C2-symmetric functionalized azolium salt from serine ester for Cu-catalyzed asymmetric conjugate addition reaction

Article abstract of DOI:10.1016/j.molcata.2014.08.006

C₂-symmetric ester-amide functionalized azolium salt was synthesized from readily available α-amino ester such as L-serine methyl ester. The combination of a Cu salt and the chiral azolium salt promoted the asymmetric conjugate addition reactio

Full text of DOI:10.1016/j.molcata.2014.08.006

Journal of Molecular Catalysis A: Chemical 395 (2014) 66–71
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
C2-symmetric functionalized azolium salt from serine ester for
Cu-catalyzed asymmetric conjugate addition reaction
Junko Kondo, Ayako Harano, Kenta Dohi, Satoshi Sakaguchi∗
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 May 2014
Received in revised form 28 July 2014
Accepted 2 August 2014
Available online 10 August 2014
C2-symmetric ester-amide functionalized azolium salt was synthesized from readily available ␣-amino
ester such as L-serine methyl ester. The combination of a Cu salt and the chiral azolium salt promoted
the asymmetric conjugate addition reaction of enones with dialkylzincs. Thus, treatment of acyclic enone
such as chalcone with Et2Zn afforded the corresponding 1,4-adduct with up to 85% ee. An excellent ee
value of 93% was obtained when 3-nonen-2-one was reacted with Et2Zn. The present catalytic system
was found to be useful for the 1,4-addition reaction of cyclic enone. For example, the reaction of 2-
cyclohepten-1-one with Et2Zn produced (R)-3-ethylcycloheptanone with 80% ee.
Keywords:
Asymmetric catalysis
Conjugate addition
N-Heterocyclic carbene
Ligand design
© 2014 Elsevier B.V. All rights reserved.
Amino ester
1. Introduction
to cyclic enones catalyzed by NHC–Cu complexes; however, the
highly enantioselective catalytic reaction of acyclic enones has been
The synthesis of efficient enantiopure ligands that provide a chi-
ral environment to metals for asymmetric catalysis is currently
one of the major challenges in synthetic organic chemistry. Nat-
ural amino acids provide an easily accessible, inexpensive, and
optically pure source for the chiral ligand design [1]. In the last
decade, N-heterocyclic carbenes (NHCs) have attracted increasing
attention because of their function as efficient ligands in coordi-
nation chemistry and homogeneous catalysis [2]. For the design
of an efficient chiral ligand, the introduction of an appropriate
hemilabile chiral donor group at the NHC side-arm provides a rel-
atively inflexible chelating NHC-based ligand, which is expected to
offer a key structure for constructing an efficient stereodirecting
group [3].
The Cu-catalyzed asymmetric conjugate addition (ACA) of alkyl-
ating reagents to enones is one of the most important and versatile
strategies for enantioselective carbon–carbon bond formation [4].
An impressive array of chiral ligands have been developed to con-
trol the stereochemistry of 1,4-addition reactions [5,6]. Among the
different systems investigated for ACA, NHC and phosphorus-based
polydentate ligands have shown significant promise. Despite effi-
ciency, ACA can still be improved in terms of enantioselectivity
and substrate scope. For example, much attention has been paid to
the enantioselective conjugate addition of organometallic reagents
rarely reported. The difficulty in the stereoselective reaction of
acyclic enones is assumed to be caused by the s-cis/s-trans con-
formational flexibility [6a,7]. To the best of our knowledge, only
one report by Katuski and Uchida showed the reaction of alkenyl
phenyl ketones with Et2Zn catalyzed by Cu(OTf)2 and a chiral NHC,
where the ligand precursor was an imidazolium compound con-
taining 1,2-diphenylethylenediamine skeleton as the chiral source
[8].
