Hydroxy-amide functionalized azolium salts for Cu-catalyzed asymmetric conjugate addition: Stereocontrol based on ligand structure and copper precatalyst

Article abstract of DOI:10.1021/jo300472r

A series of hydroxy-amide functionalized azolium salts have been designed and synthesized for Cu-catalyzed asymmetric conjugate addition reaction. The (CH₂)₂-bridged hydroxy-amide functionalized azolium ligand precursors 2, in addition to the previously reported CH₂-bridged azolium salts 1, have been prepared from readily available enantiopure β-amino alcohols. The combination of a Cu species with 1 or 2 efficiently promoted the 1,4-addition reaction of cyclic enones with dialkylzincs. For example, the reaction of 2-cyclohepten-1-one (17) with Bu₂Zn in the presence of catalytic amounts of Cu(OTf)₂ and 1 gave (S)-3-butylcycloheptanone (20) in 99% yield and 96% ee. On the other hand, when the reaction was carried out under the influence of Cu(OTf)₂ combined with 2, (R)-20 in preference to (S)-20 was obtained in 98% yield and 80% ee. In this manner, the enantioselecvity was switched by controlling the structure of chiral ligand. Additionally, the reversal of enantioselectivity was also achieved by changing the Cu precatalyst from Cu(OTf)₂ to Cu(acac)₂ with the same ligand. The combination of Cu(acac) ₂ with CH₂-bridged azolium salt 1 in the reaction of 17 with Bu₂Zn led to formation of (R)-20 as a major product in 55% yield and 80% ee. This result was in contrast to the Cu(OTf)₂/1 catalytic system, where the 1,4-adduct with opposite configuration was obtained. Moreover, use of the Cu(acac)₂/2 catalytic system produced (S)-20, while (R)-20 was formed by the Cu(OTf)₂/2 catalytic system. Thus, it was found that either varying the linker of the chiral ligands or changing the counterion of Cu species between a OTf and acac ligand initially on the metal led to dual enantioselective control in the 1,4-addition reaction.

Full text of DOI:10.1021/jo300472r

Article
pubs.acs.org/joc
Hydroxy-amide Functionalized Azolium Salts for Cu-Catalyzed
Asymmetric Conjugate Addition: Stereocontrol Based on Ligand
Structure and Copper Precatalyst
Naoatsu Shibata, Misato Yoshimura, Haruka Yamada, Ryuichi Arakawa, and Satoshi Sakaguchi*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564-8680, Japan
S
* Supporting Information
ABSTRACT: A series of hydroxy-amide functionalized
azolium salts have been designed and synthesized for Cu-
catalyzed asymmetric conjugate addition reaction. The
(CH2)2-bridged hydroxy-amide functionalized azolium ligand
precursors 2, in addition to the previously reported CH2-
bridged azolium salts 1, have been prepared from readily
available enantiopure β-amino alcohols. The combination of a
Cu species with 1 or 2 efficiently promoted the 1,4-addition
reaction of cyclic enones with dialkylzincs. For example, the
reaction of 2-cyclohepten-1-one (17) with Bu2Zn in the
presence of catalytic amounts of Cu(OTf)2 and 1 gave (S)-3-
butylcycloheptanone (20) in 99% yield and 96% ee. On the other hand, when the reaction was carried out under the influence of
Cu(OTf)2 combined with 2, (R)-20 in preference to (S)-20 was obtained in 98% yield and 80% ee. In this manner, the
enantioselecvity was switched by controlling the structure of chiral ligand. Additionally, the reversal of enantioselectivity was also
achieved by changing the Cu precatalyst from Cu(OTf)2 to Cu(acac)2 with the same ligand. The combination of Cu(acac)2 with
CH2-bridged azolium salt 1 in the reaction of 17 with Bu2Zn led to formation of (R)-20 as a major product in 55% yield and
80% ee. This result was in contrast to the Cu(OTf)2/1 catalytic system, where the 1,4-adduct with opposite configuration was
obtained. Moreover, use of the Cu(acac)2/2 catalytic system produced (S)-20, while (R)-20 was formed by the Cu(OTf)2/2
catalytic system. Thus, it was found that either varying the linker of the chiral ligands or changing the counterion of Cu species
between a OTf and acac ligand initially on the metal led to dual enantioselective control in the 1,4-addition reaction.
features that make NHCs a very interesting class of ligands is
the easy access to their ligand precursors (mostly azolium salts).
The azolium salts are very easy to functionalize often by simple
reactions that allow the introduction of manifold of N-sub-
stituents (or wingtips). Thus, numerous functionalized azolium
salts have been developed so far.4,6
INTRODUCTION
■
The selection of either enantiomer via transition-metal-
catalyzed asymmetric reaction is typically achieved by preparing
both enantiomers of a chiral ligand.1 For the preparation of the
chiral ligand, chiral induction may often be realized by using
chiral molecules of natural origin such as amino acids. However,
in some cases where the ligand is a natural product or derived
from a natural product, the necessary antipodes may not be
easily available. From a single chiral source, the reversal of
enantioselectivity of a reaction has been achieved so far by
design and control of the ligand structure. However, the
preparation of both enantiomers of a target molecule using a
single ligand derived from a natural product remains a chal-
lenging endeavor.2
Recently, we designed and synthesized the CH2-bridged
hydroxy-amide functionalized azolium salt 1 shown in Scheme 1.
Scheme 1. Ligand Design
The Cu-catalyzed 1,4-addition of organometallic reagents to
α,β-unsaturated compounds is a powerful method for the
efficient construction of carbon−carbon bonds. In the past
decade, catalytic asymmetric conjugate addition reactions with
high enantioselectivities have been successfully achieved by
using a variety of chiral ligands.3 Among the growing number of
the chiral ligands, N-heterocyclic carbenes (NHCs) have been
recognized as useful ligands since the first publications by
Alexakis and Mangeney in 2001.4,5 One of the most attractive
Received: March 4, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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Compound 1 acts as a chelating ligand with a carbene unit and
a second coordinating group on the side arm at NHC. This
combination generates a strongly coordinating polydentate
ligand that can lock stereodirecting functional groups in a fixed
conformation. Thus, Pd-catalyzed intermolecular Heck-type
couplings7 as well as Ir-catalyzed hydrosilane reduction of
ketones8 with high enantioselectivities (over 90% ee) have been
developed. In addition, the functionalized azolium salt 1 was
tested in the Cu-catalyzed asymmetric conjugate addition of
dialkylzincs to cyclic enones.9 Interestingly, the reversal of
enantioselectivity with the same ligand could be achieved by
changing the Cu precatalyst from Cu(OTf)2 to Cu(acac)2.
Encouraged by this success, we have now designed (CH2)2-
bridged hydroxy-amide functionalized azolium salt 2 for
asymmetric conjugate addition reaction (Scheme 1). We as-
sumed that a metal chelate generated from chiral ligand
precursor 2 would differ from a species generated from 1. This
might cause changing of the highly hindered face that would
block approach of the reaction substance. It was found that in
comparison with the product that was obtained in the 1,4-
addition reaction by Cu(OTf)2 combined with 1, the
combination of Cu(OTf)2 and 2 led to the formation of the
1,4-adduct with opposite configuration. Additionally, dual
enantioselective control of the 1,4-addition reaction with the
ligand precursor 2 was achieved by changing the Cu precatalyst
from Cu(OTf)2 to Cu(acac)2. Now, we have synthesized a
series of azolium compounds 2a−m having the N-hydroxy-
amide functional groups with the (CH2)2 linker and studied the
influence of the structure of the ligand and the Cu precatalyst
on the stereoselective induction for optimization of the con-
jugate addition reaction. Herein, we describe the systematic
studies of the dependence of reaction stereocontrol on the
ligand structure and Cu precatalyst.
chloride in place of chloroacetyl chloride failed due to the
formation of the corresponding acryl amide derivative. There-
fore, we proposed an alternative synthetic route to azolium com-
pound 2 (route b). The first step involved the formation of
hydroxy-amide functionalized azole derivative 7 by reacting 3 with
ester 6, which was synthesized in quantitative yield through an aza-
Michael reaction between methyl acrylate and benzimidazole.11
Subsequent treatment of 7 with an alkyl halide yielded the desired
(CH2)2-bridged hydroxy-amide functionalized azolium salt 2.
