Enantioselectivity switch in copper-catalyzed conjugate addition reactions under the influence of a chiral N-heterocyclic carbene-silver complex

Article abstract of DOI:10.1039/c5ra25926f

The asymmetric 1,4-addition of Et₂Zn to 2-cyclohexen-1-one using a Cu(i) salt/N-heterocyclic carbene (NHC)-Ag complex catalytic system afforded optically active 3-ethylcyclohexanone. The reversal of enantioselectivity using the same catalytic s

Full text of DOI:10.1039/c5ra25926f

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Enantioselectivity switch in copper-catalyzed
conjugate addition reactions under the influence of
a chiral N-heterocyclic carbene–silver complex†
Cite this: RSC Adv., 2016, 6, 7755
Received 5th December 2015
Accepted 11th January 2016
*
Keitaro Matsumoto, Yuki Nakano, Naoatsu Shibata and Satoshi Sakaguchi
DOI: 10.1039/c5ra25926f
www.rsc.org/advances
The asymmetric 1,4-addition of Et2Zn to 2-cyclohexen-1-one using salt thus obtained promoted the enantioselective 1,4-addition
a Cu(I) salt/N-heterocyclic carbene (NHC)–Ag complex catalytic of dialkylzinc reagents to enones.7 Alexakis and Roland reported
system afforded optically active 3-ethylcyclohexanone. The reversal of that the use of an NHC–Ag complex instead of an azolium salt
enantioselectivity using the same catalytic system was achieved by carbene precursor in the Cu-catalyzed ACA reaction of cyclic
changing the order of the addition of substrates.
enone with Et2Zn (4) increased the stereoselectivity.8 Thus, we
envisioned that the stereoselectivity of an ACA reaction would
be enhanced by using a “Cu precatalyst/NHC–Ag complex”
catalytic system. During the course of our study, we discovered
that the enantioselectivity of the reaction was reversed by
varying the order of the addition of the substrates such as the
enone and dialkylzinc. When dialkylzinc was added to a mixture
of Cu(I) precatalyst, NHC–Ag complex and enone, the 1,4-addi-
tion reaction afforded the corresponding adduct with good
enantioselectivity. Surprisingly, the conjugate adduct with the
opposite conguration was obtained as the major product by
adding the enone as the last component to the mixture of Cu(I)
salt, NHC–Ag complex and dialkylzinc. Herein, we report our
ndings on the switching of enantioselectivity with the in situ
generated NHC–Cu species by using a single chiral source.
This study commenced with the synthesis of an NHC–Ag
complex (Scheme 1). The ethylene-bridged, hydroxyamide-
functionalized azolium salt 1 was synthesized in two steps
from a b-amino alcohol according to a previously reported
procedure.7b In this study, the chiral ligand precursors 1a, 1b
and ent-1b derived from (+)-leucinol, (+)-2-amino-1-butanol and
(ꢀ)-2-amino-1-butanol, respectively, were selected. The NHC–Ag
complexes were easily synthesized using the Ag2O method.9 The
Asymmetric catalysis is an efficient tool for the synthesis of
enantiomerically enriched compounds using chiral catalysts. In
this regard, it is important to develop novel chiral ligands for
efficient asymmetric transformations. Despite enormous prog-
ress, it is a signicant challenge to develop asymmetric catalytic
methods that afford both the enantioenriched products using
a single chiral source.1 Hence, in recent years, much attention
has been paid to study the induction of both enantiomers
without using the antipode of the chiral source.2
Enantioselective conjugate addition reaction is one of the
most important tools for the synthesis of valuable optically
active compounds. Recently, several efficient chiral ligands have
been developed for this transformation.3 Over the last decades,
N-heterocyclic carbenes (NHCs) have been developed as useful
ligands for the Cu-catalyzed 1,4-addition of organometallic
reagents to a,b-unsaturated carbonyl compounds.4,5 One of the
most attractive features of NHC ligands is the easy access to
their precursors; thus, diverse NHC ligands can be obtained for
efficient metal-catalyzed asymmetric reactions.4 The common
methods for catalytic asymmetric conjugate addition (ACA)
reactions involve in situ generated catalysts from azolium salts
(a precursor of NHC) and a Cu species.5
Recently, we designed and synthesized
a
chiral
hydroxyamide-functionalized azolium salt that acts as the
precursor of NHC from an a-amino acid.6 To our delight, the
combination of a Cu catalyst precursor and the chiral azolium
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials
and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan. E-mail:
satoshi@kansai-u.ac.jp
† Electronic supplementary information (ESI) available: Experimental details,
Scheme S1, S2, data for Fig. 1 and spectral data. See DOI: 10.1039/c5ra25926f
Scheme 1 Preparation of NHC–Ag complexes.