As
a part of our research program on developing chiral
NHC ligand precursors from natural amino acid derivatives, we
reported the Cu-catalyzed enantioselective conjugate addition
reaction of cyclic enone using a C2-symmetric bis(hydroxy-amide)-
functionalized azolium ligand precursor [9,10a]. Recently, we also
reported that structurally similar bis(ester-amide)-functionalized
azolium compound can be synthesized from amino esters such
as serine ester [10b]. Fortunately, the combination of a Cu salt
and the bis(ester-amide)-functionalized NHC ligand promoted
the 1,4-addition of acyclic enones. While the C2-symmetric chi-
ral ligand derived from serine ester has been studied in a few
examples of ACA reaction of acyclic enones, their applications in
ACA reaction of both acyclic and cyclic enones have not been yet
studied. This prompted us to continue to study the potential of
this promising class of C2-symmetric functionalized NHC ligand
to expand the substrate scope of ACA reaction. Herein, we report
the Cu-catalyzed ACA reaction under the influence of bis(ester-
amide)-functionalized NHC ligand precursors for both acyclic and
cyclic enones.
∗
Corresponding author. Tel.: +81 6 6368 0867; fax: +81 6 6339 4026.
E-mail address: satoshi@kansai-u.ac.jp (S. Sakaguchi).
http://dx.doi.org/10.1016/j.molcata.2014.08.006
1381-1169/© 2014 Elsevier B.V. All rights reserved.

J. Kondo et al. / Journal of Molecular Catalysis A: Chemical 395 (2014) 66–71
67
Table 1
O
ACA reaction of 5 with Et2Zn catalyzed by Cu salt and L1 to afford (S)-6.a
X
O
X
H2N
CH2OH
COOMe
X
Et3N
HN
CH2OH
CH2Cl2, -20 °C
COOMe
serine methyl ester
.
1 (X=Br), 2 (X=Cl)
Entry
Cu salt
Solvent
Yield (%)b
Ee (%)c
O
1
2
3
4
5
6
7
8
Cu(OTf)2
[Cu(CH3CN)4](OTf)
Cu(hfacac)2
THF
THF
THF
THF
THF
THF
79
64
44
23
15
95
76
30
22
30
99
82
86
84
74
22
93
80
74
76
73
46
23
77
62
53
2
76
72
78
72
75
79
85
82
85
N
1
NH
d
HN
CH2OH
COOMe
KOH,
CH3CN, r.t.
N
N
Cu(acac)2
Cu(hfacac)(btmsa)e
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(hfacac)2
N
3
4
2-MeTHFf
Et2O
Toluene
EtOAc
THF
THF
THF
THF
THF
O
9
N
10
11g
12h
13i
14j
15k
16l
17m
18m
HN
CH2OH
2
Cl
1,4-dioxane, rf.
COOMe
COOMe
NH
O
THF
THF
THF/EtOAc
HOH2C
L1
a
5 (1 mmol), Et2Zn (3 mmol), Cu salt (5.0 mol%), L1 (4.5 mol%), solvent (9 mL), r.t.,
Scheme 1. Facile synthetic route to C2-symmetric azolium salt L1 from serine ester.
3 h.
b
Determined by 1H-NMR analysis using 1-methylnaphthalene as the internal
standard.
c
2. Results and discussion
Determined by HPLC analysis.
d
e
f
Bis(hexafluoroacetylacetonato)copper(II).
[Bis(trimethylsilyl)acetylene](hexafluoroacetylacetonato)copper(I).
2-Methyltetrahydrofuran.
C2-symmetric azolium compound L1, which is the NHC ligand
precursor developed in our laboratory, was prepared by a three-
step synthesis from a natural amino ester (Scheme 1). The
reaction of serine methyl ester with bromoacetyl bromide or
chloroacetyl chloride afforded the corresponding ␣-bromo- or
␣-chloroacetamide derivative, 1 or 2, respectively, in almost
quantitative yield. The ester-amide group was attached to the
benzimidazole ring by reacting 1 with benzimidazole (3) in the
presence of KOH in CH3CN at room temperature. Subsequently, the
reaction of functionalized benzimidazole 4 with 2 afforded ben-
zimidazolium salt L1 in 71% yield. This synthetic approach offers
several advantages: (i) the starting materials are readily available;
(ii) all reaction conditions are simple; (iii) azolium ligand precursor
L1 is air-stable and easy to handle.