Scheme 3 summarizes the results of the preparation of
the desired azolium compounds, namely, 2a−2m, and their
Scheme 3. Preparation of Ligand Precursors 2
RESULTS AND DISCUSSION
■
Synthesis of Hydroxy-amide Functionalized Azolium
Salt 2. Due to increasing economic and ecological pressure, the
development of a readily accessible chiral ligand that can be
prepared from a commercially available chiral source via one- or
two-step syntheses has become important.10 As we have de-
scribed previously, the CH2-bridged hydroxy-amide functional-
ized azolium ligand precursor 1 could be prepared by coupling
reaction between N-alkylbenzimidazole 5 and α-chloroacetamide
derivative 4, which was prepared from chloroacetyl chloride and
enantiopure β-amino alcohol 3 (Scheme 2, route a).7c However,
Scheme 2. Facile Route to Azolium Ligand Precursors 1 and
2 from Enantiopure β-Amino Alcohol 3
intermediates, namely, 7a−7h. We were also interested in the
influence of the counterion of the azolium ligand on the stereo-
selectivity of the 1,4-addition reaction. Therefore, azolium halides
2i−2k were prepared by coupling of 7d with benzyl chloride,
bromide, and iodide, respectively. Thus, a series of (CH2)2-bridged
hydroxy-amide functionalized azolium salts 2a−2m having both
an alkyl group at the stereogenic center and a methyl or benzyl
substituent at the azolium ring could be obtained in two steps
from commercially available β-amino alcohols 3.
Cu-Catalyzed Asymmetric Conjugate Addition Reac-
tion. To test the possibility of achieving an asymmetric
conjugate addition by using the chiral ligand precursor, we
i
chose azolium salt 2i (R1 = Bu, R2 = Bn), prepared from (S)-
leucinol, for the reaction of 2-cyclohexen-1-one (8) with Et2Zn
catalyzed by a Cu salt. To compare the relative abilities between
(CH2)2-bridged azolium salt and CH2-bridged azolium salt, the
attempts to prepare the (CH2)2-bridged hydroxy-amide
functionalized azolium salt 2 by the use of 3-chloropropionyl
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results of the reaction employing 1i (R1 = iBu, R2 = Bn) are also
listed in Table 1 as entries 1 and 2. The treatment of 8 with
Table 2. Evaluation of Various Azolium Ligands 2 for
Cu(OTf)2- or Cu(acac)2-Catalyzed 1,4-Addition Reaction of
a
8 with Et2Zn
Table 1. Initial Studies on Stereocontrol Based on Ligand
Structure and Cu Precatalyst in 1,4-Addition Reaction
with Cu(acac)2 method
a
b
with Cu(OTf)2 method A
B
entry
azolium
yield (%)
ee (%)
yield (%)
ee (%)
1
2a
2b
2c
2d
2e
2f
96
99
99
95
78
94
70
90
99
92
91
76
87
39 (R)
45 (R)
44 (R)
47 (R)
47 (R)
58 (R)
12 (R)
33 (R)
61 (R)
58 (R)
60 (R)
46 (R)
66 (R)
44 (R)
77
93
71
98
5
80 (S)
82 (S)
57 (S)
72 (S)
3 (S)
2
3
4
5
6
11
60
73
16
19
91
93
3
7 (R)
azolium salt (R1, R2,
X)
yield
(%)
7
2g
2h
2i
66 (S)
59 (S)
60 (S)
72 (S)
65 (S)
78 (S)
entry Cu catalyst
method
ee (%)
8
b
9
1
2
3
4
5
Cu(OTf)2
Cu(acac)2
Cu(OTf)2
Cu(acac)2
Cu(acac)2
1i (iBu, Bn, Cl)
A
A
A
A
B
99
69
99
92
91
81 (S)
41 (R)
61 (R)
24 (S)
65 (S)
bc
,
10
11
12
13
14
2j
1i
2i (iBu, Bn, Cl)
2k
2l
c
c
2i
2i
2m
c
10i
46
8
32 (R)
a
8 (1 mmol), Et2Zn (3 mmol), Cu precatalyst (6 mol %), azolium salt
a
b
c
See Table 1, footnote a. With Cs2CO3 (8 mol %). Structure:
(4.5 mol %), THF (9 mL), rt, 3 h. Method A: to a solution of Cu
precatalyst and azolium salt in THF, 8 was added first, then Et2Zn.
Method B: Et2Zn was added first, then 8. Yields were determined by
b
GLC using an internal standard technique. Previously reported data
c
(see ref 9b). With Cs2CO3 (8 mol %).
Et2Zn in THF in the presence of catalytic amounts of
Cu(OTf)2 and 2i afforded 3-ethylcyclohexanone (9) in almost
quantitative yield (entry 3). It is worth noting that the use of
azolium ligand 2i, whose sole difference is the (CH2)2 linker,
produced (R)-9 (61% ee) in preference to (S)-9, while (S)-9
(81% ee) was obtained with Cu(OTf)2 combined with azolium
ligand 1i (entry 1 vs entry 3). In this manner, enantioselectivity
was reversed by controlling the structure of the chiral ligand.12
As mentioned in the Introduction, switching the stereo-
selectivity in the conjugate addition reaction using the azolium
ligand 1 was achieved by simply changing the Cu precatalyst
from Cu(OTf)2 to Cu(acac)2 (Table 1, entries 1 vs 2).9 It was
also found that a similar reversal of enantioselectivity occurred
by changing the Cu precatalyst with azolium salt 2. When the
reaction of 8 with Et2Zn was carried out under the influence of
Cu(acac)2 combined with 2i in the presence of Cs2CO3, (S)-9
instead of (R)-9 was formed with a 24% ee (entry 4). The effect
of additives such as Cs2CO3 in the Cu(acac)2-catalyzed reaction
will be described later (Table 3). Additionally, it was found that
the order of substrate addition influenced this reaction.13 Slightly
better enantioselectivity (65% ee) was obtained by first adding the
R2Zn and then the enone (entry 5). Thus, it can be said from the
results in Table 1 that dual enantioselective control was achieved
not only through the structural modification of the chiral ligand
but also through a change of Cu precatalyst. Moreover, one of the
most attractive features of this reaction is that it can be carried out
at ambient temperature without temperature control.
Figure 1. Screening of various azolium ligands 2 in the Cu(OTf)2-
catalyzed conjugate addition reaction of 8 with Et2Zn (front) or the
Cu(acac)2-catalyzed conjugate addition reaction of 8 with Et2Zn
(back). Data are shown in Table 2.
Clearly, the increase in the steric demand of the alkyl sub-
stituent on the ligand led to improved enantioselectivites.
Compound 2f, having a sterically hindered tert-butyl group,
efficiently produced (R)-9 in 94% yield and 58% ee (Table 2
entry 6 and Fugure 1). We were also interested in the influence
of the counterion of the azolium ligand on the stereoselectivity
of the 1,4-addition reaction. It was found that the yield and
stereoselectivity obtained by the Cu(OTf)2-catalyzed conjugate
addition reaction using 2i was very similar to those obtained by
using 2j or 2k (entries 9−11). The ligand screening test also
revealed that replacement of the methyl with a benzyl sub-
stituent on the azolium ring, which is far from the stereogenic
center of the chiral ligand, led to a marked increase in
enantioselectivity (entry 4 vs entry 11). Thus, we designed and
synthesized azolium ligand 2m with (S)-tert-leucinol and benzyl
iodide. As expected, 8 was reacted with Et2Zn under the
The easy access to the hydroxy-amide functionalized azolium
ligand precursors 2 allowed us to synthesize a series of
derivatives to optimize the reaction. Table 2 and Figure 1 show
the representative results of the 1,4-addition reaction of 8
with Et2Zn with the Cu(OTf)2/2 catalytic system and the
Cu(acac)2/2 catalytic system with different ligand derivatives.
