Functionalized N-heterocyclic carbene ligands for dual enantioselective control in the Cu-catalyzed conjugate addition of dialkylzinc compounds to acyclic enones

Article abstract of DOI:10.1002/ejoc.201201082

A series of highly tunable, functionalized azolium compounds have been synthesized from chiral α-amino acid derivatives such as β-amino alcohols or α-amino esters. The combination of a Cu salt and a chiral azolium efficiently facilitated the asymmetric co

Full text of DOI:10.1002/ejoc.201201082

FULL PAPER
DOI: 10.1002/ejoc.201201082
Functionalized N-Heterocyclic Carbene Ligands for Dual Enantioselective
Control in the Cu-Catalyzed Conjugate Addition of Dialkylzinc Compounds to
Acyclic Enones
Kenta Dohi,[a] Junko Kondo,[a] Haruka Yamada,[a] Ryuichi Arakawa,[a] and
Satoshi Sakaguchi*[a]
Keywords: Asymmetric catalysis / Homogeneous catalysis / Copper / Zinc / Ligand design / Carbenes / Conjugate addition /
Enantioselectivity
A series of highly tunable, functionalized azolium com-
pounds have been synthesized from chiral α-amino acid de-
rivatives such as β-amino alcohols or α-amino esters. The
combination of a Cu salt and a chiral azolium efficiently facil-
itated the asymmetric conjugate addition (ACA) reactions of
acyclic enones with dialkylzinc under ambient conditions
without temperature control. Of the (hydroxy amide)-func-
tionalized azolium ligand precursors, which were derived
from β-amino alcohols, an azolium salt containing a tert-butyl
group as the stereodirecting group was found to be the best
choice of ligand. Ligand screening revealed that the use of
an azolium salt containing a sterically bulky alkyl substituent
such as N-CHRRЈ on the azolium ring led to a marked in-
crease in the enantioselectivity of the ACA reaction. Thus, a
new efficient (hydroxy amide)-functionalized azolium ligand
developed. The treatment of benzalacetone (30) with Et2Zn
in the presence of catalytic amounts of [Cu(OTf)]2(C6H6) and
26 at room temperature gave the corresponding 1,4-adduct
31 with excellent enantioselectivity (92% ee). On the other
hand, the enantioselectivity of the ACA reactions of acyclic
enones with dialkylzinc was successfully reversed by the use
of (ester amide)-functionalized azolium salts, which were ob-
tained from α-amino esters. Several functionalized azolium
ligand precursors from readily available serine esters have
been designed and synthesized. Finally, it was found that 30
could react with Et2Zn under the influence of a bis(hexafluo-
roacetylacetonato)copper(II) salt and C2-symmetric azolium
salt 36 to afford ent-31 in almost quantitative yield with 89%
ee. A plausible reaction mechanism for the switching of the
stereoselectivity in the ACA reaction by these two function-
precursor such as 26, which was prepared from 1-(di- alized azolium compounds is described.
phenylmethyl)benzimidazole and (S)-tert-leucinol, has been
Cu-catalyzed ACA reactions (Scheme 1).[1d] The pioneers in
Introduction
this field are Hoveyda and co-workers who developed the
chelating ligand A with a carbene unit and binaphthol as a
second coordinating group on the side-arm of the NHC.[3,4]
Moreover, the combination of a Cu salt and the chiral hy-
droxyalkyl-functionalized azolium salt B, developed by
Mauduit and co-workers, exhibits excellent catalytic activity
in the ACA reaction of substituted or unsubstituted cyclic
enones with alkylating reagents such as alkylzinc com-
pounds or Grignard reagents.[5]
Most of the above-mentioned studies were performed on
the conjugate addition reactions of organometallic com-
pounds with cyclic enones. In contrast, very few highly
enantioselective reactions of acyclic enones have been re-
ported. It has been assumed in the literature that the lower
stereoselectivity of the ACA reactions of acyclic enones was
caused by s-cis/s-trans conformational flexibility.[6] To the
best of our knowledge, there is only one report on the cop-
per-catalyzed ACA of Et2Zn to an acyclic enone employing
a chiral NHC ligand that gives satisfactory enantio-
selectivity.[7] Katsuki and Uchida described the highly enan-
tioselective ACA reactions of alkenyl phenyl ketones with
The copper-catalyzed asymmetric conjugate addition
(ACA) reaction is a powerful and versatile synthetic tool
that affords enantiomerically enriched building blocks.
Since the 1990s, a wide range of chiral ligands have emerged
that have led to excellent selectivities with various alkylating
reagents and Michael acceptors.[1] In recent years, N-het-
erocyclic carbenes (NHCs) have been recognized as versatile
ligands in organometallic chemistry due to their strong do-
nating ability.[2] Their most attractive feature is their easy
manipulation by the modification of the backbone and sub-
stituents leading to stable complexes with a metal center.
Thus, during the past decade, a variety of functionalized
NHC ligands have been designed and synthesized for use in
[a] Department of Chemistry and Materials Engineering, Faculty
of Chemistry, Materials and Bioengineering, Kansai University,
Suita, Osaka 564-8680, Japan
Fax: +81-6-6339-4026
E-mail: satoshi@kansai-u.ac.jp
Homepage: http://www2.ipcku.kansai-u.ac.jp/~satoshi/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201082.
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K. Dohi, J. Kondo, H. Yamada, R. Arakawa, S. Sakaguchi
FULL PAPER
Scheme 1. Representative chelating ligands with a hydroxy group
on the side-arm of the NHC.
Scheme 2. Ligand design for dual enantioselective control in the
ACA reactions of cyclic enones with dialkylzinc compounds.
Et2Zn catalyzed by Cu(OTf)2 in combination with the bi-
phenol-NHC precursor C (Scheme 1), which was based on
the 1,2-diphenylethylenediamine skeleton as a source of chi-
rality. Furthermore, Mauduit and co-workers mentioned
that it is impossible to generate a general catalyst for all
conjugate addition reactions and extremely difficult to an-
ticipate the reactivity or stereoselectivity of reac-
tions.[1d,1h,5e,5g]
In organic synthesis, it is very important to introduce a
versatile ligand that is useful in the ACA reactions of both
cyclic and acyclic enones.[1c] For example, the straightfor-
ward asymmetric synthesis of (R)-muscone, the key flavor
component of musk, was accomplished through the conju-
gate addition of Me2Zn to a cyclic enone such as (E)-cyclo-
pentadec-2-en-1-one under the influence of Cu(OTf)2 in
combination with a chiral phosphate ligand.[8] The total
synthesis of the antimycobacterial agent erogorgiaene was
achieved by the enantioselective 1,4-addition of Me2Zn to
an acyclic enone such as a benzalacetone derivative in the
presence of catalytic amounts of Cu(OTf)2 and a phos-
Because both ligand precursors are prepared from natu-
ral α-amino acids, it is possible to achieve dual enantioselec-
tive control through the structural modification of chiral
ligands. To investigate the potential of this promising class
of functionalized NHCs, we have continued our efforts to
improve the chiral functionalized azolium ligand. In this
paper, we describe the systematic study of the copper-cata-
lyzed ACA reactions of acyclic enones with dialkylzinc by
using chiral ligands D and E, and we report on the dual
stereoselective control achieved by tuning the chiral ligand
in both reactions.
Results and Discussion
Synthesis of Chiral Azolium Salts from α-Amino Acid
Derivatives
The synthetic routes to enantiopure azolium salts are
phane ligand.[9] Therefore the development of an general shown in Scheme 3.[10–12] The reaction of chloroacetyl
efficient chiral ligand for enantioselective conjugate ad- chloride with β-amino alcohol afforded α-chloroacetamide
dition reactions is urgently needed.
in almost quantitative yield. This was subsequently coupled
We have previously reported the highly enantioselective with N-alkylated benzimidazole to yield the corresponding
conjugate addition reactions of cyclic enones with R2Zn by (hydroxy amide)-functionalized azolium chloride. The N-al-
using a combined catalyst of a copper salt and a (hydroxy kylated benzimidazole could be prepared with ease by the
amide)-functionalized azolium salt D (Scheme 2).[10] This reaction between benzimidazole and the corresponding
NHC ligand precursor offers several advantages:
alkyl halide. Because various chiral β-amino alcohols are
i. The starting materials, such as β-amino alcohols, are commercially available, the azolium compounds 1–14 can
readily available from naturally occurring α-amino acids,
ii. the ligand precursors can be prepared by a two-step syn-
thesis from β-amino alcohols, and
be synthesized by this route.
In addition, (ester amide)-functionalized azolium com-
pounds were obtained by a route similar to the (hydroxy
iii. the azolium compounds are air-stable and easy to amide)-functionalized azolium salts by using α-amino esters
handle. In addition, we have developed a chiral azolium salt in place of β-amino alcohols. Previously we showed that
containing an ester amide side-chain (E), which was pre- serine ester with a hydroxymethyl substituent (R1
=
pared from serine ester.[11] Interestingly, the absolute config- CH2OH) was the best choice of chiral source among vari-
urations of the conjugate adducts obtained in the ACA re- ous naturally occurring α-amino esters examined.[11] There-
actions of cyclic enones with R2Zn using the (ester amide)- fore we prepared azolium salts 15–21 derived from serine
functionalized azolium salt E differed from those obtained esters. These newly prepared azolium ligand precursors
in the ACA reactions using the (hydroxy amide)-function- were obtained as air-stable, white solids by a two-step syn-
alized azolium salt D (Scheme 2).
thesis from readily available enantiopure compounds.