For the catalytic ACA, the reaction of chalcone (5) with Et2Zn
to afford 1,3-diphenylpentan-1-one (6) was selected as the model
reaction [6,8]. The performance of azolium salt L1 in the Cu-
catalyzed ACA was evaluated (Table 1). The reaction in the presence
of catalytic amounts of Cu(OTf)2 and L1 at room temperature
afforded (S)-6 in 79% yield and with 74% ee (entry 1). The use of
a Cu(I) salt, such as [Cu(CH3CN)4](OTf), resulted in almost same
enantioselectivity with a slightly lower yield (entry 2). Although the
reaction was catalyzed by Cu(hfacac)2 and L1 to afford (S)-6 with
moderate enantioselectivity (73% ee), the Cu precatalysts such as
Cu(acac)2 and Cu(hfacac)(btmsa) did not work efficiently (entries
3–5). The first promising result was achieved when the reaction
was performed with inexpensive Cu(NO3)2. Thus, a combination of
Cu(NO3)2 and L1 catalyzed the reaction of 5 with Et2Zn in THF at
ambient temperature to afford the corresponding adduct (S)-6 in
95% yield and with 77% ee (entry 6).
g
h
i
Catalyst loading Cu/L1 (4.5/4.5 mol%).
Catalyst loading Cu/L1 (6.0/4.5 mol%).
Catalyst loading Cu/L1 (4.0/4.5 mol%).
Catalyst loading Cu/L1 (6.0/3.0 mol%).
Reaction was conducted at 0 ◦C for 3 h.
Reaction was conducted at −20 ◦C for 3 h.
Reaction was conducted at −20 ◦C for 24 h.
j
k
l
m
biphenyl backbone promoted the conjugate addition of Et2Zn to 5.
In their catalytic system, the use of THF afforded the 1,4-adduct
with R configuration (99% ee), whereas the use of toluene afforded
the adduct with S configuration (92% ee) [6c]. In contrast, such a
reversal of enantioselectivity based on the solvent employed was
not observed in this catalytic system.
The effects of the copper/ligand ratio and catalyst loading on
the stereoselectivity of the reaction of 5 with Et2Zn in THF were
examined (entries 11–14). The reaction with a Cu/ligand ratio of
1:1, 1.3:1, and 2:1 occurred in a similar manner to afford the corre-
sponding adduct in 72% ee, 78% ee, and 75% ee, respectively (entries
11, 12, and 14). These results show that probably the same catalytic
active species were formed under these reaction conditions. The
decrease in the reaction temperature to −20 ◦C improved the enan-
tioselectivity (82–85% ee), even though the longer reaction time
was needed (entries 16 and 17). At −20 ◦C, 5 reacted with Et2Zn in
the presence of catalytic amounts of Cu(hfacac)2 and L1 to afford
(S)-6 in 80% yield and with good enantioselectivity (85% ee) (entry
18).
With the encouraging results obtained using C2-symmetric
azolium ligand precursor L1, a series of NHC-based ligands were
screened (Tables 2 and 3). The chiral ligands evaluated in this study
are ester-amide-functionalized azolium salts L1–L6 derived from
serine, leucine, or tert-leucine (Scheme 2).
First, the enantiomer of benzimidazolium salt ent-L1 was pre-
pared from commercially available D-serine methyl ester by a
similar procedure used for L1 (Scheme 1). The Cu-catalyzed con-
jugate addition reaction of 5 with Et2Zn under the influence of
ent-L1 proceeded in a similar manner as the reaction under L1 to
The solvent effect was also examined. Other ethereal solvents
such as 2-methyltetrahydrofuran and diethyl ether afforded (S)-6
with difficulty (entries 7 and 8). The reaction using a nonpolar sol-
vent such as toluene significantly decreased the enantioselectivity
(only 2% ee), whereas the enantioselectivity of the reaction in a
polar solvent such as EtOAc was similar to that in THF (entries 9 and
10). Recently, Zhang and co-workers reported that the combination
of Cu(OAc)2 and phosphoramidite ligands bearing a D2-symmetric

68
J. Kondo et al. / Journal of Molecular Catalysis A: Chemical 395 (2014) 66–71
Table 2
and L4, respectively, were selected. The reaction of 5 with Et2Zn
catalyzed by Cu(NO3)2 and L3 afforded (S)-6 in 99% yield and
with moderate enantioselectiviy (52% ee) (entry 4). Almost similar
result was obtained in the case of the reaction under the influ-
ence of L4 (45% ee) (entry 5). The pincer-type ligands act as tightly
coordinating polydentate ligands and provide C2-symmetric and
meridional environment around the metal center [11]. Therefore,
the metal complex of the pincer ligand such as L1 may become a
suitable catalyst to recognize the prochiral face of a substrate rather
than L3 or L4. Additionally, the ACA reaction of several chalcone
derivatives with Et2Zn by the Cu(NO3)2/L1 catalytic system was
investigated (entries 6–8). Unfortunately, however, the product
yields and enantioselectivities were slightly lowered under these
reaction conditions, respectively.