First, we studied the Cu(OTf)2 catalyst system. To investigate the
effect of the stereodirecting group in the chiral ligand, we screened
several azolium chlorides 2a−2h (entries 1−8, left column).
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influence of Cu(OTf)2 in combination with 2m to afford (R)-9
with 66% ee (entry 13).
Cs2CO3 proceeded with some difficulty to afford (S)-9 in 62%
yield and 74% ee (entry 1). Almost all of the bases except for
Na2CO3 promoted the reaction rate (entries 2−12). Addition-
ally, we found that the 1,4-addition of Et2Zn to 8 could also be
catalyzed by bis(8-quinolinato)Cu(II), which has similar
chelation to Cu(acac)2 (entry 13). Advantageously, the reaction
with the bis(8-quinolinato)Cu(II)/2b catalytic system pro-
ceeded even in the absence of a base (entry 1 vs entry 13).
Finally, we studied the scope and the limitations of the
reaction protocol (Table 4). Despite an excellent yield, the
Next, we focused on the Cu(acac)2/2 catalytic system that
produced (S)-configured product 9 (Table 2, right column). In
contrast to the Cu(OTf)2/2 catalytic system, the results of the
reaction with a series of azolium halides 2a−2h indicated an
unusual relationship between the steric factor of the ligand and
the enantioselectivity of the reaction (Table 2 entries 1−8 and
Figure 1). Decreased steric bulkiness of the alkyl substituent at
the ligand led to greater enantioselectivity. For instance,
azolium salts 2a and 2b, having a methyl and an ethyl group
at the stereogenic center, respectively, gave the highest enantio-
selectivities in excellent yields (entries 1 and 2). By contrast,
ligands 2e and 2f, derived from (S)-sec-leucinol and (S)-tert-
leucinol, respectively, gave adduct 9 in poor yields as nearly
racemic mixtures (entries 5 and 6). Ligand 2f actually favored
the opposite absolute configuration, albeit slightly (entry 6). In
contrast to the above-mentioned Cu(OTf)2-catalyzed reaction,
the halide ion of the azolium salts has a significant influence on
the yields in the Cu(acac)2-catalyzed reaction (entries 9−11).
The combination of Cu(acac)2 and azolium iodide, 2k, gave the
conjugate addition product in 91% yield (entry 11). However,
use of the corresponding azolium chloride and bromide, 2i and
2j, resulted in poor yields, although the enantioselectivities
of these reactions were comparable to that obtained in the reaction
catalyzed by the Cu(acac)2/2k system (entries 9 and 10).
We also designed hydroxy-amide functionalized azolium
ligand 10i, in which the azolium ring and amide group were
connected by a (dimethyl)methylene bridge. Although the
combination of Cu(OTf)2 and 10i provided (R)-configured
product 9 in moderate yield and ee, no reversal of enantio-
selectivity was observed by changing the Cu precatalyst from
Cu(OTf)2 to Cu(acac)2 (entry 14). The reaction with the
Cu(acac)2/10i system took place with difficulty under these
reaction conditions. These results indicated that selection of the
linker on the chiral ligand was an important factor for dual
enantiocontrol.
Table 4. Switching of Enantioselectivity in Cu-Catalyzed 1,4-
a
Addition Reaction
a
Enone (1 mmol), R2Zn (3 mmol), Cu (6 mol %), azolium (4.5 mol %),
Having established the catalytic activity of the Cu(acac)2/2b
system, we turned our attention to the effect of an additive
such as Cs2CO3. Table 3 summarizes the Cu(acac)2-catalyzed
THF (9 mL), rt, 3 h. For Cu(OTf)2-catalyzed reaction: to a solu-
tion of Cu(OTf)2 and azolium in THF, enone was added first, then
R2Zn. For Cu(acac)2-catalyzed reaction: to a solution of Cu(acac)2,
azolium and Cs2CO3 (8 mol %) in THF, R2Zn was added first,
b
c
then enone. Reaction was run for 27 h. Previously reported data
Table 3. Reaction of 8 with Et2Zn by the Cu(acac)2/2b
a
(see ref 9b).
Catalytic System Under the Influence of Various Bases
entry
base
none
yield (%)
ee (%)
reaction of 2-cyclopenten-1-one (11) with Et2Zn by the
Cu(OTf)2/2m system resulted in the formation of a racemic
mixture of the corresponding conjugate adduct 12 (entry 1).
On the other hand, the same reaction with the Cu(acac)2/2b
system produced (S)-12 in 82% ee (entry 2). The asymmetric
conjugate addition of Et2Zn to 11 using the CH2-bridgied
azolium salt 1 was difficult to be achieved in both Cu(OTf)2
and Cu(acac)2 catalytic systems, leading to poor enantiose-
lectivities of the product 12.9 Therefore, it should be noted that
a significant improvement was observed in the combination of
Cu(acac)2 with the (CH2)2-bridged azolium ligand precursor 2
(entry 2).
Again, unfortunately, the reaction of 8 with Me2Zn with the
Cu(OTf)2/2m system gave poor enantioselectivity (entry 3).
By contrast, the use of Cu(acac)2 as a precatalyst led to a
dramatic increase in ee (97% ee) to give 3-methylcyclohex-
anone (13) with the opposite configuration (entry 4). In the
literature, Hoveyda and Mauduit mentioned that it is
impossible to generate a general catalyst for all conjugate
1
62
82
60
92
90
93
93
94
71
91
90
90
74 (S)
77 (S)
76 (S)
77 (S)
77 (S)
82 (S)
76 (S)
75 (S)
79 (S)
72 (S)
76 (S)
77 (S)
86 (S)
2
Li2CO3
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
AcOK
3
4
5
6
7
8
AcOCs
KHCO3
KOH
tBuOK
pyridine
none
9
10
11
12
b
13
97
a
b
See Table 1, footnote a (method B). Bis(8-quinolinato)Cu(II) was
used instead of Cu(acac)2.
1,4-addition reaction with the Cu(acac)2/2b system under the
influence of various bases. The reaction in the absence of
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addition and more difficult to anticipate the reactivity or the
stereoselectivity.3c,6r,14
CONCLUSION
■
We have described a switchable enantioselectivity in a Cu-
catalyzed conjugate addition reaction. Hydroxy-amide function-
alized azolium salts were found to be versatile chiral ligand
precursors for dual enantioselective control. The stereo-
selectivity of the conjugate addition could be controlled not
only by the structure of the chiral ligand but also by the copper
precatalyst. Either varying the linker of the chiral ligands or
changing the counterion of Cu species between a OTf and acac
ligand initially on the metal led to a complete reversal in the
facial selectivity of approach of the substrates. Considering that
both the ligand precursors 1 and 2 are prepared from natural α-
amino acids, it can be said that obtaining both enantiomers in
the asymmetric catalytic reaction was successfully achieved.
The dual enantioselective control was observed in the
reactions of 8 with Bu2Zn to produce 3-butylcyclohexanone
(14) and 4,4-dimethyl-2-cyclohexen-1-one (15) with Et2Zn to
furnish 3-ethyl-4,4-dimethylcyclohexanone (16) (entries 5−8).
For example, treatment of 15 with Et2Zn in the presence of
catalytic amounts of Cu(OTf)2 combined with 2m produced
(S)-16 in 84% ee, whereas (R)-16 was produced in 99% ee with
the Cu(acac)2/2b catalytic system (entries 7 and 8).
