91:9 to >99.5:<0.5 enantiomer ratio (82% to >99.5% ee),
whereas Cu(acac)2 in place of Cu(OTf )2 led to the adducts with
opposite configurations in 19:81 to 7:93 er (62% to 86% ee). The
present method might provide a new synthetic strategy for
obtaining both enantiomers of a given compound in the Cu-
catalyzed ECA reaction. Further studies focusing on coordina-
tion chemistry and organometallic chemistry of the catalytic
active Cu species that would be formed by the reaction of
Cu(OTf)2 or Cu(acac)2 with the azolium compounds to gain
insight into the mechanisms of the reversal of enantioselectivity
are currently in progress. In addition, applications of the chiral
chelating polydentate NHC catalysts for development of effi-
cient catalytic enantioselective transformations are the subject
of ongoing research in our laboratory.
113.5, 64.0, 48.5, 47.4, 33.3, 16.9. Anal. Calcd for C13H18ClN3O2
0.5H2O: C, 53.33; H, 6.54; N, 14.35. Found: C, 52.96; H, 6.36; N,
14.29.
3
1-[2-((S)-1-Hydroxy-2-butanylamino)-2-oxoethyl]-3-methyl-
benzimidazolium chloride (2): yield 70%; mp 164.8-165.1 °C; 1H
NMR (DMSO) δ 9.76 (s, 1H), 8.52 (br, 1H), 8.05-8.03 (m, 1H),
7.93-7.92 (m, 1H), 7.72-7.69 (m, 2H), 5.36 (d, J = 16.4 Hz, 1H),
5.29 (d, J=16.4 Hz, 1H), 4.82 (t, J=5.6 Hz, 1H), 4.14 (s, 3H),
3.67-3.59 (m, 1H), 3.43-3.33 (m, 2H), 1.64-1.53 (m, 1H), 1.42-
1.32 (m, 1H), 0.84 (t, J=7.6 Hz, 3H); 13C NMR δ 164.1, 143.5,
131.3, 131.3, 126.5, 126.3, 113.5, 113.2, 62.4, 52.8, 48.3, 33.2, 23.4,
10.3. Anal. Calcd for C14H20ClN3O2: C, 56.47; H, 6.77; N, 14.11.
Found: C, 56.12; H, 6.58; N, 14.06.
1-[2-((S)-1-Hydroxy-3-methyl-2-pentanylamino)-2-oxoethyl]-
3-methylbenzimidazolium chloride (6): yield 48%; mp 177.3-
177.5 °C; 1H NMR (DMSO) δ 9.83 (s, 1H), 8.66 (d, J = 8.7 Hz,
1H), 8.03-8.01 (m, 1H), 7.96-7.94 (m, 1H), 7.69-7.67 (m, 2H),
5.42 (d, J=16.3 Hz, 1H), 5.34 (d, J=16.3 Hz, 1H), 4.78 (t, J =
11.0 Hz, 1H), 4.13 (s, 3H), 3.63-3.56 (m, 1H), 3.46-3.36 (m,
2H), 1.59-1.58 (m, 1H), 1.46-1.41 (m, 1H), 1.13-1.02 (m, 1H),
0.83 (d, J=7.3 Hz, 3H), 0.79 (d, J=7.3 Hz, 3H); 13C NMR δ
164.3, 143.7, 131.5, 131.3, 126.6, 126.4, 113.6, 113.4, 60.8,
55.5, 48.5, 34.8, 33.3, 24.7, 15.4, 11.2. Anal. Calcd for C16H24-
ClN3O2 1.25H2O: C, 55.17; H, 7.67; N, 12.06. Found: C, 55.05;
3
H, 7.47; N, 12.05.