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Table 1 Switching of enantioselectivity in ACA reactiona
treatment of precursor 1a with 0.5 equiv. of Ag2O in CH2Cl2 at
room temperature under open-air conditions afforded the cor-
responding monodentate NHC–Ag complex 2a in 92% yield.
NHC–Ag complexes 2b and ent-2b were synthesized in a similar
manner. Notably, these newly synthesized Ag complexes were
air and moisture stable; thus, they could be easily handled
under air atmosphere and stored as solids without any special
precaution. These compounds were completely characterized by
1H and 13C NMR spectroscopies in DMSO-d6 and elemental
analysis. In the 1H NMR spectra of azolium salt 1a and NHC–Ag
complex 2a, the signal at d 9.1 ppm for the azolium proton was
observed in azolium salt 1a, but not in NHC–Ag complex 2a.
Furthermore, the signals at approximately d 7.8 and 4.5 ppm
corresponding to the N–H and O–H protons, respectively, in salt
1a were still present in the spectrum of complex 2a, indicating
that no anionic amidato- and alkoxy-tethered NHC–Ag complex
was formed.6c In the 13C NMR spectra of compounds 1a and 2a,
the signal of the carbene C shied to a higher frequency by ꢁ40
ppm upon deprotonation. The characteristic carbene C signal at
d 191.0 ppm was observed in NHC–Ag complex 2a.
The reaction of 2-cyclohexen-1-one (3) with Et2Zn (4) in the
presence of catalytic amounts of “(CuOTf)2$C6H6/NHC–Ag
complex” in THF was selected as the model reaction. Table 1
summarizes the 1,4-addition of Et2Zn (4) to enone 3 under the
inuence of NHC–Ag complex 2a or 2b under selected reaction
conditions, affording 3-ethylcyclohexanone (5). The reaction
was conducted by adding enone 3 rst, followed by 4, to a THF
solution of (CuOTf)2$C6H6 (6 mol%) and NHC–Ag complex 2a (4
mol%) under Ar atmosphere (method A). The reaction con-
ducted using method A at room temperature afforded (R)-5 as
the major product in 78% yield and with 67% ee (entry 1). Under
air atmosphere, the corresponding 1,4-adduct was obtained in
a low yield and with moderate enantioselectivity (entry 2). When
the reaction temperature was decreased to ꢀ20 ꢂC, a slight
improvement in the enantioselectivity was observed, affording
(R)-5 with 72% ee (entry 3).
Cu salt
(mol%)
NHC–Ag
(mol%)
Yieldc
(%)
eed
(%)
Entry
Methodb
Product
1
6
6
6
6
4
4
4
2
6
6
6
6
4
4
4
4
2a (4)
2a (4)
2a (4)
2a (4)
2a (6)
2a (10)
2a (10)
2a (6)
2b (4)
2b (4)
2b (4)
2b (4)
2b (6)
2b (10)
2b (10)
2a (10)
A
A
A
B
B
B
B
B
A
A
A
B
B
B
B
A
(R)-5
(R)-5
(R)-5
78
46
87
67
51
72
2e
3f
4g
5
(S)-5
(S)-5
(S)-5
(S)-5
(R)-5
(R)-5
(R)-5
30
84
75
74
99
65
84
10
79
88
82
61
45
74
6
7e
8e
9
10e
11f
12g
13
14
15e
16
(S)-5
(S)-5
(S)-5
(R)-5
49
97
84
89
58
75
87
18
a
Reaction conditions: 3 (0.5 mmol), 4 (1.5 mmol), (CuOTf)2$C6H6 (2–6
mol%), 2 (4–10 mol%), in THF (7–9 mL) at room temperature for 3 h
b
under Ar. Method A: to a solution of Cu precatalyst and 2 in THF, 3
was added rst, then 4. Method B: 4 was added rst, then 3.
c
Determined by GC using the internal standard method.
Determined by GC on a chiral stationary phase. Under air. At ꢀ20
d
e
f
ꢂC. g Almost no reaction occurred.