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Cu-Catalyzed Addition Reactions of Dialkylzinc Compounds
Table 1. Evaluation of chiral azolium ligands 1–14 and the Cu pre-
catalyst in the ACA reaction of 3-nonen-2-one (22) with Et2Zn.[a]
Entry
Azolium Cu
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
1
2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
[Cu(OTf)]2(C6H6)
[Cu(CH3CN)]4OTf
[Cu(CH3CN)]4BF4
Cu(acac)2
Cu(NO3)2
CuCl2
73
93
97
91
93
97
91
88
99
95
90
60
99
99
90
87
88
58
95
38
99
35
45
56
46
55
60
64
80
64
65
77
77
79
75
82
83
71
70
85
62
88
3
4
5
6
7
8
9
9
10
11
12
13
14
15
16
17
18
19
20
21[b]
10
11
12
13
14
8
8
8
8
8
8
8
Cu(NO3)2
[a] Reagents and conditions: 22 (1 mmol), Et2Zn (3 mmol), Cu salt
(6 mol-%), azolium salt (4.5 mol-%), THF (9 mL), room temp., 3 h.
Yield and ee were determined by GLC analysis. Average of two
runs. [b] In this case, 6 mol-% of 8 was used.
Scheme 3. Synthetic routes to a series of (hydroxy amide)- and (es-
ter amide)-functionalized NHC ligand precursors.
lectivity (80% ee; entry 8). Note that the isopropyl group
on the azolium ring, which is far from the stereogenic cen-
ter, led to a marked increase in enantioselectivity. The effect
of the R2 substituent will be discussed later. Based on this
finding, we decided to evaluate the efficiency of several azo-
ACA Reactions with (Hydroxy Amide)-Functionalized
Azolium Compounds
We started by screening ligand precursors 1–14 in the lium ligands 7–14 containing various N-alkyl groups in the
Cu(OTf)2-catalyzed ACA reaction of 3-nonen-2-one (22) ACA reaction as well as the asymmetric induction (en-
with Et2Zn to give (S)-4-ethylnonan-2-one (23; Table 1). tries 7–14). We found that the azolium salts 9 and 10 with
First, the alkyl substituent (R1 group) at the stereogenic an N-CH2R moiety [R2 = nBu (for 9) and iBu (for 10)] gave
center of the ligand was evaluated. Clearly, of the ligand lower selectivities than the azolium ligands 8, 11, 13, and
precursors 1–6, the increase in the steric demand of the 14, which involve an N-CHRRЈ moiety (entries 9 and 10 vs.
alkyl substituent on the ligand led to improved enantio- entries 8, 11, 13, and 14). Although the stereoselectivity of
selectivities (entries 1–6). For example, the use of com- the ACA reaction with azolium salt 12 (R2 = tBu) was com-
pound 6 containing a sterically hindered tert-butyl group parable to that obtained with 8 (R2 = iPr), the yield was
efficiently produced 23 in 97% yield with 60% ee (entry 6). somewhat lower (60%; entry 12). This might be due to the
One of the most attractive features of the functionalized highly hindered tert-butyl group at the azolium ring block-
NHC ligand is that the easy tuning of not only the hydroxy ing the approach of one of the reagents, such as enone 22.
amide functional group but also the N-alkyl group (R2) on
The screening of Cu salts showed that [Cu(OTf)]2(C6H6)
the ligand allows the development of a huge variety of as well as Cu(NO3)2 gave the 1,4-adduct 23 in excellent
NHC ligands. The replacement of a methyl group (ligand yields and with good enantioselectivities (entries 15–20).
precursor 6) by a benzyl group (ligand precursor 7) at the Note that no reversal of enantioselectivity was observed
azolium ring slightly increased the enantioselectivity (en- when the Cu precatalyst was changed from Cu(OTf)2 to
try 7).
Cu(acac)2 (entry 8 vs. entry 18). This observation is in con-
We found that the chiral azolium ligand precursor 8 (R1 trast to the ACA reaction of a cyclic enone with Et2Zn un-
= tBu, R2 = iPr) was also effective in the ACA reaction, der the influence of the (hydroxy amide)-functionalized
producing the desired product 23 with satisfactory stereose- azolium salt.[10] The reaction with Cu(NO3)2/8 in a ratio of
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K. Dohi, J. Kondo, H. Yamada, R. Arakawa, S. Sakaguchi
FULL PAPER
1:1 proceeded similarly to afford the corresponding adduct Table 2. Ligand design for the ACA reactions of acyclic enones
with R2Zn.[a]
23 in high yield and with good enantioselectivity (entry 21).
To investigate the influence of the R1 and R2 substituents
on the ligand precursors in the ACA reaction of an acyclic
enone other than 22, 5-methyl-3-hexen-2-one (24) was al-
lowed to react with Et2Zn in the presence of Cu(OTf)2 and
a series of azolium ligands 1–14 (see Figure S1 in the Sup-
porting Information). The results obtained from this ligand
screening test in the ACA reaction of 24 were similar to
those obtained in the ACA reaction of 22. The sterically
hindered tert-butyl group at the stereogenic center of the
ligand (R1 group) was the best choice of substituent.
Furthermore, the enantioselectivity of the ACA reaction
improved when the reaction was conducted with chiral li-
gands 8, 13, and 14, which involve the N-CHRRЈ moiety.
In addition, further examination of the Cu precatalysts and
chiral azolium ligands revealed that the combination of
[Cu(OTf)]2(C6H6) and 14 led to the desired product 25 in
almost quantitative yield and with good enantioselectivity
(84% ee; see Table S1 in the Supporting Information).
As shown above, we have clearly demonstrated that a bet-
ter enantiodiscrimination can be obtained by replacing the
linear alkyl substituent (N-CH2R) by a branched alkyl sub-
stituent (N-CHRRЈ) at the R2 group of the chiral ligand.
In addition to the successful ligands 8, 13, and 14, we de-
signed and synthesized two other substituted benzyl-based
ligands, namely 26 (R2 = diphenylmethyl) and 27 (R2
=
fluorenyl; Table 2). As expected, the 1,4-addition of 22 to
Et2Zn proceeded efficiently under the influence of the
Cu(NO3)2/26 catalytic system to give 23 in 99% yield and
89% ee (entry 1). Similar results were obtained in the ACA
reaction with the Cu(NO3)2/27 catalytic system (entry 2).
Similarly, 24 and Et2Zn were converted into the corre-
sponding adduct 25 with good enantioselectivities (entries 3
and 4). Moreover, the ACA reactions of 22 and 24 with
Me2Zn were achieved by using the Cu salt/26 catalytic sys-
tem and gave the 1,4-adducts 28 and 29 with 73 and 82%
ee, respectively, although somewhat longer reaction times
were needed (entries 5 and 6).
[a] Reagents and conditions: Acyclic enone (1 mmol), Et2Zn
(3 mmol), [Cu(OTf)]2(C6H6) (6 mol-%), azolium salt (4.5 mol-%),
THF (9 mL), room temp., 3 h. The yields and ee values were deter-
mined by GLC analysis. Data in parentheses show isolated yields.
Average of two runs. [b] Cu(NO3)2 (6 mol-%), azolium salt (6 mol-
Under the optimized reaction conditions, the conjugate
addition of dialkylzinc compounds to benzalacetone (30)
was investigated (Table 2, entries 7–12). It was found that %). [c] Me2Zn (3 mmol) was used instead of Et2Zn. The reaction
was run for 24 h. [d] A conversion of Ͼ98% was observed by GLC
the catalytic system of [Cu(OTf)]2(C6H6) in combination
with 8, 13, or 26 is suitable for the ACA reaction of 30
analysis. The moderate yield was due to the volatility of 29. [e] 2-
MeTHF was used instead of THF. [f] Bu2Zn (3 mmol) was used
with Et2Zn at ambient temperature, furnishing 4-phenyl-2-
instead of Et2Zn. The reaction was run in THF (3 mL).
hexanone (31) with good enantioselectivity (89–92% ee; en-
tries 7–10). An excellent ee of 96% was obtained from the
ACA Reactions with (Ester Amide)-Functionalized Azolium
reaction of 30 with Bu2Zn catalyzed by [Cu(OTf)]2(C6H6)
Compounds
and 26 in THF (entry 12). Moreover, one of the most at-
tractive features of this reaction is that it can be performed
at ambient temperature without temperature control.