1-[2-((S)-1-Hydroxy-3-phenyl-2-propanylamino)-2-oxoethyl]-
3-methylbenzimidazolium chloride (8): yield 68%; mp 208.8-
209.1 °C; 1H NMR (DMSO) δ 9.75 (s, 1H), 8.86 (d, J = 9.0 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.71-7.63 (m, 3H), 7.24-7.16 (m,
5H), 5.30 (d, J = 16.4 Hz, 1H), 5.24 (d, J = 16.4 Hz, 1H), 5.02 (t,
J = 5.7 Hz, 1H), 4.12 (s, 3H), 3.96-3.92 (m, 2H), 3.43-3.35 (m,
2H), 2.90-2.86 (m, 1H), 2.71-2.36 (m, 1H); 13C NMR δ 164.0,
143.6, 138.9, 131.4, 131.2, 129.1, 128.1, 126.6, 126.4, 126.0,
113.5, 113.3, 62.5, 53.2, 48.5, 36.5 33.3. Anal. Calcd for
C19H22ClN3O2: C, 63.42; H, 6.16; N, 11.68. Found: C, 63.26;
H, 6.10; N, 11.63.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-benzilbenzimidazolium chloride (10): yield 62%; mp 230.6-
230.8 °C; 1H NMR (DMSO) δ 9.95 (d, J = 4.1 Hz, 1H), 8.37 (br,
1H), 7.99-7.91 (m, 2H), 7.69-7.62 (m, 2H), 7.49-7.35 (m, 5H),
5.84 (s, 2H), 5.43 (d, J = 16.3 Hz, 1H), 5.32 (d, J = 16.3 Hz, 1H),
4.63 (br, 1H), 3.63-3.55 (m, 2H), 3.45-3.32 (m, 1H), 0.86 (s,
9H); 13C NMR δ 164.7, 143.5, 133.9, 131.6, 130.4, 128.9, 128.7,
128.1, 126.7, 126.6, 113.8, 113.6, 60.2, 59.7, 49.7, 48.7, 33.5, 26.8.
Anal. Calcd for C22H28ClN3O2: C, 65.74; H, 7.02; N, 10.45.
Found: C, 65.46; H, 6.93; N, 10.31.
1-[2-((S)-1-Hydroxy-3-phenyl-2-propanylamino)-2-oxoethyl]-
3-benzilbenzimidazolium chloride (11): yield 53%; mp 195.7-
195.9 °C; 1H NMR (DMSO) δ 9.97 (s, 1H), 8.89 (d, J = 8.2 Hz,
1H), 7.99-7.96 (m, 1H), 7.65-7.60 (m, 3H), 7.49-7.48 (m, 2H),
7.43-7.37 (m, 3H), 7.24-7.12 (m, 5H), 5.83 (s, 2H), 5.32 (d, J =
16.5 Hz, 1H), 5.25 (d, J = 16.5 Hz, 1H), 5.04 (t, J = 5.2 Hz, 1H),
3.98-3.91 (m, 1H), 3.42 (t, J = 5.2 Hz, 2H), 2.91-2.86 (m, 1H),
2.70-2.65 (m, 1H); 13C NMR δ 163.9, 143.4, 138.9, 134.0, 131.5,
130.4, 129.1, 129.0, 128.7, 128.2, 128.1, 126.8, 126.6, 126.0,
113.9, 113.6, 62.5, 53.3, 49.7, 48.7, 36.6. Anal. Calcd for
Experimental Section
General. All chemicals were obtained from commercial
sources and were used as received. N-Alkylated azoles except
for 1-methylbenzoimidazole, 1-methylimidazole, 1-byutylimi-
dazole, 1-benzylimidazole, and 1-allylimidazole have been pre-
pared according to the literature procedure.19 Chiral azolium
salts 1-29 and 32-35 have been synthesized according to our
previous papers.14 1H and 13C NMR spectra were recorded on
spectrometers at 400 and 100 MHz, respectively. Chemical shifts
were reported in ppm relative to TMS for H and 13C NMR
1
spectra. CD3OD, (CD3)2SO, or CDCl3 was used as the NMR
solvent. Thin-layer chromatography (TLC) analysis was per-
formed with glass-backed plates precoated with silica gel and
examined under UV (254 nm) irradiation. Flash column chro-
matography was executed on silica gel 60 (Merck, mesh:
230-400; particle size: 0.040-0.063 nm).