The catalytic systems were suitable for the reaction of
2-cyclohepten-1-one (17) with various dialkylzincs (entries 9−
18). The 1,4-addition reaction of 17 with Me2Zn proceeded
efficiently under the influence of the Cu(OTf)2/2m system to
afford (R)-3-methylcycloheptanone (18) in 92% yield with
moderate enantioselectivity (entry 9). The use of Cu(acac)2 in
place of Cu(OTf)2 resulted in the opposite configuration
forming (S)-18 with 96% ee (entry 10). It is noteworthy that
excellent enantioselectivity was obtained in the reaction using
Me2Zn under ambient conditions. The synthetic utility of the
Cu-catalyzed asymmetric 1,4-addition of Me2Zn has been
demonstrated by its application as a key step in numerous syn-
theses of natural products and biologically active compounds.3a
In the conjugate addition reactions of 17 with Et2Zn, the
ligand structure and copper precatalyst exerted remarkable
control over the outcomes (entries 11−14). The combination
of azolium salt 1m and Cu(OTf)2 produced (S)-3-ethylcyclo-
heptanone (19) in good yield with excellent 91% ee, and
Cu(acac)2/2b gave a similarly good yield at 81% ee (entries 11
and 14). By contrast, the R-configured conjugate adduct 19 was
successfully obtained by using the Cu(acac)2/1i and Cu-
(OTf)2/2m catalytic systems (entries 12 and 13). In the
reaction of 17 with Bu2Zn, an excellent ee value of 96% was
obtained with the Cu(OTf)2/1m system, while the same
reaction using Cu(acac)2 afforded the corresponding conjugate
adduct of the opposite configuration (entries 15 and 16).
Enantioselectivity was also reversed by changing the copper
precatalyst when the reaction was carried out with azolium salt
2 (entries 17 and 18).
Previously, we have shown the synthesis of the NHC-Pd,
NHC-Ag, and NHC-Ir complexes by employing the hydroxy-
amide functionalized azolium salt 1 as NHC precursor.7,8
However, it was difficult to obtain a NHC-Cu complex from
the hydroxy-amide functionalized azolium salt. Attempt to
prepare a NHC-Cu species by allowing 1 to react with Cu2O or
with CuCl in the presence of tBuOK failed due to the formation
of an unidentified product.15 Recently, two important reports
concerning the synthesis of NHC-Cu complexes by Nechaev
and Cazin have been independently published.16 They showed
that some of the NHC-Cu compounds were unstable and dif-
ficult to synthesize from azolium salts, owing to the formation
of haloamidinium salts or azolidin-2-ones instead of NHCs. In
the literature, the most common methods for the catalytic
asymmetric 1,4-addition reaction involve the in situ generated
catalyst from azolium salt and a Cu species.6,17 We believe that
this class of transformations can be performed under opera-
tionally simple conditions. Although it might be better from the
mechanistic viewpoint to use a well-defined copper complex,
we could not obtain such a complex from the hydroxy-amide
functionalized azolium salt at this stage.18
EXPERIMENTAL SECTION
■
General. All chemicals were obtained from commercial sources and
were used as received. H and 13C NMR spectra were recorded on
1
spectrometers at 400 and 100 MHz, respectively. Chemical shifts were
reported in ppm relative to TMS for 1H and 13C NMR spectra.
(CD3)2SO or CDCl3 was used as the NMR solvent. Thin-layer
chromatography (TLC) analysis was performed with glass-backed
plates precoated 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). Compounds 6 and 7
were synthesized according to the literature procedures.11,2i
General Procedure for Preparation of Hydroxy-amide
Derivatives 7. Amino alcohol (2 mmol) was placed in a Schlenk
tube, and methyl 3-(1-benzimidazolyl)propionate (6) (2 mmol, 408
mg) and NaH 60% w/w dispersion in mineral oil (20 mol %, 16 mg)
were then added. The mixture was heated at 120 °C for 5 min. After
removing the formed methanol in vacuo, the crude residue was purified
by column chromatography (SiO2, CH2Cl2/MeOH 97/3) to yield
compound 7.
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxypropan-2-yl)-
propanamide (7a). White solid (380 mg, 77%); mp 149.8−150.0 °C.
1H NMR (DMSO): δ 8.10 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.63−
7.58 (m, 2H), 7.25−7.16 (m, 2H), 4.63 (t, J = 5.5 Hz, 1H), 4.44 (t, J =
6.6 Hz, 2H), 3.74−3.67 (m, 1H), 3.27−3.21 (m, 1H), 3.12−3.06 (m,
1H), 2.60 (t, J = 6.6 Hz, 2H), 0.90 (t, J = 6.6 Hz, 3H). 13C NMR:
δ 169.0, 144.0, 143.3, 133.6, 122.2, 121.4, 119.3, 110.4, 64.2, 46.5, 40.7,
35.7, 17.0. Anal. Calcd for C13H17N3O2·0.125CHCl3·0.125H2O: C,
60.59; H, 6.78; N, 16.15. Found: C, 60.38; H, 6.64; N, 15.94.
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxybutan-2-yl)-
propanamide (7b). White solid (413 mg, 79%); mp 150.6−150.8 °C.
1H NMR (DMSO): δ 8.10 (s, 1H), 7.64 (br,1H), 7.62−7.58 (m, 2H),
7.25−7.16 (m, 2H), 4.59 (br, 1H), 4.45 (t, J = 7.6 Hz, 2H), 3.59−
3.51 (m, 1H), 3.28−3.24 (m, 1H), 3.16−3.11 (m, 1H), 2.70−2.58
(m, 2H), 1.51−1.41 (m, 1H), 1.21−1.10 (m, 1H), 0.65 (t, J =
7.6 Hz, 3H). 13C NMR: δ 169.2, 143.9, 143.3, 133.6, 122.1, 121.3,
119.2, 110.4, 62.7, 52.1, 40.7, 35.7, 23.4, 10.1. Anal. Calcd for
C14H19N3O2·0.25H2O: C, 63.26; H, 7.39; N, 15.81. Found: C, 63.14;
H, 7.28; N, 15.60.
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxy-3-methylbutan-2-yl)-
propanamide (7c). White solid (506 mg, 92%); mp 151.9−152.1 °C.
1H NMR (DMSO): δ 8.10 (s, 1H), 7.62−7.58 (m, 2H), 7.56 (br, 1H),
7.25−7.16 (m, 2H), 4.49 (t, J = 5.5 Hz, 1H), 4.47−4.43 (m, 2H),
3.57−3.50 (m, 1H), 3.27 (t, J = 5.5 Hz, 2H), 2.73−2.61 (m, 2H),
1.75−1.66 (m, 1H), 0.71 (d, J = 6.9 Hz, 3H), 0.65 (d, J = 6.9 Hz, 3H).
13C NMR: δ 169.3, 143.8, 143.3, 133.6, 122.0, 121.3, 119.2, 110.4,
61.1, 55.5, 35.6, 27.9, 19.4, 17.9. Anal. Calcd for C15H21N3O2: C,
65.43; H, 7.69; N, 15.26. Found: C, 65.36; H, 7.67; N, 15.23.
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxy-4-methylpentan-2-
yl)propanamide (7d). White solid (567 mg, 98%); mp 136.6−
136.8 °C. 1H NMR (CDCl3): δ 7.82 (s, 1H), 7.73−7.71 (m, 1H), 7.41−
7.38 (m, 1H), 7.30−7.24 (m, 2H), 6.22 (d, J = 8.2 Hz, 1H), 4.56−4.42
(m, 2H) 4.01−3.95 (m, 1H), 3.53−3.49 (m, 1H), 3.41−3.37
(m, 1H), 2.71−2.59 (m, 2H), 1.36−1.33 (m, 1H), 1.26−1.19 (m, 2H),
4083
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The Journal of Organic Chemistry
Article
0.83 (d, J = 3.2 Hz, 3H), 0.81 (d, J = 3.2 Hz, 3H). 13C NMR: δ 169.8,
143.3, 143.2, 133.3, 123.1, 122.3, 120.0, 109.6, 64.9, 49.7, 41.0, 39.9,
36.7, 24.7, 22.8, 22.1. Anal. Calcd for C16H23N3O2: C, 66.41; H, 8.01;
N, 14.52. Found: C, 66.21; H, 8.10; N, 14.39.