Encouraged by the results using C2-symmetric chiral NHC ligand
L1 derived from natural amino acid such as serine (Tables 1 and 2),
we next investigated the structurally similar azolium ligand pre-
cursors L5 and L6 prepared from commercially available chiral
␣-amino ester, leucine and tert-leucine, respectively (Scheme 2 and
Table 3).
Evaluation of chiral azolium ligands L1–L4 derived from serine ester in the
Cu(NO3)2-catalyzed reaction of 5 with Et2Zn to afford (R)- or (S)-6.a
Entry
Azolium salt
Yield (%)b
Ee (%)b
1
L1
ent-L1
L2
L3
L4
L1
L1
L1
95
92
87
99
99
63
63
60
77 (S)
76 (R)
68 (S)
52 (S)
45 (S)
80 (S)
76 (S)
67 (S)
2c
3
4
5
6d
7e
8f
a
5 (1 mmol), Et2Zn (3 mmol), Cu(NO3)2 (5.0 mol%), azolium salt (4.5 mol%), THF
(9 mL), r.t., 3 h.
b
See Table 1 b and c.
c
Azolium ligand precursor was prepared from D-serine methyl ester.
Result for the reaction of 4-chlorochalcone yielding (S)-3-(4-chlorophenyl)-1-
d
phenylpentan-1-one.
e
Result for the reaction of 4ꢀ-chlorochalcone yielding (S)-1-(4-chlorophenyl)-3-
phenylpentan-1-one.
f
Result for the reaction of 4-methoxychalcone yielding (S)-3-(4-
methoxyphenyl)-1-phenylpentan-1-one.
The replacement of the hydroxymethyl group (azolium L1)
to isobutyl group (azolium L5) at the stereogenic center on the
NHC side-arm decreased the enantioselectivity (18% ee) in the
Cu-catalyzed conjugate addition of Et2Zn to 5 (Table 3, entry 1).
Although the use of more sterically hindered tert-butyl group
(azolium L6) slightly improved the stereoselectivity (36% ee), the
conjugate adduct was obtained in a very low yield (8%) (entry 2).
Table 3
Further investigations on the Cu-catalyzed ACA of Et2Zn to 5 under the influence of
azolium salts L5–L7 to afford (R)- or (S)-6.a
Entry
Cu salt
Azolium
Yield (%)b
Ee (%)b
1
2
3
4
Cu(NO3)2
Cu(NO3)2
Cu(NO3)2
Cu(OTf)2
[Cu(CH3CN)4](OTf)
[Cu(CH3CN)4](OTf)
[Cu(CH3CN)4](OTf)
L5
L6
L7
L7
L7
L7
L7
65
8
18 (S)
36 (S)
37 (S)
7 (S)
26 (S)
74 (S)
56 (S)
70
41
26
98
87
We previously designed and synthesized
a C2-symmetric
bis(hydroxy-amide)-functionalized benzimidazolium salt L7 from
a chiral ␤-amino alcohol such as tert-leucinol that could be pre-
pared easily by the reduction of tert-leucine [11a]. When 5 was
reacted with Et2Zn catalyzed by Cu(NO3)2 and L7 in THF at room
temperature, the desired product (S)-6 was obtained in 70% yield
(Table 3, entry 3). The enantioselectivity obtained using L7 was
comparable to that obtained using L6 (entry 2 vs. entry 3). After
several experiments, we were pleased to find that the use of L7
increased the enantioselectivity of the ACA reaction (entry 6). The
treatment of 5 with Et2Zn in the presence of catalytic amounts
of [Cu(CH3CN)4](OTf) and L7 at room temperature afforded (S)-6
in 98% yield and with good enantioselectivity (74% ee). However,
lowering the reaction temperature to −20 ◦C decreased the enan-
tioselectivity (entry 7). This is in contrast to the result of the reaction
using Cu(NO3)2/L1 catalytic system where a high enantioselectiv-
ity was achieved (up to 85% ee) in the conjugated addition reaction
at −20 ◦C (Table 1, entries 16–18).