We have previously shown that the facial selectivities of
the copper-catalyzed 1,4-addition of dialkylzinc compounds
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Cu-Catalyzed Addition Reactions of Dialkylzinc Compounds
to cyclic enones with the (hydroxy amide)-functionalized 30 with Et2Zn catalyzed by [Cu(hfacac)2] in 1:1 THF/
NHC ligand D are reversed in comparison with the reaction EtOAc (left column) or by Cu(NO3)2 in THF (right col-
with the (ester amide)-functionalized NHC ligand E; the umn) with different ligand precursors to produce ent-31.
azolium D directs the 1,4-addition of R2Zn to the Si face The stereoselectivities of the [Cu(hfacac)2]-catalyzed 1,4-ad-
of the cyclic enone, whereas the 1,4-addition under the in- dition reactions performed with azolium salt 16 or 17,
fluence of E occurs on the opposite face (Scheme 2).[11] which contain ethyl (R3 = Et) or benzyl (R3 = Bn) esters,
Thus, we anticipated that the chiral ligand E derived from were comparable to that obtained with 15 (R3 = Me; en-
an α-amino ester such as serine ester might be suitable for tries 1–3, left column). In contrast, the combination of
dual enantiocontrol in the ACA reactions of acyclic enones. Cu(NO3)2 with 17 in place of 15 resulted in slightly im-
To test the possibility of achieving an enantioselective cata- proved enantioselectivity (entries 1 and 3, right column).
lytic conjugate addition reaction, we chose to study the re- This ligand screening test revealed that ent-31 was obtained
action of benzalacetone (30) with Et2Zn catalyzed by a Cu in quantitative yield with 72% ee when the reaction was
salt combined with the (ester amide)-functionalized azol- performed under the influence of [Cu(hfacac)2] and 18 (R2
ium salt 15 (R1 = CH2OH, R2 = R3 = Me; Scheme 3). = Bn, R3 = Me; entry 4, left column). However, unfortu-
Table 3 shows representative results for the ACA reaction nately, the use of 21 (R2 = CHPh2, R3 = Me) did not im-
performed under various reaction conditions. The treat- prove the enantioselectivity of either catalytic system (en-
ment of 30 with Et2Zn in the presence of catalytic amounts try 7). This result contrasts that of the above-mentioned
of [Cu(OTf)]2(C6H6) and 15 in THF at room temperature ACA reactions of acyclic enones with dialkylzinc com-
afforded the expected ent-31 in 63% yield with 44% ee (en- pounds in the presence of (hydroxy amide)-functionalized
try 1). Encouraged by this success, we examined various Cu azolium salt 26, in which the replacement of the N-methyl
precatalysts and solvents for further reaction optimization substituent (6, R2 = Me) by the diphenylmethyl substituent
(entries 2–9). The first promising result was obtained with (26, R2 = CHPh2) at the azolium ring led to a significant
Cu(NO3)2 and bis(hexafluoroacetylacetonato)copper(II) increase in the enantioselectivity (Table 2).
([Cu(hfacac)2]) as the Cu precatalyst, furnishing ent-31 in
58 and 66% ee, respectively (entries 4 and 5). Variation of
the solvent revealed that the yield of the conjugate adduct
was improved by using Et2O or EtOAc (entries 7 and 8).
Finally, it was found that 30 underwent 1,4-addition of
Et2Zn in the mixed solvent of THF and EtOAc (1:1, v/v)
to afford ent-31 in 96% yield with 65% ee (entry 9).
Table 4. [Cu(hfacac)2]- and Cu(NO3)2-catalyzed ACA reactions of
30 with Et2Zn using various (ester amide)-functionalized azolium
salts to give ent-31.[a]
Entry
Azolium
With [Cu(hfacac)2][b]
With Cu(NO3)2
Yield [%]
ee [%]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
15
16
17
18
19
20
21
33
34
35
36
36
36
96
95
95
99
96
99
95
27
93
46
90
90[c]
91
65
67
67
72
68
70
50
15
40
22
85
89[c]
92
90
72
98
83
99
95
90
16
99
32
86
–
58
68
67
59
60
58
62
10
40
9
Table 3. Screening of Cu salts and solvents in the ACA reaction of
30 with Et2Zn under the influence of (ester amide)-functionalized
azolium salt 15 to give ent-31.[a]
Entry
Cu salt
Solvent
Yield [%]
ee [%]
1
2
3
4
[Cu(OTf)]2(C6H6) THF
63
55
25
90
76
99
91
98
96
44
46
47
58
66
49
56
53
65
9
Cu(OTf)2
Cu(acac)2
THF
THF
10
11
12
13[d]
85
–
93
Cu(NO3)2
THF
THF
2-MeTHF
Et2O
EtOAc
THF/EtOAc
5[b]
6[b,c]
7[b]
8[b]
9[b,d]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
[Cu(hfacac)2]
99
[a] Reagents and conditions: 30 (1 mmol), Et2Zn (3 mmol),
[Cu(hfacac)2] or Cu(NO3)2 (6 mol-%), azolium salt (4.5 mol-%),
THF (9 mL), room temp., 3 h. The yields and ee values were deter-
mined by GLC analysis. Average of two runs. [b] A 1:1 mixture of
THF and EtOAc was used as solvent. [c] A 1:1 mixture of THF
and tBuOAc was used as solvent. [d] Acyclic enone 22 (1 mmol) in
place of 30 was treated with Et2Zn (3 mmol) to afford ent-23.
[a] Reagents and conditions: 30 (1 mmol), Et2Zn (3 mmol), Cu salt
(6 mol-%), 15 (4.5 mol-%), solvent (9 mL), room temp., 3 h. The
yields and ee values were determined by GLC analysis. Average of
two runs. [b] [Cu(hfacac)2] = bis(hexafluoroacetylacetonato)cop-
per(II). [c] 2-MeTHF = 2-methyltetrahydrofuran. [d] A 1:1 mixture
of THF and EtOAc was used as solvent.
Because the variation of the R2 and R3 groups on the
(ester amide)-functionalized azolium ligands 15–21 was not
The fact that the functionalized NHC ligand precursors effective in achieving a highly stereoselective reaction
derived from β-amino alcohols and α-amino esters gave the (Table 4, entries 1–7), the different (ester amide)-function-
opposite major enantiomer of the product is highly interest- alized azolium salts 33–36, which could be prepared from
ing from a conceptual and mechanistic point of view, but inexpensive α-amino esters, were synthesized and evaluated
not completely satisfying due to the moderate ee (65% ee) in an attempt to find a more efficient catalytic system. The
obtained in the formation of the 1,4-adduct, as shown in chiral azolium ligand 33, which only differs from 15 by the
Table 3. Therefore we next focused on screening the highly presence of the SH functional group, was synthesized from
tunable (ester amide)-functionalized azolium ligand precur- commercially available l-cysteine methyl ester by a route
sors. Table 4 summarizes the results of the ACA reaction of similar to that shown in Scheme 1. However, the ACA reac-
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K. Dohi, J. Kondo, H. Yamada, R. Arakawa, S. Sakaguchi
FULL PAPER
tion of 30 with Et2Zn in the presence of catalytic amounts droxyalkyl-functionalized azolium ligand A, Mauduit and
of [Cu(hfacac)2] or Cu(NO3)2 in combination with 33 re- co-workers suggested that a plausible reaction mechanism
sulted in the production of the corresponding conjugate ad- involves an anionic alkoxy/NHC–Cu complex containing a
duct, ent-31, in low yield and with poor enantioselectivity covalent copper–oxygen bond as a second coordination si-
(entry 8). These results will be discussed later. The 1,4-ad- te.[5c] Recently, a reaction intermediate similar to that
dition of Et2Zn to 30 by using the ligand precursor 34 de- formed in the NHC–Cu-catalyzed allylic substitution reac-
rived from l-threonine methyl ester occurred in the same tion was proposed by Jung and Hoveyda.[15] On the other
high yield as in the case of the ligand precursor 15, however, hand, we have previously shown that an anionic amidate/
the reaction proceeded with moderate enantioselectivity NHC–Pd complex was formed from the (hydroxy amide)-
(entry 9). We also designed the chiral ligand 35, which was functionalized azolium salt D and an appropriate palladium
prepared from a natural amino acid such as l-tyrosine. precursor such as [PdCl2(CH3CN)2].[12] This indicates that
When 30 was treated with Et2Zn under the influence of 35, the azolium salt D acts as a chelating ligand with a carbene
which bears a hydroxy group at a position far from the unit and a second coordinating group such as an anionic
stereogenic center of the chiral ligand, the desired product, amidate on the side-arm of the NHC. This combination
ent-31, was obtained with poor enantioselectivity (en- generates a strongly coordinating polydentate ligand that
try 10).
can lock the stereodirecting functional group in a fixed con-
formation.
We speculate that the Cu-catalyzed 1,4-addition reaction
described herein might proceed through the formation of an
anionic amidate/NHC–Cu intermediate species (Scheme 4).
The proposed reaction mechanisms for the ACA reaction
with the (hydroxy amide)-functionalized azolium ligand D
and the (ester amide)-functionalized azolium ligand E are
shown in Scheme 4. In the case of the ACA reaction per-
formed with ligand precursor D, the copper complex I in-
volving a carbene, amidate, and ethyl group might be gener-
ated. An enone would be envisioned to coordinate by ap-
proaching from the front side because of the steric repulsion
of the stereodirecting group such as R1 group on the back
side. In addition, the formation of a zinc alcoholate from
the hydroxy group initially on the azolium precursor would
facilitate the coordination of the enone by an interaction
between the carbonyl group of the enone and the zinc spe-
cies. Consequently, an ethyl group would add to the enone
from the back side as shown in I. In contrast, model IЈ
would lead to a conjugate adduct with the opposite config-
uration. In structural model IЈ, however, there would be sig-
nificant steric repulsion between the R2 group on the NHC
ring and the alkyl substituent at the β position of the enone.