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxy-3-methylpentan-2-
yl)propanamide (7e). White solid (475 mg, 82%); mp 162.8−
163.0 °C. 1H NMR (DMSO): δ 8.10 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H),
7.62−7.58 (m, 2H), 7.25−7.15 (m, 2H), 4.59 (br, 1H), 4.50−4.39 (m,
2H), 3.58−3.52 (m, 1H), 3.30−3.29 (m, 2H), 2.74−2.59 (m, 2H),
1.47−1.37 (m, 1H), 1.25−1.14 (m, 1H), 0.90−0.79 (m, 1H), 0.70 (t,
J = 7.3 Hz, 6H). 13C NMR: δ 169.2, 143.9, 143.3, 133.6, 122.1, 121.3,
119.3, 110.4, 60.8, 54.6, 40.8, 35.6, 34.6, 24.5, 15.3, 11.2. Anal. Calcd
for C16H23N3O2·0.35H2O: C, 64.99; H, 8.08; N, 14.21. Found: C,
64.92; H, 8.08; N, 14.21.
(m, 2H), 2.87−2.77 (m, 2H), 1.69−1.61 (m, 1H), 0.68 (d, J = 6.4 Hz,
3H), 0.61 (d, J = 6.4 Hz, 3H). 13C NMR: δ 168.8, 143.1, 131.6, 130.7,
126.5, 126.4, 113.7, 113.5, 61.0, 55.7, 43.4, 34.4, 33.2, 28.0, 19.3, 17.9.
+
HRMS (ESI+) calcd for C16H24N3O2 : 290.1869, found 290.1864.
1-[3-((S)-1-Hydroxy-4-methyl-2-pentanylamino)-3-oxoprop-
yl]-3-methylbenzimidazolium Iodide (2d). Colorless liquid (211
1
mg, 49%). H NMR (CDCl3): δ 10.38 (s, 1H), 7.89−7.87 (m, 1H),
7.70−7.64 (m, 3H), 7.33 (d, J = 8.8 Hz, 1H), 5.00−4.93 (m, 1H),
4.82−4.76 (m, 1H), 4.21 (s, 3H), 4.03−3.93 (m, 2H), 3.52−3.49 (m,
1H), 3.21 (br, 1H), 3.12−3.06 (m, 1H), 1.96−1.34 (m, 2H), 1.26−
1.12 (m, 1H), 0.83 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H). 13C
NMR: δ 169.2, 142.1, 131.6, 131.5, 127.4, 127.3, 113.5, 112.4, 64.6,
50.4, 43.8, 39.7, 35.4, 34.1, 24.7, 22.8, 22.1. HRMS (ESI+) calcd for
+
C17H26N3O2 : 304.2025, found 304.2017.
1-[3-((S)-1-Hydroxy-3-methyl-2-pentanylamino))-3-oxo-
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxy-3,3-dimethylbutan-
propyl]-3-methylbenzimidazolium Iodide (2e). Colorless liquid
2-yl)propanamide (7f). White solid (515 mg, 89%); mp 197.5−
1
1
(349 mg, 81%). H NMR (DMSO): δ 9.62 (s, 1H), 8.46 (d, J = 8.2
197.7 °C. H NMR (DMSO): δ 8.12 (s, 1H), 7.61 (br, 1H), 7.60−
Hz, 1H), 8.09−8.07 (m, 1H), 8.01−7.99 (m, 1H), 7.71−7.67 (m, 2H),
7.24−7.19 (m, 3H), 7.12−7.10 (m, 2H), 4.71 (t, J = 6.4 Hz, 2H), 4.46
(t, J = 5.5 Hz, 1H), 4.01 (s, 3H), 4.07 (s, 3H), 3.56−3.49 (m, 1H),
3.30−3.24 (m, 2H), 2.87−2.76 (m, 2H), 1.41−1.31 (m, 1H), 1.20−
1.10 (m,1H), 0.84−0.77 (m, 1H), 0.69−0.65 (m, 6H). 13C NMR: δ
168.5, 143.1, 131.6, 130.7, 126.5, 126.4, 113.7, 113.5, 60.7, 54.7, 43.4,
34.7, 34.4, 33.1, 24.5, 15.2, 11.1. HRMS (ESI+) calcd for
7.52 (m, 2H), 7.25−7.15 (m, 2H), 4.51−4.41 (m, 2H), 4.44 (br, 1H),
3.61−3.56 (m, 1H), 3.27−3.15 (m, 2H), 2.78−2.64 (m, 2H), 0.72 (s,
9H). 13C NMR: δ 169.6, 143.9, 143.3, 133.6, 122.1, 121.3, 119.3, 110.4,
60.5, 58.6, 40.8, 35.6, 33.4, 26.7. Anal. Calcd for C16H23N3O2·0.5H2O: C,
64.40; H, 8.11; N, 14.08. Found: C, 64.74; H, 7.93; N, 14.05.
3-(Benzimidazol-1-yl)-N-((S)-2-hydroxy-1-phenylethy)-
propanamide (7g). White solid (402 mg, 65%); mp 158.5−158.7 °C.
1H NMR (DMSO): δ 8.33 (d, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.64−7.59
(m, 2H), 7.25−7.15 (m, 7H), 4.82 (t, J = 5.7 Hz, 1H), 4.83−4.78
(m, 1H), 4.45 (t, J = 6.9 Hz, 2H), 3.52−3.42 (m, 2H), 2.74 (t, J = 6.6
Hz, 2H). 13C NMR: δ 169.2, 144.0, 143.3, 140.8, 133.6, 128.0, 126.8,
126.7, 122.2, 121.4, 119.3, 110.4, 64.5, 54.9, 40.6, 35.5. Anal. Calcd for
C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C, 69.69; H, 6.18;
N, 13.46.
+
C17H26N3O2 : 304.2025, found 304.2021.
1-[3-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-3-oxo-
propyl]-3-methylbenzimidazolium Iodide (2f). Colorless liquid
1
(358 mg, 83%). H NMR (DMSO): δ 9.63 (s, 1H), 8.11−8.09 (m,
1H), 8.01−7.98 (m, 1H), 7.70−7.68 (m, 2H), 7.63 (d, J = 9.6 Hz,
1H), 4.72 (t, J = 6.2 Hz, 2H), 4.37 (t, J = 5.0 Hz, 1H), 4.05 (s, 3H),
3.58−3.49 (m, 2H), 3.20−3.14 (m, 1H), 2.87−2.83 (m, 2H), 0.70 (s,
9H). 13C NMR: δ 169.0, 143.0, 131.6, 130.7, 126.5, 126.4, 113.6,
113.5, 60.2, 58.8, 43.4, 34.3, 33.2, 33.1, 26.6. HRMS (ESI+) calcd for
3-(Benzimidazol-1-yl)-N-((S)-1-hydroxy-3-phenylpropan-2-
yl)propanamide (7h). White solid (530 mg, 82%); mp 119.4−
+
C17H26N3O2 : 304.2025, found 304.2018.
1
119.6 °C. H NMR (DMSO): δ 8.05 (s, 1H), 7.82 (d, J = 8.2 Hz,
1-[3-((S)-1-Hydroxy-2-phenyl-2-ethanylamino)-3-oxoprop-
1H), 7.64−7.56 (m, 2H), 7.27−7.07 (m, 7H), 4.74 (t, J = 5.3 Hz, 1H),
4.38 (t, J = 6.6 Hz, 2H), 3.90−3.82 (m, 1H), 3.29−3.16 (m, 2H),
2.77−2.72 (m, 1H), 2.59 (t, J = 6.6 Hz, 2H), 2.54−2.41 (m, 1H).
13C NMR: δ 169.1, 143.9, 143.3, 138.9, 133.6, 129.0, 128.0, 125.8,
122.1, 121.4, 119.3, 110.4, 62.2, 52.3, 40.6, 36.3, 35.6. Anal. Calcd for
C19H21N3O2·0.5H2O: C, 68.28; H, 6.70; N, 12.57. Found: C, 68.36;
H, 6.63; N, 12.34.
General Procedure for Preparation of Azolium Salts 2. To
compound 7 (1 mmol) were added alkyl halide (1 mmol) and 5 mL of
solvent, and the reaction mixture was stirred under reflux for 24 h.