5
6c
7c,d
a
5 (1 mmol), Et2Zn (3 mmol), Cu salt (5.0 mol%), azolium salt (4.5 mol%), THF
(9 mL), r.t., 3 h.
b
See Table 1 b and c.
c
Et2Zn (4 mmol), [Cu(CH3CN)4](OTf) (4.0 mol%), azolium salt (6.0 mol%), 2-
MeTHF (6 mL).
d
Reaction was conducted at −20 ◦C for 24 h.
afford (R)-6 in 92% yield and with 76% ee (Table 2, entries 1 and
2). The replacement of the methyl ester (azolium ligand L1) by
an ethyl ester (azolium ligand L2) slightly decreased the yield and
enantioselectivity (entry 3).
It is important to highlight the greater selectivity of the C2-
symmetric ligand such as bis(ester-amide)-functionalized azolium
salt L1 than that of the chiral ligand precursor with both the ester-
amide and alkyl functional groups on the azolium ring. Two azolium
ligand precursors with N-methyl and N-benzyl substituents, L3
Finally, to evaluate the substrate scope and limitations of the
developed catalytic reaction, a set of seven ␣,␤-unsaturated enones
was investigated regarding the effect of the structural differences
of the substrates on the product yield and enantioselectivity. To
demonstratethe versatilityof bis(ester-amide)-functionalizedNHC
ligand precursor L1, two catalytic systems were selected as follows:
Method A: the combination of Cu(NO3)2 and L1; Method B: the
combination of Cu(hfacac)2 and L1 (Table 4).
These catalytic systems were suitable for the 1,4-addition reac-
tion of benzalacetone (7). The reaction of 7 with Et2Zn in the
presence of catalytic amounts of Cu(NO3)2 and L1 in THF at room
temperature afforded (S)-4-phenylhexan-2-one in 86% yield and
with 85% ee (entry 1). The facial selectivity of the addition of the
alkylating reagent to 7 was similar to that observed in the reaction
of 5 with Et2Zn as shown in Table 1. Almost the same result was
obtained when the reaction of 7 with Et2Zn was performed using
Cu(hfacac)2/L1 catalytic system (entry 2).
O
N
O
HN
R2
R1
N
N
Cl
R3
HN
R2
N
Cl
NH
R5
R4
O
R1
L1, L2, L5, L6, L7
L3, L4
From serine ester
L1 (R1=CH2OH, R2=COOMe)
L3 (R3=CH2OH, R4=COOMe, R5=Me)
L4 (R3=CH2OH, R4=COOMe, R5=Bn)
L2 (R1=CH2OH, R2=COOEt)
From leucine, tert-leucine and tert-leucinol
L5 (R1=iBu, R2=COOMe)
L6 (R1=tBu, R2=COOMe)
An excellent ee value of 93% was obtained when 3-nonen-2-one
(8) was reacted with Et2Zn catalyzed by Cu(NO3)2 and L1 to afford
(R)-4-ethylnonan-2-one (entry 3). Similar enantioselectivity (92%
ee) was achieved in the Cu(hfacac)2-catalyzed reaction (entry 4).
L7 (R1=tBu, R2=CH2OH)
Scheme 2. List of chiral azolium ligand precursors.