We have previously demonstrated that a C2-symmetric
bis(hydroxy amide)-functionalized benzimidazolium salt ef-
ficiently performs a copper-catalyzed ACA addition of
R2Zn to cyclic enones with up to 96% ee.[13] Therefore we
designed and synthesized a similar bis(ester amide)-func-
tionalized benzimidazolium salt 36 from l-serine methyl
ester. We were pleased to find that the use of 36 led to
an increase in the enantioselectivity of the ACA reaction
(Table 4, entry 11). The treatment of 30 with Et2Zn by using
the combined catalytic system [Cu(hfacac)2] and 36 af-
forded ent-31 in 90% yield with good enantioselectivity
(85% ee). Similar results were obtained by using the
Cu(NO3)2/36 catalytic system (entry 11). Moreover, the
ACA reaction catalyzed by [Cu(hfacac)2] and 36 in a mixed
solvent of THF/tBuOAc at room temperature gave ent-31
in 90% yield and 89% ee (entry 12). In addition, the
enantioselectivity was reversed in the reaction of 22 with
Et2Zn under the influence of catalytic amounts of
[Cu(hfacac)2] or Cu(NO3)2 in combination with 36, furnish-
ing ent-23 with up to 93% ee (entry 13).[14]
Mechanistic Aspects
Although the mechanism of this reaction remains un-
clear, it is likely that the reaction proceeds through an or-
dered transition state involving the catalyst structure bear-
ing a precoordinating substituent. For the ACA reaction
Scheme 4. Proposed reaction mechanisms for the ACA reaction
catalyzed by a copper salt in combination with the hy- using the functionalized azolium salts D and E.
7148 Eur. J. Org. Chem. 2012, 7143–7152
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Cu-Catalyzed Addition Reactions of Dialkylzinc Compounds
As shown in Table 3, the use of the ligand precursor 26, more, high product yields were observed in the ACA reac-
which contains a sterically bulky diphenylmethyl substitu- tions with copper salts in combination with azolium ligand
ent at the R2 position, resulted in an increase in the enantio- 37 (Scheme 5). An independent reaction revealed that no
selectivity of the ACA reaction. This suggests that model IЈ Cu-catalyzed 1,4-addition reaction of 30 with Et2Zn oc-
would be disfavored because of steric hindrance. Conse- curred in the absence of an azolium ligand precursor. This
quently, the ACA reaction with the (hydroxy amide)-func- strongly indicates that the coordination of an appropriate
tionalized azolium D would be expected to proceed via re- NHC ligand to the metal center not only induces the stereo-
action model I.
selectivity of the ACA reaction but also enhances the reac-
On the other hand, we also speculate that the reversal of tion rate. The strong ligand-accelerated catalysis (LAC) by
enantioselectivity in the ACA reaction with the (ester NHCs in the Cu-catalyzed conjugate addition reactions of
amide)-functionalized azolium ligand E might be explained enones with dialkylzinc compounds was first reported by
as shown in Scheme 4. We chose a natural serine ester that Woodward and co-workers.[16]
bears a hydroxymethyl substituent as the origin of the chiral
induction. As indicated in structures D and EЈ in Scheme 4,
the alkyl group (R1 group) at the chiral carbon center in
Conclusions
ligand D is on the front side, whereas the ester group
(CO2R3 group) at the chiral carbon center of ligand E (EЈ)
Dual enantioselective control in the ACA reactions of
acyclic enones with R2Zn was successfully achieved by the
design and tuning of the chiral ligand structure. Highly
enantioselective catalytic 1,4-addition reactions were estab-
lished by using two types of functionalized azolium com-
pounds. These compounds were prepared with ease through
a two-step synthesis from readily available enantiopure β-
amino alcohols and α-amino esters. The high degree of
asymmetric catalysis achieved by using (hydroxy amide)-
functionalized azolium salt D is presumably due to the fa-
cial selection of the enone, which is a result of steric repul-
sion between the R2 group on the NHC ring and the alkyl
substituent at the β position of the enone (Scheme 4, inter-
mediate I vs. IЈ). In addition, the CH2OH substituent on
the (ester amide)-functionalized azolium salt E derived
from serine ester seems critical for the switching of enantio-
selectivity. We believe that the catalytic systems described in
this report are alternatives to those used previously in the
ACA reactions of acyclic enones with dialkylzinc.
is on the back side. According to this assumption, the
CO2R3 group in EЈ would correspond to the R1 group in
D, that is, E (EЈ) is formally the enantiomer of D. This
might cause significant changes in the enantioselective con-
trol of the ACA reaction. Therefore we proposed reaction
mechanism II in which the CO2R3 group is represented by
the R4 group. The intermediate II formally becomes the en-
antiomer of intermediate I. In addition, it seems likely that
a zinc alcoholate would determine the approaching direc-
tion of the enone. As shown in entry 8 of Table 4, the use of
33 (containing a CH2SH group) in place of 15 (containing
CH2OH group) led to a low yield of the conjugate adduct
with poor enantioselectivity. This suggests that the hydroxy
amide functionality of the chiral ligand, which might lead
to the generation of a zinc alcoholate intermediate in I or
II, is of critical importance for highly enantioselective ACA
reactions.
To obtain further information we prepared the function-
alized azolium ligand precursor 37 from O-benzyl-l-serine
methyl ester in which the hydroxy group is protected by a
benzyl group (Scheme 5). The treatment of 30 with Et2Zn
in the presence of either the [Cu(hfacac)2]/37 or Cu(NO3)2/
37 catalytic system afforded ent-31 with reduced enantio-
selectivity (Scheme 5). These lower enantioselectivities
might be caused by preventing the formation of a zinc alco-
holate in the intermediate II from 37 (Scheme 4). Further-
Experimental Section
General: All chemicals were obtained from commercial sources and
were used as received. 1H and 13C NMR spectra were recorded
with spectrometers at 400 and 100 MHz, respectively. Chemical
1
shifts are reported in ppm relative to TMS for H and 13C NMR
spectra. (CD3)2SO or CDCl3 was used as the NMR solvent. 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).
General Procedure for the Preparation of Azolium Salts: N-Alkyl-
benzimidazole (3 mmol), 1,4-dioxane (12 mL), and α-chloro-
acetoamide derivative (3 mmol) derived from chloroacetyl chloride
and (S)-tert-leucinol or serine ester were added to a flask. After
stirring the reaction mixture at 110 °C for 24 h, 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 remov-
ing the methanol in vacuo from the filtrate, the crude residue was
purified by column chromatography (SiO2, CH2Cl2/MeOH = 9:1)
to yield the corresponding azolium salt. Azolium salts 1–7 and 15–
18 have been reported in preceding papers.[10–12] Because of their
Scheme 5. Cu-catalyzed ACA reaction of 30 with Et2Zn using the
functionalized azolium salt 37 derived from O-benzylserine methyl
ester.
Eur. J. Org. Chem. 2012, 7143–7152
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7149

K. Dohi, J. Kondo, H. Yamada, R. Arakawa, S. Sakaguchi
FULL PAPER
highly hygroscopic character, the elemental analyses of 8, 11–14,
21, and 33 were not performed.
1 H, NH), 7.97 (d, J = 7.3 Hz, 1 H, CHbenzimid), 7.85 (d, J = 7.3 Hz,
1 H, CHbenzimid), 7.60–7.53 (m, 2 H, CHbenzimid), 5.90 (d, J =
16.0 Hz, 1 H, NCH2CO), 5.67 (d, J = 16.0 Hz, 1 H, NCH2CO),
3.82–3.77 (m, 1 H, NHCH), 3.75–3.71 (m, 2 H, CH2OH), 3.08 (br.,
1 H, OH), 1.89 (s, 9 H, CH3tBu), 0.92 (s, 9 H, CH3tBu) ppm. 13C
NMR (CDCl3): δ = 165.8 (CO), 141.9, 133.3, 129.8, 126.8, 126.2,
115.3, 114.5, 61.4 (CH2OH), 61.0 (NHCH), 60.9 (CH2CO), 49.5
(CtBu), 33.7 (CtBu), 29.1 (CH3tBu), 27.0 (CH3tBu) ppm. HRMS
3-(2-{[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]amino}-2-oxo-
ethyl)-1-(1-methylethyl)-1H-benzimidazolium Chloride (8): White
solid (yield 75%). [α]2D7 = +0.9 (c = 0.75, CH3OH). 1H NMR
(DMSO): δ = 10.09 (s, 1 H, CHbenzimid), 8.55 (br., 1 H, NH), 8.14–
7.67 (m, 4 H, CHbenzimid), 5.45 (d, J = 16.0 Hz, 1 H, NCH2CO),
5.36 (d, J = 16.0 Hz, 1 H, NCH2CO), 5.14–5.08 [m, 1 H, CH-
(CH3)2], 4.69 (br., 1 H, OH), 3.59 (br., 2 H, CH2OH), 3.40–3.48
(m, 1 H, NHCH), 1.63 (d, J = 6.4 Hz, 6 H, CH3), 0.87 (s, 9 H,
CH3tBu) ppm. 13C NMR (CDCl3): δ = 165.7 (CO), 141.8, 132.4,
130.2, 127.1, 126.7, 114.4, 112.7, 61.1 (CH2OH), 60.9 (NHCH),
51.5 (CH2CO), 49.6 [CH(CH3)2], 33.7 (CtBu), 27.0 (CH3tBu), 22.0
+
(ESI+): calcd. for C19H30N3O2 332.2332; found 332.2312.