General Procedure for the Prepation of Azolium Salts. To 1,4-
dioxane were added N-benzylbenzimidazole (0.293 M) and
R-chloroacetoaminde derived from chloroacetyl chloride and
β-aminoalcohol20 (0.267 M). After the reaction mixture was stirred
at 110 °C for 16 h, the solvent was removed under reduced pressure.
The residue was dissolved in methanol, and then activated carbon
was added. After 16 h, the activated carbon was removed by
filtration. The filtrate was concentrated under reduced pressure to
(19) (a) Starikova, O. V.; Dolgushin, G. V.; Larina, L. I.; Ushakov, P. E.;
Komarova, T. N.; Lopyrev, V. A. Russ. J. Org. Chem. 2003, 39, 1467–1470.
(b) Lee, H. M.; Lu, C. Y.; Chen, C. Y.; Chen, W. L.; Lin, H. C.; Chiu, P. L.;
Cheng, P. Y. Tetrahedron 2004, 60, 5807–5825. (c) Osyanin, V. A.; Purygin,
P. P.; Belousova, Z. P. Russ. J. Gen. Chem. 2005, 75, 111–117.
(20) Guillemot, G.; Neuburger, M.; Pfaltz, A. Chem.;Eur. J. 2007, 13,
8960–8970.
C25H26ClN3O2 0.25H2O: C, 68.17; H, 6.06; N, 9.54. Found:
3
C, 68.29; H, 5.92; N, 9.58.
J. Org. Chem. Vol. 75, No. 16, 2010 5713

Shibata et al.
JOCArticle
1-[2-((S)-1-Hydroxy-2-butanylamino)-2-oxoethyl]-3-benzylimi-
dazolium chloride (14): yield 72%; 1H NMR (DMSO) δ 9.40 (br,
1H), 8.60 (br, 1H), 7.86-7.84 (m, 1H), 7.72-7.70 (s, 1H), 7.45-
7.38 (m, 5H), 5.50 (s, 2H), 5.02 (s, 2H), 4.91 (d, J = 5.9 Hz, 2H),
3.81-3.72 (m, 1H), 3.42-3.26 (m, 2H), 1.06 (d, J = 6.8 Hz, 3H);
13C NMR δ 164.1, 137.4, 134.9, 129.0, 128.7, 128.2, 124.2, 121.8,
64.0, 51.9, 50.7, 47.2, 16.9. Because of the highly hydroscopic
character collection of analytical data failed.
1H NMR (DMSO) δ 9.26 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.81 (t,
J=1.6 Hz, 1H), 7.74 (t, J=1.6 Hz, 1H), 5.09 (d, J=16.4 Hz, 1H),
5.04 (d, J = 16.4 Hz, 1H), 4.60 (d, J = 16.4 Hz, 1H), 4.23 (t, J =
7.2 Hz, 2H), 3.62-3.57 (m, 2H), 3.39-3.33 (m, 1H), 1.81-1.74 (m,
2H), 1.30-1.21 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H), 0.87 (s, 9H); 13
C
NMR δ 165.0, 137.2, 123.8, 121.7, 60.3, 59.6, 50.8, 48.5, 33.6, 31.3,
26.8, 18.7, 13.2. Anal. Calcd for C15H28ClN3O2: C, 56.68; H, 8.88;
N, 13.22. Found: C, 56.41; H, 8.77; N, 13.19.