Evaporation of all volatile materials and purification of the residue by
chromatography (SiO2, CH2Cl2/MeOH 95/5) gave the corresponding
coupling product.
yl]-3-methylbenzimidazolium Iodide (2g). Colorless liquid (347
1
mg, 77%). H NMR (DMSO): δ 9.62 (s, 1H), 8.46 (d, J = 8.2 Hz,
1H), 8.09−8.07 (m, 1H), 8.01−7.99 (m, 1H), 7.71−7.67 (m, 2H),
7.24−7.19 (m, 3H), 7.12−7.10 (m, 2H), 4.85 (t, J = 5.5 Hz, 1H),
4.81−4.75 (m, 1H), 4.70 (t, J = 6.4 Hz, 1H), 4.01 (s, 3H), 3.50−3.39
(m, 2H), 2.95−2.83 (m, 2H). 13C NMR: δ 168.6, 143.1, 140.7, 131.6,
130.7, 128.0, 126.7, 126.6, 126.5, 126.4, 113.6, 113.5, 64.4, 55.0, 43.2,
+
34.1, 33.1. HRMS (ESI+) calcd for C19H22N3O2 : 324.1712, found
324.1703.
1-[3-((S)-1-Hydroxy-3-phenyl-2-propanylamino)-3-oxoprop-
yl]-3-methylbenzimidazolium Iodide (2h). Colorless liquid (93
1
mg, 20%). H NMR (DMSO): δ 9.58 (s, 1H), 8.05−8.00 (m, 2H),
7.91 (d, J = 8.2 Hz, 1H), 7.71−7.68 (m, 5H), 4.74 (t, J = 5.5 Hz, 1H),
4.62 (t, J = 7.3 Hz, 2H), 4.04 (s, 3H), 3.90−3.82 (m, 1H), 3.28−8.20
(m, 2H), 2.79−2.66 (m, 3H). 13C NMR: δ 163.9, 143.5, 138.7, 131.4,
131.2, 129.1, 128.1, 126.6, 126.4, 126.0, 113.6, 113.1, 62.4, 53.0, 48.4,
1-[3-((S)-1-Hydroxy-2-propanylamino)-3-oxopropyl]-3-
methylbenzimidazolium Iodide (2a). Colorless liquid (311 mg,
1
80%). H NMR (DMSO): δ 9.69 (s, 1H), 8.07−8.06 (m, 1H), 8.01−
+
36.6, 34.3, 33.3. HRMS (ESI+) calcd for C20H24N3O2 : 338.1869,
7.99 (m, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.70−7.68 (m, 2H), 4.69 (t, J =
6.8 Hz, 1H), 4.66−7.63 (m, 1H), 4.07 (s, 3H), 3.74−3.65 (m, 1H),
3.24−3.10 (m, 2H), 2.77−2.74 (m, 2H), 0.89 (d, J = 6.8 Hz, 3H). 13C
NMR: δ 168.3, 143.1, 131.6, 130.8, 126.4, 126.4, 113.6, 113.5, 64.1,
found 338.1861.
1-[3-((S)-1-Hydroxy-4-methyl-2-pentanylamino)-3-oxoprop-
yl]-3-benzilbenzimidazolium Chloride (2i). Colorless liquid (112
+
46.5, 43.2, 34.4, 33.2, 16.9. HRMS (ESI+) calcd for C14H20H3O2 :
1
mg, 27%). H NMR (CDCl3): δ 11.02 (s, 1H), 8.23 (d, J = 8.5 Hz,
262.1556, found 262.1550.
1H), 7.84 (d, J = 8.5 Hz, 1H), 7.60−7.55 (m, 1H), 7.50−7.47 (m,
4H), 7.38−7.29 (m, 3H), 5.82 (d, J = 15.1 Hz, 1H), 5.75 (d, J = 15.1
Hz, 1H), 4.98−4.93 (m, 1H), 4.82−4.78 (m, 1H), 4.47 (br, 1H),
3.87−3.83 (m, 1H), 3.51−3.40 (m, 3H), 3.09−3.04 (m, 1H), 1.47−
1.41 (m, 1H), 1.35−1.28 (m, 1H), 1.23−1.11 (m, 1H), 0.79 (d, J = 6.8
Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). 13C NMR: δ 168.8, 142.7, 132.6,
131.9, 130.8, 129.2, 129.1, 128.1, 127.0, 127.0, 113.5, 113.3, 64.3, 51.5,
50.2, 43.9, 39.8, 35.1, 24.6, 22.7, 22.3. HRMS (ESI+) calcd for
1-[3-((S)-1-Hydroxy-2-butanylamino)-3-oxopropyl]-3-meth-
ylbenzimidazolium Iodide (2b). Colorless liquid (330 mg, 82%).
1H NMR (DMSO): δ 8.10 (s, 1H), 7.64 (br, 1H), 7.62−7.58 (m, 2H),
7.25−7.16 (m, 2H), 4.58 (br, 1H), 4.45 (t, J = 6.6 Hz, 2H), 3.59−3.51
(m, 1H), 3.33 (s, 3H), 3.25−3.24 (m, 2H), 3.16−3.11 (m, 1H), 2.70−
2.58 (m, 2H), 1.51−1.41 (m, 1H), 1.21−1.10 (m, 1H), 0.66 (t, J = 7.3
Hz, 3H). 13C NMR: δ 168.6, 143.2, 142.9, 131.6, 130.7, 126.4, 113.6,
113.6, 62.6, 52.2, 34.4, 33.1, 31.6, 23.3, 10.0. HRMS (ESI+) calcd for
+
C23H30N3O2 : 380.2338, found 380.2324.
+
C15H22N3O2 : 276.1712, found 276.1717.
1-[3-((S)-1-Hydroxy-4-methyl-2-pentanylamino)-3-oxoprop-
yl]-3-benzilbenzimidazolium Bromide (2j). Colorless liquid (276
1-[3-((S)-1-Hydroxy-3-methyl-2-butanylamino)-3-oxoprop-
1
yl]-3-methylbenzimidazolium Iodide (2c). Colorless liquid (330
mg, 60%). H NMR (CDCl3): δ 10.80 (s, 1H), 7.84−7.82 (m, 1H),
1
mg, 79%). H NMR (DMSO): δ 9.66 (s, 1H), 8.09−8.07 (m, 1H),
7.82 (m, 2H), 7.63−7.59 (m, 1H), 7.55−4.48 (m, 4H), 7.40−7.35 (m,
3H), 5.81 (d, J = 15.1 Hz, 1H), 5.74 (d, J = 15.1 Hz, 1H), 5.01−4.94
(m, 1H), 4.76−4.71 (m, 1H), 3.94−3.86 (m, 1H), 3.60−3.53 (m, 3H),
8.02−7.99 (m, 1H), 7.70−7.67 (m, 3H), 4.71 (t, J = 6.4 Hz, 1H), 4.50
(t, J = 5.0 Hz, 1H), 4.06 (s, 3H), 3.54−3.46 (m, 1H), 3.27−3.24
4084
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The Journal of Organic Chemistry
Article
3.47−3.38 (m, 2H), 3.09−3.03 (m, 1H), 1.52−1.43 (m, 1H), 1.39−
1.32 (m, 1H), 1.22−1.14 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H), 0.80
(d, J = 6.4 Hz, 3H). 13C NMR: δ 168.9, 142.4, 132.4, 131.8, 130.8,
129.3, 129.1, 128.2, 128.2, 127.1, 127.0, 113.5, 113.3, 64.4, 51.6, 50.2,
44.0, 39.8, 35.3, 24.6, 22.7, 22.2. HRMS (ESI+) calcd for
ASSOCIATED CONTENT
* Supporting Information
Spectra for products and chiral GC traces. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
+
C23H30N3O2 : 380.2338, found 380.2325.