3-(2-{[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]amino}-2-oxo-
ethyl)-1-(1-methylbutyl)-1H-benzimidazolium Chloride (13): White
solid (yield 60%). [α]2D7 = +0.2 (c = 1.0, CH3OH). 1H NMR
(DMSO): δ = 10.17 (s, 1 H, CHbenzimid), 8.60 (br., 1 H, NH), 8.18–
8.15 (m, 1 H, CHbenzimid), 8.02–8.00 (m, 1 H, CHbenzimid), 7.69–
7.64 (m, 2 H, CHbenzimid), 5.47 (dd, J = 3.7, 16.0 Hz, 1 H,
NCH2CO), 5.39 (dd, J = 3.7, 16.0 Hz, 1 H, NCH2CO), 5.06–4.98
[m, 1 H, CH(C3H7)(CH3)], 4.69 (br., 1 H, OH), 3.62–3.55 (m, 2 H,
CH2OH), 3.44–3.37 (m, 1 H, NHCH), 2.07–1.86 (m, 2 H, CH2),
1.62 (d, J = 6.4 Hz, 3 H, CH3), 1.33–1.13 (m, 2 H, CH2), 0.87 (s,
9 H, CH3tBu), 0.85 (m, 3 H, CH3) ppm. 13C NMR (DMSO): δ =
164.8 (CO), 142.3, 131.6, 130.4, 127.0, 126.5, 114.0, 113.8, 60.3
(CH2OH), 59.9 (NHCH), 54.5 (CH2CO), 48.9 [CH(C3H7)(CH3)],
33.6 (CtBu), 26.8 (CH3tBu), 20.1 (CH2), 20.1 (CH2), 18.5 (CH3), 13.4
(CH3), 22.0 (CH3) ppm. HRMS (ESI+): calcd. for C18H28N3O2
+
318.2176; found 318.2155.
1-Butyl-3-(2-{[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]amino}-2-
oxoethyl)-1H-benzimidazolium Chloride (9): White solid (yield
64%); m.p. 212.9–213.5 °C. [α]2D7 = +0.8 (c = 1.0, CH3OH). 1H
NMR (DMSO): δ = 9.97 (s, 1 H, CHbenzimid), 8.60 (br., 1 H, NH),
8.13–8.10 (m, 1 H, CHbenzimid), 8.03–7.99 (m, 1 H, CHbenzimid),
7.69–7.64 (m, 2 H, CHbenzimid), 5.50 (d, J = 16.0 Hz, 1 H,
NCH2CO), 5.40 (d, J = 16.0 Hz, 1 H, NCH2CO), 4.70 (br., 1 H,
OH), 4.56 (t, J = 6.9 Hz, 2 H, CH2C3H7), 3.62–3.55 (m, 2 H,
CH2OH), 3.43–3.35 (m, 1 H, NHCH), 1.91–1.84 (m, 2 H, CH2),
1.36–1.27 (m, 2 H, CH2), 0.90 (t, J = 7.3 Hz, 3 H, CH3), 0.86 (s, 9
H, CH3tBu) ppm. 13C NMR (DMSO): δ = 164.8 (CO), 143.3, 131.5,
130.8, 126.7, 126.6, 113.8, 113.7, 60.3 (CH2OH), 59.9 (NHCH),
48.8 (CH2CO), 46.5 (CH2C3H7), 33.6 (CtBu), 30.6 (CH2), 26.9
(CH3tBu), 19.0 (CH2), 13.4 (CH3) ppm. C19H30ClN3O2·H2O: calcd.
C 59.13, H 8.36, N 10.89; found C 59.26, H 8.29, N 10.88.
+
(CH3) ppm. HRMS (ESI+): calcd. for C20H32N3O2 346.2489;
found 346.2468.
1-(1-Ethylpropyl)-3-(2-{[(1S)-1-(hydroxymethyl)-2,2-dimethylprop-
yl]amino}-2-oxoethyl)-1H-benzimidazolium Chloride (14): White so-
lid (yield 54%). [α]2D8 = +0.7 (c = 1.0, CH3OH). 1H NMR (DMSO):
δ = 10.19 (s, 1 H, CHbenzimid), 8.63 (br., 1 H, NH), 8.21–8.16 (m, 1
H, CHbenzimid), 8.07–8.03 (m, 1 H, CHbenzimid), 7.70–7.64 (m, 2 H,
CHbenzimid), 5.50 (d, J = 16.0 Hz, 1 H, NCH2CO), 5.41 (d, J =
16.0 Hz, 1 H, NCH2CO), 4.84–4.75 [m, 1 H, CH(C2H5)2], 4.71 (br.,
1 H, OH), 3.61–3.54 (m, 2 H, CH2OH), 3.43–3.40 (m, 1 H,
NHCH), 2.05–1.98 (m, 4 H, CH2), 0.86 (s, 9 H, CH3tBu), 0.77 (t, J
= 7.3 Hz, 6 H, CH3) ppm. 13C NMR (DMSO): δ = 164.8 (CO),
142.7, 131.5, 131.0, 126.8, 126.6, 114.0, 113.8, 61.9 (CH2OH), 60.3
(NHCH), 59.9 (CH2CO), 49.0 [CH(C2H5)2], 33.6 (CtBu), 26.9
(CH3tBu), 26.8 (CH2), 26.7 (CH2), 10.0 (CH3), 10.0 (CH3) ppm.
3-(2-{[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]amino}-2-oxo-
ethyl)-1-(2-methylpropyl)-1H-benzimidazolium Chloride (10): White
solid (yield 64%); m.p. 169.9–170.1 °C. [α]2D8 = +0.7 (c = 1.0,
CH3OH). 1H NMR (DMSO): δ = 9.97 (s, 1 H, CHbenzimid), 8.62
(br., 1 H, NH), 8.16–7.65 (m, 4 H, CHbenzimid), 5.52 (d, J = 16.0 Hz,
1 H, NCH2CO), 5.43 (d, J = 16.0 Hz, 1 H, NCH2CO), 4.69 (br., 1
H, OH), 4.42 (d, J = 6.9 Hz, 2 H, CH2C3H7), 3.62–3.55 (m, 2 H,
CH2OH), 3.44–3.37 (m, 1 H, NHCH), 2.26–2.19 (m, 1 H, CH),
0.92 (d, J = 6.9 Hz, 6 H, CH3), 0.86 (s, 9 H, CH3tBu) ppm. 13C
NMR (DMSO): δ = 164.8 (CO), 143.6, 131.4, 131.0, 126.6, 126.5,
113.9, 113.6, 60.3 (CH2OH), 59.9 (NHCH), 53.1 (CH2CO), 48.7
(CH2C3H7), 33.6 (CtBu), 30.7 (CH), 28.3 (CH3), 26.8 (CH3tBu), 19.3
(CH3) ppm. C19H30ClN3O2·H2O: calcd. C 59.13, H 8.36, N 10.89;
found C 59.28, H 8.15, N 10.87.
+
HRMS (ESI+): calcd. for C20H32N3O2 346.2489; found 346.2466.
3-(2-{[(1S)-1-(Ethoxycarbonyl)-2-hydroxyethyl]amino}-2-oxoethyl)-
1-(1-phenylmethyl)-1H-benzimidazolium Chloride (19): White solid
(yield 47%); m.p. 210.4–210.5 °C. [α]2D8 = –3.0 (c = 0.5, CH3OH).
1H NMR (DMSO): δ = 10.11 (br., 1 H, CHbenzimid), 9.44 (br., 1 H,
NH), 8.00–7.93 (m, 2 H), 7.68–7.61 (m, 2 H), 7.52–7.49 (m, 2 H),
7.42–7.34 (m, 3 H, Ph), 5.86 (s, 2 H, CH2Ph), 5.48 (s, 2 H,
NCH2CO), 5.39 (br., 1 H, OH), 4.35–4.31 (m, 1 H, NHCH), 4.09–
4.04 (m, 2 H, CH2CH3), 3.81–3.68 (m, 2 H, CH2OH), 1.13 (t, J =
7.0 Hz, 3 H, CH3) ppm. 13C NMR (DMSO): δ = 169.8 (CO), 164.9
(CO), 143.6, 134.0, 131.6, 130.4, 129.0, 128.7, 128.2, 126.8, 126.7,
113.9, 113.7, 61.0 (CH2O), 60.6 (CH2O), 55.3 (NHCH), 49.8
(CH2), 48.5 (CH2), 14.0 (CH3) ppm. C21H24ClN3O4·0.6H2O: calcd.
C 58.84, H 5.92, N 9.80; found C 58.79, H 5.79, N 9.75.