J. Kondo et al. / Journal of Molecular Catalysis A: Chemical 395 (2014) 66–71
69
Table 4
ACA reaction of acyclic and cyclic enones.a
N
N
N
N
R
R
Entry
Enone
Method
Yield (%)
86
Ee (%)
85
steric
O
O
Cu
Cu
N
N
repulsion
Et
Et
1b
A
R'
R'
O
O
Ph
Zn
Zn
O
O
2b
3b
7
B
A
90
99
85
93
(R'=CO2Et)
(favored)
Ln
Ln
A
B (disfavored)
Scheme 3. Proposed reaction modes.
4b
8
8
B
A
91
92
80
5c,d
17e
for both acyclic and cyclic enones has been rarely reported. 2-
Cyclohexen-1-one (10) efficiently underwent the 1,4-addition with
Et2Zn catalyzed by Cu(NO3)2/L1 catalytic system in THF at room
temperature to afford (R)-3-ethylcyclohexanone in 98% yield and
with 71% ee (entry 8). Previously, we have shown that the Cu-
catalyzed conjugate addition of Et2Zn to cyclic enone 10 under the
influence of the C2-symmetric bis(hydroxy-amide)-functionalized
azolium ligand precursor L7 afforded the corresponding (S)-adduct
[10a]. Thus, the facial selectivities of the 1,4-addition reaction of
cyclic enone catalyzed by (ester-amide)-functionalized NHC ligand
L1 were found to be reversed compared to that of the reaction cat-
alyzed by (hydroxy-amide)-functionalized NHC ligand L7. These
are in contrast to the results obtained in the reaction of acyclic enone
5 catalyzed by L1 or L7, where no switching enantioselectivity was
observed (Table 2, entry 1 vs. Table 3, entry 6). At this stage we have
no explanation of this interesting difference between cyclic enone
and acyclic enone. Further investigations are currently ongoing.
The reaction of 4,4-dimethyl-2-cyclohexen-1-one (11) pro-
ceeded slowly probably because of the steric hindrance of the
substrate, affording the corresponding conjugate adduct in a poor
yield, but with a relatively good enantioselectivity (86% ee) (entry
10). A prolonged reaction time afforded the 1,4-adduct in a moder-
ate yield (57%) without any loss of the enantioselectivity (entry 11).
The reaction with a cyclic enone comprising a seven-membered
ring such as 2-cyclohepten-1-one (12) slightly increased the enan-
tioselectivity of the reaction than that of the reaction of 10 (entry
14). The use of method B in the reaction of 12 with Et2Zn afforded
(R)-3-ethylcycloheptanone in a moderate yield (78%) and with good
enantioselectivity (80% ee) (entry 14). 2-Cyclopenten-1-one (13)
reacted with Et2Zn with difficulty catalyzed by this catalytic sys-
tem (entry 15). The conformations of the five-membered ring differ
from those of the six- and seven-membered rings, and there are two
puckered conformations such as the envelope and half-chair for the
five-membered ring [12]. Hence, the lower enantioselectivity in the
asymmetric addition reaction of 13 with Et2Zn may be caused by
the conformational differences between the five-membered ring
and six- or seven-membered ring.
6
7
A
B
76
89
77
86
9
8
9
A
B
98
99
71
71
10
10
A
17e
86
11d
12
11
11
A
B
57e
20e
85
84
13
A
95e
78e
71
14
15
12
B
A
80
51
f
–
a
Method A: Enone (1 mmol), Et2Zn (3 mmol), Cu(NO3)2 (5.0 mol%), L1 (4.5 mol%),
THF (9 mL), r.t., 3 h; Method B: Cu(hfacac)2 (5.0 mol%), L1 (4.5 mol%), THF/AcOEt
(4.5/4.5 mL), r.t., 3 h; Yield of the conjugate adduct was determined by GLC analysis.
b
Data taken from Ref. [10b].
Me2Zn in place of Et2Zn was used.
The reaction was conducted for 24 h.
Isolated yield.
c
d
e
f
Owing to the volatility and low yield of the reaction product, the correct yield
We speculated that the present Cu-catalyzed 1,4-addition reac-
tion of chalcone with Et2Zn might proceed through the formation
of an anionic amidate/NHC–Cu species as an intermediate. The pro-
posed reaction modes in the ACA reaction are shown in Scheme 3.