1-[2-((S)-1-Hydroxy-2-propanylamino)-2-oxoethyl]-3-benzyli-
midazolium chloride (15): yield 68%; mp 136.8-137.0 °C; H
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-(2-methylethyl)imidazolium chloride (24): yield 78%; mp 210.0-
210.4 °C; 1H NMR (DMSO) δ 9.29 (s, 1H), 8.22 (d, J = 8.4 Hz,
1H), 7.92 (s, 1H), 7.73 (s, 1H), 5.04 (d, J = 16.4 Hz, 1H), 4.99 (d,
J = 16.4 Hz, 1H), 4.73-4.67 (m, 1H), 4.57 (t, J = 4.8 Hz, 1H),
3.62-3.57 (m, 2H), 3.38-3.32 (m, 1H), 1.49 (d, J = 6.4 Hz, 6H),
0.87 (s, 9H); 13C NMRδ164.9, 136.0, 123.9, 119.8, 60.3, 59.6, 52.2,
50.7, 33.6, 26.8, 22.3, 22.3. Anal. Calcd for C14H26ClN3O2: C,
55.34; H, 8.63; N, 13.83. Found: C, 55.32; H, 8.43; N, 13.82.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-(naphthalen-1-ylmethyl)imidazolium chloride (25): yield 62%;
1
NMR (DMSO) δ 9.31 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.82 (s,
1H), 7.73 (s, 1H), 7.46-7.39 (m, 5H), 5.48 (s, 2H), 5.03 (d, J =
16.4 Hz, 1H), 4.98 (d, J = 16.4 Hz, 1H), 4.78 (t, J = 4.0 Hz, 1H),
3.66-3.57 (m, 1H), 3.40-3.30 (m, 2H), 1.63-1.52 (m, 1H),
1.40-1.29 (m, 1H), 0.84 (t, J = 7.6 Hz, 3H); 13C NMR δ 164.4,
137.4, 134.8, 129.0, 128.7, 128.2, 124.2, 121.8, 62.5, 52.9, 51.8,
50.7, 23.5, 10.4. Anal. Calcd for C16H22ClN3O2 0.125H2O: C,
3
58.94; H, 6.88; N, 12.89. Found: C, 58.77; H, 6.64; N, 12.89.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-benzylimidazolium chloride (18): yield 81%; mp 213.8-
1
mp 230.7-230.9 °C; H NMR (DMSO) δ 9.30 (s, 1H), 8.23-
1
8.16 (m, 2H), 8.04-8.01 (m, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.74
(d, J = 1.6 Hz, 1H), 7.65-7.49 (m, 4H), 6.01 (s, 2H), 5.08 (d, J =
16.6 Hz, 1H), 5.02 (d, J = 16.6 Hz, 1H), 4.56 (t, J = 4.8 Hz, 1H),
3.60-3.56 (m, 2H), 3.36-3.30 (m, 1H), 0.85 (s, 9H); 13C NMR δ
165.0, 137.6, 133.4, 130.3, 130.3, 129.6, 128.8, 127.3, 127.2,
126.4, 125.6, 124.1, 122.9, 122.2, 60.3, 59.6, 50.9, 49.7, 33.6,
26.8. Anal. Calcd for C22H28ClN3O2: C, 65.74; H, 7.02; N,
10.45. Found: C, 65.71; H, 6.98; N, 10.46.
214.0 °C; H NMR (DMSO) δ 9.33 (s, 1H), 8.21 (d, J = 9.2
Hz, 1H), 7.82 (t, J = 1.6 Hz, 1H), 7.73 (t, J = 1.6 Hz, 1H), 7.44-
7.39 (m, 5H), 5.49 (s, 2H), 5.08 (d, J = 16.4 Hz, 1H), 5.02 (d, J =
16.4 Hz, 1H), 4.55 (t, J = 5.6 Hz, 1H), 3.63-3.57 (m, 2H), 3.38-
3.31 (m, 1H), 0.87 (s, 9H); 13C NMR δ 164.9, 137.4, 134.9, 128.9,
128.7, 128.1, 124.1, 121.8, 60.3, 59.6, 51.8, 50.9, 33.6, 26.8. Anal.