3-(2-{[(1S)-1-(Hydroxymethyl)-2,2-dimethylpropyl]amino}-2-oxo-
ethyl)-1-(1-methylpropyl)-1H-benzimidazolium Chloride (11): White
solid (yield 47%). [α]2D7 = +0.8 (c = 1.0, CH3OH). 1H NMR
(DMSO): δ = 10.20 (s, 1 H, CHbenzimid), 8.65 (br., 1 H, NH), 8.20–
8.16 (m, 1 H, CHbenzimid), 8.07–8.03 (m, 1 H, CHbenzimid), 7.71–
7.66 (m, 2 H, CHbenzimid), 5.54–5.39 (m, 2 H, NCH2CO), 5.02–4.94
[m, 1 H, CH(C2H5)(CH3)], 4.74 (br., 1 H, OH), 3.63–3.57 (m, 2 H,
CH2OH), 3.45–3.39 (m, 1 H, NHCH), 2.09–1.92 (m, 2 H, CH2),
1.65 (d, J = 6.9 Hz, 3 H, CH3), 0.89 (s, 9 H, CH3tBu), 0.84 (t, J =
7.3 Hz, 3 H, CH3) ppm. 13C NMR (DMSO): δ = 164.8 (CO), 142.3,
131.6, 130.5, 126.7, 126.5, 114.0, 113.8, 60.3 (CH2OH), 59.9
(NHCH), 55.9 (CH2CO), 48.9 [CH(C2H5)(CH3)], 33.6 (CtBu), 28.4
(CH2), 26.9 (CH3tBu), 19.6 (CH3), 9.9 (CH3) ppm. HRMS (ESI+):
3-(2-{[(1S)-1-(Benzyloxycarbonyl)-2-hydroxyethyl]amino}-2-oxo-
ethyl)-1-(1-phenylmethyl)-1H-benzimidazolium Chloride (20): White
solid (yield 50%); m.p. 210.0–210.2 °C. [α]2D8 = –2.3 (c = 1.0,
CH3OH). 1H NMR (DMSO): δ = 9.98 (s, 1 H, CHbenzimid), 9.32
(d, J = 7.3 Hz, 1 H, NH), 7.99–7.86 (m, 2 H), 7.64–7.62 (m, 2 H),
7.50–7.48 (m, 2 H), 7.43–7.34 (m, 8 H), 5.84 (s, 2 H, CH2Ph), 5.45
+
calcd. for C19H30N3O2 332.2332; found 332.2311.
1-(2,2-Dimethylethyl)-3-(2-{[(1S)-1-(hydroxymethyl)-2,2- (s, 2 H, NCH2CO), 5.38–5.35 (m, 1 H, OH), 5.13 (s, 2 H, OCH2Ph),
dimethylpropyl]amino}-2-oxoethyl)-1H-benzimidazolium Chloride
4.47–4.45 (m, 1 H, NHCH), 3.86–3.81 (m, 1 H, CH2OH), 3.75–
3.70 (m, 1 H, CH2OH) ppm. 13C NMR (DMSO): δ = 169.8 (CO),
165.0 (CO), 143.6, 135.8, 133.9, 131.6, 130.4, 129.0, 128.7, 128.4,
(12): White solid (yield 65%). [α]2D8 = +0.8 (c = 1.0, CH3OH). H
1
NMR (CDCl3): δ = 10.34 (s, 1 H, CHbenzimid), 8.77 (d, J = 9.6 Hz,
7150
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Cu-Catalyzed Addition Reactions of Dialkylzinc Compounds
128.2, 128.0, 127.6, 126.8, 126.7, 113.9, 113.7, 66.0 (CH2O), 61.1 H, OH), 4.27 (dd, J = 3.7, 8.2 Hz, 1 H, NHCH), 4.17–4.13 (m, 1
(CH2 O), 55.3 (NHCH), 49. 8 (CH2 ) , 4 8. 5 ( CH2 ) pp m. H, CHOH), 4.13 (s, 3 H, NCH3), 3.61 (s, 3 H, OCH3), 1.12 (d, J
C26H26ClN3O4·0.5H2O: calcd. C 63.87, H 5.57, N 8.59; found C
63.93, H 5.26, N 8.38.
= 6.4 Hz, 1 H, CH3) ppm. 13C NMR (DMSO): δ = 170.6 (CO),
165.4 (CO), 143.8, 131.6, 131.3, 126.7, 126.5, 113.7, 113.3, 66.3
(CHOH), 58.7 (CH2CO), 52.0 (CH3O), 48.3 (NHCH), 33.4
(CH3N), 20.2 (CH3) ppm. C15H20ClN3O4·1.2H2O: calcd. C 49.58,
H 6.21, N 11.56; found C 49.47, H 5.82, N 11.54.
1-(Diphenylmethyl)-3-(2-{[(1S)-2-hydroxy-1-(methoxycarbonyl)-
ethyl]amino}-2-oxoethyl)-1H-benzimidazolium Chloride (21): White
solid (yield 43%). [α]2D7 = –2.5 (c = 1.0, CH3OH). 1H NMR
(DMSO): δ = 9.55 (s, 1 H, CHbenzimid), 9.49 (d, J = 7.3 Hz, 1 H,
NH), 7.96–7.94 (m, 1 H), 7.73–7.37 (m, 13 H), 5.46–5.42 (m, 3 H,
NCH2CO, OH), 4.35 (br., 1 H, NHCH), 3.80–3.70 (m, 2 H,
CH2OH), 3.61 (s, 3 H, OCH3), 3.40 (br., 1 H, OH) ppm. 13C NMR
(DMSO): δ = 170.4 (CO), 164.9 (CO), 143.1, 136.0, 132.0, 130.7,
129.3, 129.1, 128.3, 127.0, 126.7, 114.4, 113.9, 64.0 (CH2), 61.0
(CH2), 55.3 (CH), 52.0 (CH3), 48.7 (CH) ppm. HRMS (ESI+):
3-(2-{[(1S)-2-(4-Hydroxyphenyl)-1-(methoxycarbonyl)ethyl]amino}-
2-oxoethyl)-1-methyl-1H-benzimidazolium Chloride (35): White so-
lid (yield 62%). [α]2D7 = +1.5 (c = 1.0, CH3OH). 1H NMR (DMSO):
δ = 9.81 (s, 1 H, CHbenzimid), 9.56–9.48 (m, 2 H, NH, OH), 8.01–
7.99 (m, 1 H, CHbenzimid), 7.69–7.58 (m, 3 H, CHbenzimid), 7.05 (d,
J = 8.7 Hz, 2 H, C6H4), 6.70 (d, J = 8.2 Hz, 2 H, C6H4), 5.44 (d,
J = 16.5 Hz, 1 H, NCH2CO), 5.36 (d, J = 16.5 Hz, 1 H, NCH2CO),
4.48–4.42 (m, 1 H, NHCH), 4.11 (s, 3 H, NCH3), 3.59 (s, 3 H,
OCH3 ), 3.00–2.95 (m, 1 H, CH2Ar), 2.88–2.82 (m, 1 H,
CH2Ar) ppm. 13C NMR (DMSO): δ = 171.5 (CO), 164.7 (CO),
156.3, 143.6, 131.5, 131.1, 130.1, 126.8, 126.7, 126.5, 115.2, 113.6,
+
calcd. for C26H26N3O2 444.19178; found 444.1889.
1-(Diphenylmethyl)-3-(2-{[(1S)-1-(hydroxymethyl)-2,2-dimethyl-
propyl]amino}-2-oxoethyl)-1H-benzimidazolium Chloride (26):
White solid (yield 70%); m.p. 159.8–160.2 °C. [α]2D7 = +0.5 (c = 1.0,
CH3OH). 1H NMR (DMSO): δ = 9.49 (s, 1 H, CHbenzimid), 8.52
(br., 1 H, NH), 8.00–7.98 (m, 1 H), 7.72–7.35 (m, 14 H), 5.47 (d,
J = 16.5 Hz, 1 H, NCH2CO), 5.37 (d, J = 16.5 Hz, 1 H, NCH2CO),
4.66 (t, J = 5.5 Hz, 1 H, OH), 3.61–3.54 (m, 2 H, CH2OH), 3.42–
3.37 (m, 1 H, NHCH), 0.85 (s, 9 H, CH3tBu) ppm. 13C NMR
(DMSO): δ = 164.8 (CO), 143.0, 138.0, 132.0, 130.7, 129.3, 129.1,
128.3, 126.9, 126.7, 114.3, 113.9, 63.9 (CH2OH), 60.2 (NHCH),
59. 8 (CH2 CO), 33. 6 (Ct B u ), 30. 7, 26. 8 (CH3 t B u ) ppm.
C28H32ClN3O2·CH3CO2C2H5·CH2Cl2·0.5H2O: calcd. C 60.05, H
6.57, N 6.37; found C 59.92, H 6.72, N 6.06.
113.3, 54.3 (CH2CO), 52.0 (CH3O), 48.2 (NHCH), 35.9 (CH2Ar),
+
33.3 (CH3N) ppm. HRMS (ESI+): calcd. for C20H22N3O2
368.1604; found 368.1581.