A copper ate complex A involving a carbene, amidate, and ethyl
group, might be generated. An enone would be envisioned to coor-
dinate by approaching from the front side because of the steric
repulsion of the stereodirecting group such as ethoxycarbonyl
group on the backside. In addition, the formation of a zinc alkolate
from the hydroxy group initially on the azolium precursor would
facilitate the coordination of the enone by an interaction between
the carbonyl group of enone and zinc species. Consequently, an
ethyl group would be added to the enone from the backside as
shown in A. In contrast, model B would lead to a conjugate adduct
with an opposite configuration. In structural model B, however,
could not be determined.
Notably, these high enantioselective reactions were carried out at
room temperature without temperature control. However, unfor-
tunately, Me2Zn was difficult to add to 8 by this catalytic system
probably due to the lower nucleophilicity of the alkylating reagent,
and the starting materials were recovered almost unchanged (entry
5). The conjugate addition reaction of 5-methyl-3-hexen-2-one (9)
with Et2Zn using method B afforded better result than the reaction
using method A (entries 6 and 7). Thus, (S)-4-ethyl-5-methylhexan-
2-one was synthesized in 89% yield and with 86% ee (entry 7).
A potential application of the NHC–Cu catalytic system was
investigated in the ACA of cyclic enones with dialkylzinc (Table 4,
entries 8–15). As mentioned above, an efficient catalytic system

70
J. Kondo et al. / Journal of Molecular Catalysis A: Chemical 395 (2014) 66–71
there would be significant steric repulsion between the side-arm
on the NHC ring and phenyl substituent of chalcone. Consequently,
the ACA reaction would be expected to proceed via reaction model
A to produce (S)-1,4-adduct.
(OCH2CH3), 55.2 (CH2CO), 48.4 (NHCH), 14.0 (OCH2CH3). Anal. Calc.
for C21H29ClN4O8·1.2H2O: C, 48.27; H, 6.06; N, 10.72. Found: C,
48.00; H, 5.75; N, 10.82%.
4.2.2. Compound L5
White solid. mp 190.8–192.9 ◦C. 1H NMR ((CD3)2SO): ı 9.84 (s,
1H, CHbenzimid), 9.38 (br, 2H, NH), 7.90–7.87 (m, 2H, CHbenzimid),
7.70–7.68 (m, 2H, CHbenzimid), 5.54 (d, J = 16.5 Hz, 2H, CH2CO), 5.46
(d, J = 16.5 Hz, 2H, CH2CO), 4.32–4.26 (m, 2H, NHCH), 3.60 (s, 6H,
3. Conclusion
We demonstrated that
a C2-symmetric bis(ester-amide)-
functionalized azolium salt efficiently performs the copper-
catalyzed ACA of dialkylzinc reagents to acyclic or cyclic enones, with
up to 93% ee. These air-stable, chiral ligands are particularly use-
ful because of their easy preparation. In addition, the asymmetric
catalytic reaction was carried out at ambient temperature without
controlling the temperature of the reaction mixture. We believe the
preset catalytic system provides an alternative method for catalytic
ACA reaction.
i
OCH3), 1.75–1.51 (m, 6H, CH2CH Bu), 0.91 (d, J = 6.4 Hz, 6H, CH3
iBu), 0.84 (d, J = 6.4 Hz, 6H, CH3 iBu). 13C NMR: ı 172.3 (CO), 164.8
(CO), 144.3, 131.1, 126.7, 113.6, 52.0 (CH2CO), 50.8 (CH3O), 48.3
(NHCH), 24.2 (CH iBu), 22.7 (CH2 iBu), 21.2 (CH3 iBu). Anal. Calc. for
C
26H39ClN4O6·2.2H2O: C, 53.96; H, 7.56; N, 9.68. Found: C, 53.56;
H, 6.67; N, 10.11%.