Calcd for C18H26ClN3O2 0.125CH3OH: C, 61.17; H, 7.51; N,
3
11.81. Found: C, 61.04; H, 7.46; N, 11.83.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-(4-methoxybenzyl)imidazolium chloride (26): yield 75%; mp
244.7-245.0 °C; 1H NMR (DMSO) δ 9.28 (s, 1H), 8.22 (d, J =
8.8 Hz, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H),
6.98 (d, J = 8.8 Hz, 2H), 5.40 (s, 2H), 5.07 (d, J = 16.6 Hz, 1H),
5.02 (d, J = 16.6 Hz, 1H), 4.56 (t, J = 5.2 Hz, 1H), 3.76 (s, 3H),
3.62-3.56 (m, 2H), 3.39-3.30 (m, 1H), 0.86 (s, 9H); 13C NMR δ
164.9, 159.5, 137.0, 130.0, 126.7, 124.0, 121.6, 114.3, 60.3, 59.6,
55.2, 51.4, 50.8, 33.6, 26.8. Anal. Calcd for C19H28ClN3O3: C,
59.76; H, 7.39; N, 11.00. Found: C, 59.74; H, 7.28; N, 11.04.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-(4-methylbenoate-1-ylmethyl)imidazolium chloride (27): yield
1-[2-((S)-1-Hydroxy-3-methyl-2-pentanylamino)-2-oxoethyl]-
3-benzylimidazolium chloride (19): yield 54%; mp 159.6-
159.8 °C; 1H NMR (DMSO) δ 9.31 (s, 1H), 8.30 (d, J = 8.6 Hz,
1H), 7.81 (t, J = 1.6 Hz, 1H), 7.73 (t, J = 1.6 Hz, 1H), 7.45-7.38
(m, 5H), 5.48 (s, 2H), 5.05 (d, J = 16.5 Hz, 1H), 4.98 (d, J = 16.5
Hz, 1H), 4.66 (t, J = 5.4 Hz, 1H), 3.64-3.60 (m, 1H), 3.44 (t, J =
5.4 Hz, 2H), 1.61-1.56 (m, 1H), 1.49-1.40 (m, 1H), 1.09-1.05
(m, 1H), 0.86-0.80 (m, 6H); 13CNMRδ164.4, 137.4, 134.9, 128.9,
128.7, 128.2, 124.1, 121.8, 60.7, 55.5, 51.8, 50.7, 34.9, 24.7, 15.3,
11.3. Anal. Calcd for C18H26ClN3O2 0.25CH3OH: C, 60.91; H,
7.56; N, 11.68. Found: C, 60.74; H, 7.18; N, 11.80.
3
1-[2-((S)-1-Hydroxy-2-phenyl-2-ethanylamino)-2-oxoethyl]-
3-benzylimidazolium chloride (20): yield 83%; 1H NMR (DMSO) δ
9.33 (s, 1H), 9.19 (d, J = 6.8 Hz, 1H), 7.81 (s, 1H), 7.74 (s, 1H),
7.41-7.24 (m, 10H), 5.47 (s, 2H), 5.12 (s, 1H), 4.87-4.82 (m, 1H),
3.59 (d, J = 6.3 Hz, 2H); 13C NMR δ 164.5, 140.5, 137.5, 134.9,
129.0, 128.8, 128.2, 128.1, 126.9, 124.3, 121.8, 64.6, 55.8, 51.8, 50.8.
Because of the highly hydroscopic character collection of analytical
data failed.