:
1,3-Bis(2-{[(1S)-2-Hydroxy-1-(methoxycarbonyl)ethyl]amino}-2-oxo-
ethyl)-1H-benzimidazolium Chloride (36): White solid (yield 71%);
m.p. 208.7–208.9 °C. [α]2D8 = –4.0 (c = 0.5, CH3OH). 1H NMR
(DMSO): δ = 9.80 (s, 1 H, CHbenzimid), 9.20 (br., 2 H, NH), 7.90–
7.88 (m, 2 H, CHbenzimid), 7.71–7.68 (m, 2 H, CHbenzimid), 5.46 (s,
4 H, NCH2CO), 5.28 (t, J = 5.5 Hz, 2 H, OH), 4.42–4.37 (m, 2 H,
NHCH), 3.81–3.65 (m, 4 H, CH2OH), 3.63 (s, 6 H, OCH3) ppm.
13C NMR (DMSO): δ = 170.4 (CO), 164.8 (CO), 144.4, 131.2,
126.8, 113.6, 61.1 (CH2OH), 55.1 (CH2CO), 52.1 (CH3O), 48.5
(NHCH) ppm. C19H25ClN4O8·0.8H2O: calcd. C 46.83, H 5.50, N
11.50; found C 46.74, H 4.96, N 11.21.
1-(Fluoren-9-yl)-3-(2-{[(1S)-1-(hydroxymethyl)-2,2-dimethyl-
propyl]amino}-2-oxoethyl)-1H-benzimidazolium Chloride (27):
White solid (yield 61%); m.p. 174.5–175.1 °C. [α]2D8 = +0.6 (c = 1.0,
1
CH3OH). H NMR (CDCl3): δ = 11.08 (s, 1 H, CHbenzimid), 9.13
(d, J = 8.6 Hz, 1 H, NH), 7.96 (d, J = 7.7 Hz, 1 H), 7.82 (d, J =
7.7 Hz, 2 H), 7.64 (d, J = 7.7 Hz, 1 H), 7.48–7.43 (m, 4 H), 7.38
(t, J = 7.7 Hz, 1 H), 7.30 (s, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 7.12
(t, J = 7.7 Hz, 1 H), 7.05 (t, J = 7.7 Hz, 1 H), 6.31 (br., 1 H), 6.19
(d, J = 15.9 Hz, 1 H, NCH2CO), 5.95 (d, J = 15.9 Hz, 1 H,
NCH2CO), 3.87–3.64 (m, 3 H, CH2OH, NHCH), 0.88 (s, 9 H,
CH3tBu) ppm. 13C NMR (CDCl3): δ = 166.1 (CO), 145.1, 140.6,
140.5, 139.1, 132.6, 130.3, 130.2, 129.1, 128.6, 128.5, 126.9, 126.5,
126.0, 125.8, 120.5, 114.0, 113.8, 63.3 (CH2OH), 61.2 (NHCH),
50.1 (CH), 33.7 (CtBu), 27.0 (CH3tBu) ppm. C28H30ClN3O2·2H2O:
calcd. C 65.68, H 6.69, N 8.21; found C 65.57, H 6.59, N 7.85.
3-(2-{[(1S)-2-(Benzyloxy)-1-(methoxycarbonyl)ethyl]amino}-2-oxo-
ethyl)-1-(phenylmethyl)-1H-benzimidazolium Chloride (37): White
solid (yield 53%); m.p. 142.3–142.6 °C. [α]2D8 = –1.2 (c = 0.5,
1
CH3OH). H NMR (DMSO): δ = 10.18 (s, 1 H, CHbenzimid), 9.55
(d, J = 7.3 Hz, 1 H, NH), 8.01–7.97 (m, 1 H), 7.90–7.88 (m, 1 H),
7.65–7.61 (m, 2 H), 7.52–7.50 (m, 2 H), 7.42–7.27 (m, 8 H), 5.88
(s, 2 H, CH2Ph), 5.55 (d, J = 16.9 Hz, 1 H, NCH2CO), 5.50 (d, J
= 16.9 Hz, 1 H, NCH2CO), 4.63–4.58 (m, 1 H, NHCH), 4.57 (d,
J = 12.4 Hz, 1 H, OCH2Ph), 4.50 (d, J = 12.4 Hz, 1 H, OCH2Ph),
3.83–3.79 (m, 1 H, CH2OBn), 3.71–3.68 (m, 1 H, CH2OBn), 3.63
(s, 3 H, OCH3) ppm. 13C NMR (DMSO): δ = 169.9 (CO), 165.1
(CO), 143.6, 143.6, 137.8, 134.0, 131.6, 130.4, 129.0, 128.7, 128.3,
128.2, 127.6, 126.8, 126.7, 113.9, 113.7, 72.2 (CH2O), 68.9 (CH2O),
52.8 (CH2CO), 52.2 (CH3O), 49.8 (CH2Ph), 48.5 (NHCH) ppm.
C26H26ClN3O4·0.4H2O: calcd. C 64.10, H 5.54, N 8.63; found C
64.10, H 5.79, N 8.27.
3-(2-{[(1S)-2-Mercapto-1-(methoxycarbonyl)ethyl]amino}-2-oxo-
ethyl)-1-methyl-1H-benzimidazolium Chloride (33): White solid;
m.p. 145.2–145.5 °C. [α]2D8 = –3.3 (c = 0.2, CH3OH). 1H NMR
(DMSO): δ = 9.95 (s, 1 H, CHbenzimid), 9.83 (br., 1 H, NH), 8.05–
7.98 (m, 2 H, CHbenzimid), 7.68–7.66 (m, 2 H, CHbenzimid), 5.61 (d,
J = 16.5 Hz, 1 H, NCH2CO), 5.52 (d, J = 16.5 Hz, 1 H, NCH2CO),
4.50–4.45 (m, 1 H, NHCH), 4.13 (s, 3 H, NCH3), 3.61 (s, 3 H,
OCH3), 2.91–2.81 (m, 2 H, CH2SH) ppm. 13C NMR (DMSO): δ =
170.1 (CO), 165.2 (CO), 143.8, 131.5, 131.3, 126.7, 126.5, 113.7,
113.6, 55.2 (CH2CO), 52.2 (CH3O), 48.3 (NHCH), 33.4 (CH3N),
25.3 (CH2SH) ppm. C14H18ClN3O2S·0.8CH2Cl2: calcd. C 43.17, H
4.80, N 10.20; found C 43.36, H 4.77, N 10.39.
General Procedure for the Cu-Catalyzed Asymmetric Reactions of
Enones with R2Zn: A Cu salt (0.06 mmol) and enone (1 mmol) were
added to a solution of the azolium salt (0.045 or 0.06 mmol) in
THF (9 mL) . After cooling the mixture 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 stir-
ring at room temperature for 3 h, the reaction was quenched with
10% aq. HCl. The product yield was determined by GLC using a
internal standard technique. The enantiomeric excess was measured
by chiral GLC or chiral LC (see the Supporting Information). The
conjugate adduct was isolated as follows: After quenching the reac-
3-(2-{[(1S)-2-Hydroxy-1-(methoxycarbonyl)propyl]amino}-2-oxoe-
thyl)-1-methyl-1H-benzimidazolium Chloride (34): White solid (yield
77%); m.p. 121.1–121.3 °C. [α]2D7 = –3.1 (c = 1.0, CH3OH). 1H
NMR (DMSO): δ = 9.89 (s, 1 H, CHbenzimid), 9.31 (d, J = 8.7 Hz,
1 H, NH), 8.05–8.02 (m, 1 H, CHbenzimid), 7.95–7.90 (m, 1 H, tion mixture with 10% aq. HCl, the resulting mixture was extracted
CHbenzimid), 7.71–7.66 (m, 2 H, CHbenzimid), 5.55 (d, J = 16.5 Hz,
1 H, NCH2CO), 5.48 (d, J = 16.5 Hz, 1 H, NCH2CO), 5.35 (br., 1
with diisopropyl ether (3ϫ10 mL) and dried with Na2SO4. The
product was purified by silica gel column chromatography (hexane/
Eur. J. Org. Chem. 2012, 7143–7152
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7151

K. Dohi, J. Kondo, H. Yamada, R. Arakawa, S. Sakaguchi
FULL PAPER
47, 7358–7362; g) M. K. Brown, T. L. May, C. A. Baxter, A. H.
Hoveyda, Angew. Chem. 2007, 119, 1115–1118; Angew. Chem.
Int. Ed. 2007, 46, 1097–1100; h) K.-s. Lee, M. K. Brown, A. W.
Hird, A. H. Hoveyda, J. Am. Chem. Soc. 2006, 128, 7182–7184;
i) J. J. Van Veldhuizen, S. B. Garber, J. S. Kingsbury, A. H. Ho-
veyda, J. Am. Chem. Soc. 2002, 124, 4954–4955.
Et2O). Because of the volatility of conjugate adducts such as 29,
the solvent was removed carefully under reduced pressure. The
yields are the average of two runs. The 1,4-adducts 23,[17] 25,[17]
28,[18] 29,[19] 31,[17] and 32[20] have been reported in the literature.
Supporting Information (see footnote on the first page of this arti-
cle): Evaluation of the chiral azolium ligands used in the ACA
reaction of 24 with Et2Zn catalyzed by Cu(OTf)2, results of the
ACA reaction of 24 with Et2Zn under selected reaction conditions,
NMR spectra, and chiral GC and LC traces.
[4] P. L. Arnold, M. Rodden, K. M. Davis, A. C. Scarisbrick, A. J.
Blake, C. Wilson, Chem. Commun. 2004, 1612–1613.