4.2.3. Compound L6
White solid. mp 169.6–170.5 ◦C. 1H NMR ((CD3)2SO): ı 9.88 (s,
1H, CHbenzimid), 9.21 (br, 2H, NH), 7.93–7.91 (m, 2H, CHbenzimid),
7.69–7.67 (m, 2H, CHbenzimid), 5.65 (d, J = 16.5 Hz, 2H, CH2CO), 5.55
(d, J = 16.5 Hz, 2H, CH2CO), 4.14 (d, J = 8.2 Hz, 2H, NHCH), 3.61 (s, 6H,
OCH3), 0.99 (s, 18H, CH3 tBu). 13C NMR: ı 170.9 (CO), 165.0 (CO),
144.3, 131.1, 126.7, 113.5, 61.2 (CH2CO), 51.5 (CH3O), 48.3 (NHCH),
33.7 (C tBu), 26.5 (CH3 tBu). Anal. Calc. for C26H39ClN4O6·2H2O: C,
54.30; H, 7.54; N, 9.74. Found: C, 54.16; H, 7.21; N, 9.82%.
4. Experimental
4.1. General procedures
All chemicals were obtained from commercial sources and were
used as received. 1H and 13C NMR spectra were recorded on spec-
trometers at 400 and 100 MHz, respectively. Chemical shifts were
reported in ppm relative to TMS for 1H and 13C NMR spectra. CDCl3,
CD3OD, and (CD3)2SO were used as the NMR solvent. Thin-layer
chromatography (TLC) analysis was performed with glass-backed
plates pre-coated with silica gel and examined under UV (254 nm)
irradiation. Flash column chromatography was executed on silica
gel 60 (230–400; particle size: 0.040–0.063 nm).
4.3. General procedure for Cu-catalyzed asymmetric reaction of
enone with Et2Zn
To a solution of azolium salt (0.045 mmol) in THF (9 mL) were
added Cu(NO3)2·5H2O (0.050 mmol) and enone (1 mmol). After the
mixture was cooled to 0 ◦C, Et2Zn (3 mmol, 1 mol/L in hexanes,
3 mL) was added to the reaction vessel. The color immediately
changed from yellow to dark brown. After stirring at room tem-
perature for 3 h, the reaction was quenched with 10% HCl aq. The
resulting mixture was extracted with diisopropyl ether (3 × 10 mL)
and dried over Na2SO4. The product was purified by silica gel col-
umn chromatography (hexane/Et2O). The enantiomeric excess was
measured by the chiral GLC or chiral LC (See Appendix A. Supple-
mentary data).
4.2. General procedure for preparation of azolium salt
To CH3CN (8 mL) were added KOH (5.9 mmol, 331 mg), benzimi-
dazole (3) (3.7 mmol, 437 mg) and ␣-bromoacetamide derivative 1
(3.7 mmol, 888 mg) derived from bromoacetyl bromide and serine
methyl ester. After stirring the reaction mixture at room temper-
ature for 16 h, H2O was added to form a white precipitate. The
white product was separated from the solution by filtration under
reduced pressure, and then the solid was dissolved in methanol.
The resulting solution was dried over Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure to obtain the
desired product such as substituted benzimidazole derivative 4.
The product 4 could be used without further purification in the
next step. Then, to 1,4-dioxane (15 mL) were added 4 (0.5 mmol,
139 mg) and ␣-chloroacetamide 2 (0.5 mmol, 98 mg) derived from
chloroacetyl chloride and serine methyl ester. After stirring the
reaction mixture at 110 ◦C for 2 days, the solvent was removed
under reduced pressure. The residue was dissolved in methanol,
and then activated carbon (ca. 1 g) was added. After 16 h, the
activated carbon was removed by filtration. After removing the
methanol in vacuo from the filtrate, the crude residue was puri-
fied by column chromatography (SiO2, CH2Cl2/MeOH = 9/1) to yield
the corresponding azolium salt L1. Compound L1 [10b], L3 [9d], L4
[9d] and L7 [10a] were reported previously (See Supporting infor-
mation).
Acknowledgment
This work was financially supported by a Grant-in-Aid for Scien-
tific Research (C) (23550128) from Japan Society for the Promotion
of Science (JSPS).
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2014.08.006.
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