1-[2-((S)-1-Hydroxy-3-phenyl-2-propanylamino)-2-oxoethyl]-
3-benzilimidazolium chloride (21): yield 83%; 1H NMR (DMSO)
δ 9.27 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 1.6 Hz, 1H),
7.62 (t, J = 1.6 Hz, 1H), 7.42-7.37 (m, 5H), 7.27-7.14 (m, 5H),
5.45 (s, 2H), 4.99-4.90 (m, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.92
(d, J = 16.0 Hz, 1H), 3.92-3.84 (m, 1H), 3.48-3.35 (m, 2H),
2.85-2.80 (m, 1H), 2.68-2.63 (m, 1H); 13C NMR δ 164.3, 138.8,
137.3, 134.8, 129.1, 129.0, 128.8, 128.2, 128.2, 126.0, 124.1,
121.8, 62.1, 53.3, 51.9, 50.7, 36.5. Because of the highly hydro-
scopic character collection of analytical data failed.
1
71%; mp 224.2-224.5 °C; H NMR (DMSO) δ 9.34 (s, 1H),
8.20 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.83 (t, J =
1.6 Hz, 1H), 7.76 (t, J = 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H),
5.60 (s, 2H), 5.09 (d, J = 16.4 Hz, 1H), 5.03 (d, J = 16.4 Hz, 1H),
4.53 (t, J = 5.2 Hz, 1H), 3.86 (s, 3H), 3.63-3.57 (m, 2H), 3.38-
3.32 (m, 1H), 0.87 (s, 9H); 13C NMR δ 164.9, 137.4, 134.9, 129.0,
128.7, 128.2, 124.2, 121.9, 60.3, 59.6, 51.3, 50.9, 33.6, 26.8. Anal.
Calcd for C20H28ClN3O4: C, 58.60; H, 6.89; N, 10.25. Found: C,
58.50; H, 6.76; N, 10.18.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-(4-fluorobenzyl)imidazolium chloride (28): yield 65%; mp
212.3-212.5 °C; 1H NMR (DMSO) δ 9.30 (s, 1H), 8.20 (d,
J=8.8 Hz, 1H), 7.81 (t, J=2.0 Hz, 1H), 7.71 (t, J=1.6 Hz,
1H), 7.52-7.49 (m, 2H), 7.29-7.25 (m, 2H), 5.46 (s, 2H), 5.07 (d,
J=16.4 Hz, 1H), 5.01 (d, J = 16.4 Hz, 1H), 4.54 (t, J = 5.6 Hz,
1H), 3.60-3.55 (m, 2H), 3.37-3.29 (m, 1H), 0.85 (s, 9H); 13C
NMR δ 164.9, 137.3, 131.1, 130.7, 124.1, 121.7, 116.0, 115.7, 60.3,
59.6, 51.0, 50.9, 33.6, 26.8. Anal. Calcd for C18H25ClFN3O2: C,
58.45; H, 6.81; N, 11.36. Found: C, 58.29; H, 6.70; N, 11.17.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-allylimidazolium chloride (29): yield 65%; mp 201.5-201.8 °C;
1H NMR (DMSO) δ 9.21 (s, 1H), 8.26 (d, J = 9.2 Hz, 1H),
7.75-7.72 (m, 2H), 6.12-5.98 (m, 1H), 5.37-5.22 (m, 2H), 5.10
(d, J = 15.9 Hz, 1H), 5.03 (d, J = 15.9 Hz, 1H), 4.89 (d, J = 5.7
Hz, 2H), 4.57 (br, 1H), 3.62-3.54 (m, 2H), 3.44-3.30 (m, 1H),
0.86 (s, 9H); 13C NMR δ 164.9, 137.3, 131.8, 123.9, 121.8, 119.9,
60.3, 59.6, 50.8, 50.7, 33.6, 26.8. Anal. Calcd for C14H24ClN3O2:
C, 55.71; H, 8.02; N, 13.92. Found: C, 55.52; H, 7.79; N, 13.90.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-methylimidazolium chloride (22): yield 97%; mp 239.8-
1
240.0 °C; H NMR (DMSO) δ 9.09 (s, 1H), 8.16 (d, J = 9.2
Hz, 1H), 7.68-7.66 (m, 2H), 5.04 (d, J = 16.5 Hz, 1H), 4.98 (d, J
= 16.5 Hz, 1H), 4.55 (t, J = 4.6 Hz 1H), 3.88 (s, 3H), 3.61-3.56
(m, 2H), 3.41-3.30 (m, 1H), 0.85 (s, 9H); 13C NMR δ 165.1,
137.7, 123.7, 123.0, 60.3, 59.7, 50.7, 35.8, 33.7, 26.8. Anal. Calcd
for C12H22ClN3O2: C, 52.26; H, 8.04; N, 15.24. Found: C, 52.32;
H, 7.96; N, 15.28.