[5] a) M. Tissot, D. Poggiali, H. Hénon, D. Müller, L. Guénée, M.
Mauduit, A. Alexakis, Chem. Eur. J. 2012, 18, 8731–8747; b)
S. Kehrli, D. Martin, D. Rix, M. Mauduit, A. Alexakis, Chem.
Eur. J. 2010, 16, 9890–9904; c) D. Rix, S. Labat, L. Toupet, C.
Crévisy, M. Mauduit, Eur. J. Org. Chem. 2009, 1989–1999; d)
H. Hénon, M. Mauduit, A. Alexakis, Angew. Chem. 2008, 120,
9262–9264; Angew. Chem. Int. Ed. 2008, 47, 9122–9124; e) H.
Clavier, J.-C. Guillemin, M. Mauduit, Chirality 2007, 19, 471–
476; f) D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M.
Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416–
8417; g) H. Clavier, L. Coutable, L. Toupet, J.-C. Guillemin,
M. Mauduit, J. Organomet. Chem. 2005, 690, 5237–5254.
[6] a) J. M. García, A. González, B. G. Kardak, J. M. Odriozola,
M. Oiarbide, J. Razkin, C. Palomo, Chem. Eur. J. 2008, 14,
8768–8771; b) S. R. Harutyunyan, F. López, W. R. Browne, A.
Correa, D. Penˇa, R. Badorrey, A. Meetsma, A. J. Minnaard,
B. L. Feringa, J. Am. Chem. Soc. 2006, 128, 9103–9118.
Acknowledgments
This work was financially supported by the Japan Society for the
Promotion of Science (JSPS) through a Grant-in-Aid for Scientific
Research (grant number 23550128).
[1] For selected recent reviews, see: a) J.-X. Ji, A. S. C. Chan, in:
Catalytic Asymmetric Synthesis (Ed.: I. Ojima), John Wiley &
Sons, Hoboken, NJ, 2010, pp. 439–495; b) C. Hawner, A.
Alexakis, Chem. Commun. 2010, 46, 7295–7306; c) T. Jerphag-
non, M. G. Pizzuti, A. J. Minnaard, B. L. Feringa, Chem. Soc.
Rev. 2009, 38, 1039–1075; d) J. Wencel, M. Mauduit, H.
Hénon, S. Kehrli, A. Alexakis, Aldrichim. Acta 2009, 42, 43–
50; e) A. Alexakis, J. E. Bäckvall, N. Krause, O. Pàmies, M.
Diéguez, Chem. Rev. 2008, 108, 2796–2823; f) J. Christoffers,
G. Koripelly, A. Rosiak, M. Rössle, Synthesis 2007, 1279–1300;
g) F. López, A. J. Minnaard, B. L. Feringa, Acc. Chem. Res.
2007, 40, 179–188; h) A. H. Hoveyda, A. W. Hird, M. A.
Kacprzynski, Chem. Commun. 2004, 1779–1785; i) A. Alexakis,
C. Benhaim, Eur. J. Org. Chem. 2002, 3221–3236.
[2] For selected recent reviews, see: a) J. Tornatzky, A. Kannen-
berg, S. Blechert, Dalton Trans. 2012, 41, 8215–8255; b) F.
Wang, L.-j. Liu, W. Wang, S. Li, M. Shi, Coord. Chem. Rev.
2012, 256, 804–853; c) S. Díez-González (Ed.), N-Heterocyclic
Carbenes, RSC, Cambridge, 2011; d) L. Benhamou, E. Char-
don, G. Lavigne, S. Bellemin-Laponnaz, V. César, Chem. Rev.
2011, 111, 2705–2733; e) O. Kühl, Funtionalised N-Heterocyclic
Carbene Complexes, Wiley-VCH, Weinheim, 2010; f) S. Díez-
González, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612–
3676; g) D. R. Snead, H. Seo, S. Hong, Curr. Org. Chem. 2008,
12, 1370–1387; h) F. E. Hahn, M. C. Jahnke, Angew. Chem.
2008, 120, 3166–3216; Angew. Chem. Int. Ed. 2008, 47, 3122–
3172; i) F. Glorius (Ed.), N-Heterocyclic Carbenes in Transition
Metal Catalysis, Springer, Berlin/Heidelberg, 2007; j) R. E.
Douthwaite, Coord. Chem. Rev. 2007, 251, 702–717; k) S. P.
Nolan (Ed.), N-Heterocyclic Carbenes in Synthesis Wiley-VCH,
Weinheim, Germany, 2006; l) L. H. Gade, S. Bellemin-Lapon-
naz, Coord. Chem. Rev. 2007, 251, 718–725; m) E. A. B.
Kantchev, C. J. O’Brien, M. G. Organ, Angew. Chem. 2007,
119, 2824–2870; Angew. Chem. Int. Ed. 2007, 46, 2768–2813;
n) M. S. Sigman, D. R. Jensen, Acc. Chem. Res. 2006, 39, 221–
229; o) E. Peris, R. H. Crabtree, Coord. Chem. Rev. 2004, 248,
2239–2246; p) V. César, S. Bellemin-Laponnaz, L. H. Gade,
Chem. Soc. Rev. 2004, 33, 619–636; q) M. C. Perry, K. Burgess,
Tetrahedron: Asymmetry 2003, 14, 951–961; r) W. A. Herrm-
ann, Angew. Chem. 2002, 114, 1342–1363; Angew. Chem. Int.
Ed. 2002, 41, 1290–1309.
[7] T. Uchida, T. Katsuki, Tetrahedron Lett. 2009, 50, 4741–4743.
[8] N. Fuchs, M. D’Augustin, M. Humam, A. Alexakis, R. Taras,
S. Gladiali, Tetrahedron: Asymmetry 2005, 16, 3143–3146.
[9]
R. R. Cesati, J. de Armas, A. H. Hoveyda, J. Am. Chem. Soc.
2004, 126, 96–101.
a) N. Shibata, M. Yoshimura, H. Yamada, R. Arakawa, S. Sak-
aguchi, J. Org. Chem. 2012, 77, 4079–4086; b) N. Shibata, M.
Okamoto, Y. Yamamoto, S. Sakaguchi, J. Org. Chem. 2010, 75,
5707–5715; c) M. Okamoto, Y. Yamamoto, S. Sakaguchi,
Chem. Commun. 2009, 7363–7365.
[10]
[11]
[12]
M. Yoshimura, N. Shibata, M. Kawakami, S. Sakaguchi, Tetra-
hedron 2012, 68, 3512–3518.
a) S. Sakaguchi, M. Kawakami, J. O’Neill, K. S. Yoo, K. W.
Jung, J. Organomet. Chem. 2010, 695, 195–200; b) K. S. Yoo,
J. O’Neill, S. Sakaguchi, R. Giles, J. H. Lee, K. W. Jung, J. Org.
Chem. 2010, 75, 95–101; c) S. Sakaguchi, K. S. Yoo, J. O’Neill,
J. H. Lee, T. Stewart, K. W. Jung, Angew. Chem. 2008, 120,
9466–9469; Angew. Chem. Int. Ed. 2008, 47, 9326–9329.
[13] A. Harano, S. Sakaguchi, J. Organomet. Chem. 2011, 696, 61–
67.
[14] One of the reviewers pointed out the possibility of racemization
of 36 during its preparation. In the 1H NMR analysis of 36,
however, only one component was observed (no existence of
diastereoisomers). In addition, the high enantioselectivity ob-
tained in the conjugate addition reaction of 22 with Et2Zn
might suggest that 36 was prepared with high purity. The pos-
sible racemization of the (ester amide)-functionalized azolium
salts 33–35 is currently under investigation.
[15] B. Jung, A. H. Hoveyda, J. Am. Chem. Soc. 2012, 134, 1490–
1493.
[16] P. K. Fraser, S. Woodward, Tetrahedron Lett. 2001, 42, 2747–
2749.
[17] A. Alexakis, C. Benhaim, S. Rosset, M. Humam, J. Am. Chem.
Soc. 2002, 124, 5262–5263.
[18] A. Hajra, N. Yoshikai, E. Nakamura, Org. Lett. 2006, 8, 4153–
[3] a) T. L. May, J. A. Dabrowski, A. H. Hoveyda, J. Am. Chem.
Soc. 2011, 133, 736–739; b) J. M. O’Brien, K.-s. Lee, A. H. Ho-
veyda, J. Am. Chem. Soc. 2010, 132, 10630–10633; c) K.-s. Lee,
A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 2898–2900; d)
K.-s. Lee, A. H. Hoveyda, J. Org. Chem. 2009, 74, 4455–4462;
e) M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130,
12904–12906; f) T. L. May, M. K. Brown, A. H. Hoveyda, An-
gew. Chem. 2008, 120, 7466–7472; Angew. Chem. Int. Ed. 2008,
4155.
[19] A. De Roma, F. Ruffoa, S. Woodward, Chem. Commun. 2008,
5384–5386.
[20] a) C. Monti, C. Gennari, U. Piarulli, Chem. Eur. J. 2007, 13,
1547–1558; b) G. Delapierre, T. Constantieux, J. M. Brunel, G.
Buono, Eur. J. Org. Chem. 2000, 2507–2511.
Received: August 9, 2012
Published Online: November 7, 2012
7152
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 7143–7152