AUTHOR INFORMATION
Corresponding Author
*satoshi@kansai-u.ac.jp
Notes
1-[3-((S)-1-Hydroxy-4-methyl-2-pentanylamino)-3-oxoprop-
■
yl]-3-benzilbenzimidazolium Iodide (2k). Colorless liquid (391 mg,
1
77%). H NMR (DMSO): δ 9.93 (s, 1H), 8.09 (d, J = 7.8 Hz, 1H),
7.91 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.68−7.60
(m, 2H), 7.51−7.47 (m, 2H), 7.42−7.35 (m, 3H), 5.78 (s, 2H), 4.78−
4.71 (m, 2H), 4.58 (t, J = 5.6 Hz, 1H), 3.76−3.67 (m, 1H), 3.22−3.12
(m, 2H), 2.90−2.76 (m, 2H), 1.28−1.06 (m, 3H), 0.70 (d, J = 6.3 Hz,
3H), 0.66 (d, J = 6.3 Hz, 3H). 13C NMR: δ 168.4, 143.0, 133.9, 131.1,
130.5, 128.8, 128.6, 128.2, 128.0, 126.5, 113.9, 113.7, 63.5, 49.7, 48.7,
43.5, 40.1, 39.9, 39.7, 39.5, 39.2, 39.0, 38.8, 34.0, 24.0, 23.0, 21.6.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid for
Scientific Research (C) (23550128) from Japan Society for the
Promotion of Science (JSPS), Kansai University Research
Grant: Grant-in-Aid for Encouragement of Scientists, 2011, and
the Sumitomo Foundation.
+
HRMS (ESI+) calcd for C23H30N3O2 : 380.2338, found 380.2337.
1-[3-((S)-1-Hydroxy-2-butanylamino)-3-oxopropyl]-3-benzil-
1
benzimidazolium Iodide (2l). Colorless liquid (369 mg, 77%). H
NMR (DMSO): δ 9.91 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.90 (d, J =
8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.68−7.60 (m, 2H), 7.48−7.46
(m, 2H), 7.40−7.34 (m, 3H), 5.77 (s, 2H), 4.75 (t, J = 6.4 Hz, 1H),
4.60 (t, J = 5.5 Hz, 1H), 3.59−3.49 (m, 1H), 3.26−3.17 (m, 2H),
2.89−2.76 (m, 2H), 1.47−1.37 (m, 1H), 1.22−1.09 (m, 1H), 0.59
(t, J = 7.3 Hz, 3H). 13C NMR: δ 168.6, 143.0, 133.9, 131.1, 130.6,
128.9, 128.6, 113.9, 113.8, 62.6, 52.2, 49.7, 48.5, 43.5, 34.0, 23.4, 10.1.
REFERENCES
■
(1) (a) Bartok
́
, M. Chem. Rev. 2010, 110, 1633. (b) Tanaka, T.;
Hayashi, M. Synthesis 2008, 3361. (c) Zanoni, G.; Castronovo, F.;
Franzini, M.; Vidari, G.; Giannini, E. Chem. Soc. Rev. 2003, 32, 115.
(d) Sibi, M. P.; Liu, M. Curr. Org. Chem. 2001, 5, 719.
(2) For selected recent examples, see: (a) Awano, T.; Ohmura, T.;
Suginome, M. J. Am. Chem. Soc. 2011, 133, 20738. (b) Inagaki, T.; Ito,
A.; Ito, J.; Nishiyama, H. Angew. Chem., Int. Ed. 2010, 49, 9384.
(c) Liu, Y.; Shang, D.; Zhou, X.; Zhu, Y.; Lin, L.; Liu, X.; Feng, X. Org.
Lett. 2010, 12, 180. (d) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 3779. (e) Kim, H. Y.; Shih, H. J.; Knabe, W. E.;
Oh, K. Angew. Chem., Int. Ed. 2009, 48, 7420. (f) Kim, H. Y.; Oh, K.
Org. Lett. 2009, 11, 5682. (g) Spangler, K. Y.; Wolf, C. Org. Lett. 2009,
11, 4724. (h) Abermil, N.; Masson, G.; Zhu, J. P. Org. Lett. 2009, 11,
4648. (i) Schneider, N.; Cesar, V.; Bellemin-Laponnaz, S.; Gade, L. H.
́
Organometallics 2005, 21, 4886.
(3) For selected recent reviews, see: (a) Jerphagnon, T.; Pizzuti, M.
G.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039.
+
HRMS (ESI+) calcd for C21H26N3O2 : 352.2025, found 352.2021.
1-[3-((S)-1-Hydroxy-3,3-dimethyl-2-butanylamino)-3-oxo-
propyl]-3-benzilbenzimidazolium Iodide (2m). Colorless liquid
(309 mg, 61%). 1H NMR (CDCl3): δ 10.52 (s, 1H), 7.92 (d, J = 8.2 Hz,
1H), 7.61−7.57 (m, 1H), 7.51−7.48 (m, 4H), 7.38−7.33 (m, 3H),
7.22 (d, J = 9.6 Hz, 1H), 5.79 (d, J = 15.1 Hz, 1H), 5.73 (d, J = 15.1
Hz, 1H), 5.02−4.95 (m, 1H), 4.90−4.84 (m, 1H), 3.84−3.80 (m, 1H),
3.70−3.62 (m, 3H), 3.17−3.10 (m, 1H), 0.84 (s, 9H). 13C NMR
(DMSO): δ 164.7, 143.5, 133.9, 131.6, 130.4, 129.0, 128.7, 128.1,
126.7, 126.6, 113.8, 113.6, 60.2, 59.7, 49.7, 48.7, 41.5, 33.6, 26.8.
+
HRMS (ESI+) calcd for C23H30N3O2 : 380.2338, found 380.2327.
1-[3-((S)-1-Hydroxy-4-methyl-2-pentanylamino)-2,2-dimeth-
yl-3-oxopropyl]-3-benzilbenzimidazolium Chloride (10i). Col-
orless liquid (159 mg, 37%). 1H NMR (DMSO): δ 10.28 (s, 1H), 8.04
(d, J = 8.2 Hz, 1H), 7.78−7.75 (m, 1H), 7.59−7.55 (m, 5H), 7.42−
7.35 (m, 3H), 5.81 (s, 2H), 4.73 (t, J = 5.5 Hz, 1H), 3.79 (br, 1H),
3.27−3.15 (m, 2H), 1.98 (s, 3H), 1.92 (s, 3H), 1.26−1.10 (m, 3H),
0.68 (d, J = 2.3 Hz, 3H), 0.67 (d, J = 2.3 Hz, 3H). 13C NMR: δ 169.1,
143.0, 134.0, 131.2, 130.1, 128.8, 128.5, 128.2, 126.3, 126.2, 114.9,
114.1, 64.8, 63.4, 50.0, 49.8, 25.1, 24.6, 24.0, 23.2, 21.6. HRMS (ESI+)
̀ ́
(b) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
̈
Chem. Rev. 2008, 108, 2796. (c) Hoveyda, A. H.; Hird, A. W.;
Kacprzynski, M. A. Chem. Commun. 2004, 1779. (d) Alexakis, A.;
Benhaim, C. Eur. J. Org. Chem. 2002, 3221.
(4) For selected recent reviews, see: (a) N-Heterocyclic Carbenes;
Díez-Gonzal
mou, L.; Chardon, E.; Lavigne, G.; Bellemin-Laponnaz, S.; Ces
Chem. Rev. 2011, 111, 2705. (c) Kuhl, O. Functionalised N-Heterocyclic
́
ez, S., Ed.; RSC-Publishing: Cambridge, 2011. (b) Benha-
́
ar, V.
̈
+
Carbene Complexes; Wiley-VCH: Weinheim, 2010. (d) Díez-Gonzal
S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612. (e) Wencel,
J.; Mauduit, M.; Henon, H.; Kehrli, S.; Alexakis, A. Aldrichim. Chim.
́
ez,
calcd for C24H31N3O2 : 394.2495, found 394.2491.
General Procedure for Cu(OTf)2-Catalyzed Asymmetric
Reaction of Enone with Et2Zn (Method A). To a solution of
azolium salt (0.045 mmol) in THF (9 mL) were added Cu(OTf)2
(0.06 mmol, 21.7 mg) 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 temperature for 3 h, the reaction
was quenched with 10% HCl aq. The resulting mixture was extracted
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.
́
Acta 2009, 42, 43. (f) Snead, D. R.; Seo, H.; Hong, S. Curr. Org. Chem.