1-[2-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-2-oxoethyl]-
3-butylimidazolium chloride (23): yield 58%; mp 205.6-205.9 °C;
5714 J. Org. Chem. Vol. 75, No. 16, 2010

Shibata et al.
JOCArticle
1-[2-((1R,2R)-1,3-Dihydroxy-1-phenyl-2-propanylamino)-2-
oxoethyl]-3-methylbenzimidazolium chloride (32): yield 62%;
1H NMR (DMSO) δ 9.68 (s, 1H), 8.58 (d, J = 12.0 Hz, 1H),
8.00 (d, J=8.0 Hz, 1H), 7.70-7.61 (m, 2H), 7.49 (d, J=8.0 Hz,
1H), 7.38-7.19 (m, 5H), 5.74 (d, J = 4.0 Hz, 1H), 5.27 (d, J =
16.5 Hz, 1H), 5.20 (d, J = 16.5 Hz, 1H), 4.97-4.91 (m, 1H), 4.92 (t,
J = 4.0 Hz, 1H), 4.09 (s, 3H), 3.96-3.88 (m, 1H), 3.62-3.58 (m,
1H), 3.40-3.36 (m, 1H); 13C NMR δ 164.2, 143.5, 131.1, 127.7,
126.6, 126.4, 126.1, 113.6, 113.1, 69.6, 60.6, 57.1, 48.3, 33.2. Because
of the highly hydroscopic character collection of analytical data
failed.
1-[2-((1R,2R)-1,3-Dihydroxy-1-phenyl-2-propanylamino)-2-
oxoethyl]-3-methylimidazolium chloride (33): yield 61%; 1H
NMR (DMSO) δ 9.21 (s, 1H), 8.34 (d, J=9.2 Hz, 1H), 7.77
(t, J=1.2 Hz, 1H), 7.56 (t, J=1.2 Hz, 1H), 7.45-7.17 (m, 10H),
5.61 (d, J = 4.8 Hz, 1H), 5.44 (s, 2H), 4.96 (d, J = 16.0 Hz, 1H),
4.90 (d, J = 16.0 Hz, 1H), 4.88-4.84 (m, 1H), 3.90-3.88 (m,
1H), 3.56-3.50 (m, 1H), 3.42-3.27 (m, 2H); 13C NMR δ 164.6,
143.3, 137.3, 134.8, 129.0, 128.7, 128.6, 128.3, 128.2, 127.7,
127.7, 127.4, 126.7, 126.2, 124.0, 121.8, 69.9, 60.4, 57.3, 51.8,
50.8. Because of the highly hydroscopic character collection of
analytical data failed.
1-[2-((S)-1-(Methoxycarbonyl)-3-methyl-1-butanylamino)-2-
oxoethyl]-3-benzylbenzimidazolium chloride (34): yield 60%; mp
135.5-135.8 °C; 1H NMR (DMSO) δ 10.0 (s, 1H), 9.36 (d, J =
7.2 Hz, 1H), 8.01-7.99 (m, 1H), 7.92-7.89 (m, 1H), 7.71-7.64
(m, 2H), 7.52-7.38 (m, 5H), 5.87 (s, 2H), 5.50 (d, J = 16.4 Hz,
1H), 5.43 (d, J = 16.4 Hz, 1H), 4.32-4.30 (m, 1H), 3.62 (s, 3H),
1.71-1.55 (m, 3H), 0.92 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 6.8 Hz,
3H); 13C NMR δ 172.3, 164.9, 143.6, 133.9, 131.6, 130.5, 129.0,
128.7, 128.2, 126.8, 126.7, 113.9, 113.6, 52.0, 50.8, 49.8, 48.4,
137.5, 134.8, 129.0, 128.7, 128.2, 124.2, 121.8, 52.0, 51.8, 50.7,
50.4, 24.1, 22.6, 21.3. Because of the highly hydroscopic char-
acter collection of analytical data failed.
General Procedure for Cu(OTf )2-Catalyzed Asymmetric
Reaction of Enone with Et2Zn. To a solution of azolium salt
(0.045 mmol) in THF (9 mL) were added Cu(OTf )2 (0.06 mmol)
and enone (1 mmol). After the mixture was cooled to 0 °C, Et2Zn
(3 mmol, 1 mol/L in hexanes) was added to the reaction vessel.
The color immediately changed from yellow to dark brown.
After stirring at room temperature for 3 h, the reaction was
quenched with 10% HCl aq. The resulting mixture was ex-
tracted with diisopropyl ether and dried over Na2SO4. The
product was purified by silica gel column chromatography
(hexane/EtOAc). Enantiomeric excess was measured by chiral
GLC.
General Procedure for Cu(acac)2-Catalyzed Asymmetric
Reaction of Enone with Et2Zn. To a solution of azolium salt
(0.045 mmol) in THF (9 mL) were added Cs2CO3 (0.08 mmol)
and Cu(acac)2 (0.06 mmol), and then the mixture was cooled to
0 °C. Then, Et2Zn (3 mmol, 1 mol/L in hexanes) was added to
the reaction vessel, and the mixture was stirred at room tem-
perature for 15 min. The color changed from blue to dark
brown. Then, enone (1 mmol) was added and the reaction
mixture was stirred at room temperature for 3 h.
Acknowledgment. This work was financially supported by
a Grant-in-Aid for Scientific Research (C) (20550103) from
Japan Society for the Promotion of Science (JSPS) and the
Kansai University Grant-in-Aid for progress of research in
graduate course, 2010.
24.2, 22.6, 21.2. C23H28ClN3O3 0.75H2O: C, 62.29; H, 6.71; N,
3
9.48. Found: C, 62.13; H, 6.40; N, 9.46.
Supporting Information Available: Tables S1-S3 giving
ECA reaction of 30 with Et2Zn by the Cu(OTf )2/18 catalytic
system (Table S1), solvet effect for ECA reaction of 30 with
Et2Zn by the Cu(OTf )2/18 catalytic system (Table S2), and
screening of Cu salts for ECA reaction of 30 with Et2Zn in the
presence of 29 (Table S3), spectra for products, and chiral GC
traces. This material is available free of charge via the Internet at
http://pubs.acs.org.
1-[2-((S)-1-(Methoxycarbonyl)-3-methyl-1-butanylamino)-2-
oxoethyl]-3-benzylimidazolium chloride (35): yield 98%; 1H
NMR (DMSO) δ 9.38 (s, 1H), 9.16 (d, J=7.2 Hz, 1H), 7.84
(t, J=1.6 Hz, 1H), 7.74 (t, J=1.6 Hz, 1H), 7.43-7.39 (m, 5H),
5.50 (s, 2H), 5.15 (d, J=16.4 Hz, 1H), 5.10 (d, J=16.4 Hz, 1H),
4.33-4.27 (m, 1H), 3.63 (s, 3H), 1.73-1.49 (m, 3H), 0.90 (d, J=
6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H); 13C NMR δ 172.4, 165.1,
J. Org. Chem. Vol. 75, No. 16, 2010 5715