2008, 12, 1370. (g) N-Heterocyclic Carbenes in Transition Metal
Catalysis; Glorius, F., Ed.; Springer-Verlag: Berlin/Heidelberg, 2007.
(h) Douthwaite, R. E. Coord. Chem. Rev. 2007, 251, 702. (i) N-
Heterocyclic Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-VCH:
Weinheim, 2006. (j) Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G.
Angew. Chem., Int. Ed. 2007, 46, 2768. (k) Peris, E.; Crabtree, R. H.
́
Coord. Chem. Rev. 2004, 248, 2239. (l) Cesar, V.; Bellemin-Laponnaz,
S.; Gade, L. H. Chem. Soc. Rev. 2004, 33, 619. (m) Herrmann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1290.
General Procedure for Cu(acac)2-Catalyzed Asymmetric
Reaction of Enone with Et2Zn (Method B). To a solution of
azolium salt (0.045 mmol) in THF (9 mL) were added Cs2CO3 (0.08
mmol, 26.0 mg) and Cu(acac)2 (0.06 mmol, 15.7 mg), and then the
mixture was cooled to 0 °C. Then, Et2Zn (3 mmol, 1 mol/L in
hexanes, 3 mL) was added to the reaction vessel, and the mixture was
stirred at room temperature 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.
(5) (a) Guillen, F.; Winn, C. L.; Alexakis, A. Tetrahedron: Asymmetry
2001, 12, 2083. (b) Pytkowicz, J.; Roland, S.; Mangeney, P.
Tetrahedron: Asymmetry 2001, 12, 2087.
(6) Selected recent publications: (a) O’Brien, J. M.; Hoveyda, A. H.
J. Am. Chem. Soc. 2011, 133, 7712. (b) May, T. L.; Dabrowski, J. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 736. (c) Muller, D.;
̈
Tissot, M.; Alexakis, A. Org. Lett. 2011, 13, 3040. (d) Tissot, M.;
Hernandez, A. P.; Muller, D.; Mauduit, M.; Alexakis, A. Org. Lett.
́
̈
2011, 13, 1524. (e) Kehrli, S.; Martin, D.; Rix, D.; Mauduit, M.;
4085
dx.doi.org/10.1021/jo300472r | J. Org. Chem. 2012, 77, 4079−4086

The Journal of Organic Chemistry
Article
Alexakis, A. Chem.Eur. J. 2010, 16, 9890. (f) Rix, D.; Labat, S.;
́
Toupet, L.; Crevisy, C.; Mauduit, M. Eur. J. Org. Chem. 2009, 1989.
might be involved. On the other hand, the 1,4-addition reaction
catalyzed by Cu(acac)2 combined with 1 may take place through the
model B, where anionic acetylacetonate ligand coordinates to a Cu
center.
(g) Lee, K.-s.; Hoveyda, A. H. J. Org. Chem. 2009, 74, 4455.
(h) Uchida, T.; Katsuki, T. Tetrahedron Lett. 2009, 50, 4741.
(i) Matsumoto, Y.; Yamada, K.-i.; Tomioka, K. J. Org. Chem. 2008,
73, 4578. (j) Moore, T.; Merzouk, M.; Williams, N. Synlett 2008, 21.
(k) Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904.
(l) May, T. L.; Brown, M. K.; Hoveyda, A. H. Angew. Chem., Int. Ed.
́
2008, 47, 7358. (m) Henon, H.; Mauduit, M.; Alexakis, A. Angew.
Chem., Int. Ed. 2008, 47, 9122. (n) Brown, M. K.; May, T. L.; Baxter,
C. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 1097.
(o) Clavier, H.; Guillemin, J.-C.; Mauduit, M. Chirality 2007, 19, 471.
(p) Lee, K.-s.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem.
Soc. 2006, 128, 7182. (q) Martin, D.; Kehrli, S.; d’Augustin, M.;
Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128,
8416. (r) Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J.-C.;
Mauduit, M. J. Organomet. Chem. 2005, 690, 5237. (s) Clavier, H.;
Coutable, L.; Guillemin, J.-C.; Mauduit, M. Tertahedron: Asymmetry
2005, 16, 921. (t) Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.;
Mangeney, P.; Alexakis, A. J. Organomet. Chem. 2005, 690, 5672.
(u) Arnold, P. L.; Rodden, M.; Davis, K. M.; Scarisbrick, A. C.; Blake,
A. J.; Wilson, C. Chem. Commun. 2004, 1612. (v) Alexakis, A.; Winn,
C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.; Mangeney, P. Adv. Synth.
Catal. 2003, 345, 345.
(7) (a) Sakaguchi, S.; Yoo, K. S.; O’Neill, J.; Lee, J. H.; Stewart, T.;
Jung, K. W. Angew. Chem., Int. Ed. 2008, 47, 9326. (b) Yoo, K. S.;
O’Neill, J.; Sakaguchi, S.; Giles, R.; Lee, J. H.; Jung, K. W. J. Org. Chem.
2010, 75, 95. (c) Sakaguchi, S.; Kawakami, M.; O’Neill, J.; Yoo, K. S.;
Jung, K. W. J. Organomet. Chem. 2010, 695, 195. (d) Kamisue, R.;
Sakaguchi, S. J. Organomet. Chem. 2011, 696, 1910.
(8) (a) Chiyojima, H.; Sakaguchi, S. Tetrahedron Lett. 2011, 52, 6788.
(b) Kawabata, S.; Tokura, H.; Chiyojima, H.; Okamoto, M.; Sakaguchi,
S. Adv. Synth. Catal. 2012, 354, 807.
(9) (a) Okamoto, M.; Yamamoto, Y.; Sakaguchi, S. Chem. Commun.
2009, 7363. (b) Shibata, N.; Okamoto, M.; Yamamoto, Y.; Sakaguchi,
S. J. Org. Chem. 2010, 16, 5707. (c) Harano, A.; Sakaguchi, S. J.
Organomet. Chem. 2011, 696, 61.
(10) (a) Wencel-Delord, J.; Alexakis, A.; Crevisy, C.; Mauduit, M.
́
Org. Lett. 2010, 12, 4335. (b) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.;
Snapper, M. L. Nature 2006, 443, 67.
(11) Hou, X.; Hemit, H.; Yong, J.; Nie, L.; Aisa, H. A. Synth.
Commun. 2010, 40, 973.
(12) We previously reported the ligand design for dual
enantioselective control by using β-amino alcohols and α-amino
esters, which are derived from natural amino acids: Yoshimura, M.;
Shibata, N.; Kawakami, M.; Sakaguchi, S. Tetrahedron 2011,
DOI: 10.1016/j.tet.2011.04.028.
(13) The influence of the order of addition of the substrates in NHC-
Cu catalyzed asymmetric conjugate addition reaction has been
reported; see ref 6q.
(14) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 779.
(15) In 13C NMR of the unidentified product, the absence of the
characteristic signal for the carbene carbon, which is expected to be
shifted to low field (typically ca. 200 ppm), was observed.16 The 13C
NMR signal of the product, which was obtained by the reaction of 1
with Cu2O or CuCl, appeared at 154 ppm instead of 200 ppm.
(16) (a) Kolychev, E. L.; Shuntikov, V. V.; Khrustalev, V. N.; Bush, A.
A.; Nechaev, M. S. Dalton Trans. 2011, 40, 3074. (b) Citadelle, C. A.;
Nouy, E. L.; Bisaro, F.; Slawin, A. M. Z.; Cazin, C. S. J. Dalton Trans.
2010, 39, 4489.
(17) Díez-Gonzal
43.
́
ez, S.; Nolan, S. P. Aldrichim. Chim. Acta 2008, 41,
(18) Quite recently, Hoveyda proposed the reaction mechanistic
model in the NHC-Cu-catalyzed asymmetric allylic substitution
reaction: Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134,
1490. We speculate that the present Cu-catalyzed-1,4-addition
reaction might proceed through similar mechanistic models. In the
Cu(OTf)2/1 catalytic system, the anionic amidate/NHC-Cu species A
4086
dx.doi.org/10.1021/jo300472r | J. Org. Chem. 2012, 77, 4079−4086