Next, Et2Zn (4) was added to a THF solution of (CuOTf)2$C6H6
and NHC–Ag complex 2a; aer stirring for 30 min, enone 3 was
added to the resulting reaction mixture (method B). The reac-
tion conducted using method B under the inuence of
At this stage, the ratio of the Cu salt and NHC–Ag complex
(CuOTf)2$C6H6 (6 mol%) and NHC–Ag complex 2a (4 mol%) used in method A differs from that used in method B. There-
failed (entry 4). However, the reaction using 4 mol% Cu pre- fore, the ACA reaction using method A under the inuence of
catalyst and 10 mol% chiral ligand precursor afforded the (CuOTf)2$C6H6 (4 mol%) and NHC–Ag complex 2a (10 mol%)
conjugate adduct with the opposite conguration compared to was nally examined (Table 1, entry 16). This reaction afforded
the product obtained in the ACA reaction using method A (entry (R)-5 with low enantioselectivity. These results indicate that the
6). A high ee value of 88% was obtained for (S)-5 in the ACA ratio of Cu/NHC is also an important factor for achieving the
reaction catalyzed by (CuOTf)2$C6H6/2a system using method B dual enantiocontrol with high enantioselectivity. In the litera-
under air atmosphere, even though the reason for the effect of ture, the enantioselectivity switch in the Cu-catalyzed ACA
air is unclear at this stage (entry 7). Moreover, a decrease in the reaction using dipeptide phosphine ligand was reported by
catalyst loading (Cu/NHC–Ag ¼ 2/6 mol%) did not decrease changing the reaction temperature.3e
the product yield and ee signicantly (entry 8). The ability of the
The higher performance of the combined catalytic system of
reversal of enantiocontrol in ACA reaction using NHC–Ag a Cu salt and 2b prompted us to study the ability of the chiral
complex 2b derived from (+)-2-amino-1-butanol was also NHC ligand with the opposite conguration. As expected, when
investigated. The results obtained in the ACA reaction Et2Zn (4) was added to a THF solution of (CuOTf)2$C6H6, ent-2b
with (CuOTf)2$C6H6/2b system were similar to those obtained and enone 3 (method A), the corresponding 1,4-adduct such as
with (CuOTf)2$C6H6/2a system (Table 1, entries 1–7 vs. entries (S)-5 was preferentially obtained in 82% yield and with 78% ee.
9–15).‡
In stark contrast, when Et2Zn (4) was added rst followed by
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Table 2 Evaluation of several cyclic enonesa
Entry Substratesc NHC–Ag Method Adduct Yieldb (%) ee (%)
enone 3 (method B), (R)-5 was obtained as the major product
(85% yield and 85% ee) (see Scheme S1 in ESI†).
With a set of both the enantiomers of NHC–Ag complex in
hand, the relationship between catalyst ee (eecat) and product ee
(eepro) in both the asymmetric reaction systems (methods A and B)
was investigated (Fig. 1, see also ESI†). Kagan reported that a plot
of eepro vs. eecat is a simple method to obtain the information on
the enantioselectivity of a catalytic reaction.10 Various mixtures of
NHC–Ag complexes 2b and ent-2b were carefully prepared. The
ACA reaction using method A provided sufficient chiral ampli-
cation to reach an enantiopure end state. Moreover, in the reac-
tion using method B, the chiral amplication phenomenon was
also observed. These results probably indicate that only one
molecule of the chiral auxiliary is not involved in both the active
catalyst species, even though we have no experimental evidence to
elucidate the reaction mechanism at this stage.
1
6 + 4
6 + 4
6 + 4
6 + 4
6 + 8
6 + 8
3 + 8
3 + 8
3 + 8
11 + 4
11 + 4
11 + 4
11 + 4
13 + 4
13 + 4
2a
2b
2a
2b
2b
2b
2a
2a
2b
2a
2b
2a
2b
2b
2b
A
A
B
B
A
B
A
B
B
A
A
B
B
A
B
(R)-7
(R)-7
(S)-7
(S)-7
9
84
85
83
83
86
—
95
—
95
95
71
60
95
96
9
2
96
3
79
4
91
5
6
7
8
Trace
96
Trace
90
88
42
52
41
32
79
(S)-9
10
(S)-10
(S)-10
(S)-12
(S)-12
(R)-12
(R)-12
(S)-14
(S)-14
9
10d
11d
12d
13d
14
15
63
80
a
Finally, the switching of enantioselectivity in the conjugate
addition of dialkylzinc reagents to other cyclic enones was
investigated using this protocol (Table 2). The catalytic systems
were suitable for the reaction of 2-cyclohepten-1-one (6) with
dialkylzinc (entries 1–6). The 1,4-addition reaction of 6 with Et2Zn
(4) proceeded efficiently under the inuence of (CuOTf)2$C6H6/
2b system using method A, affording (R)-3-ethylcycloheptanone
((R)-7) in an excellent yield (96%) and with 83% ee (entry 2). The
use of the same catalyst under the reaction conditions using
method B afforded (S)-7 with the opposite conguration in 91%
yield and with 86% ee (entry 4). In the reaction of enone 6 with
Me2Zn (8) using method A catalyzed by (CuOTf)2$C6H6/2b
system, most of 6 was recovered (entry 5). In contrast, (S)-9 was
obtained in an excellent yield (96%) and enantioselectivity (95%
ee) using method B (entry 6). Although the ACA reaction of 8 to 3
proceeded with difficulty using method A (entry 7), a highly
enantioselective reaction was achieved by adding 3 as the last
component to a mixture of Cu(I) salt, 2a and 8 (method B),
affording (S)-10 in 90% yield and with 95% ee (entry 8).
Method A: reaction was run as under the same reaction conditions as
shown in Table 1, entry 3 or entry 11. Method B: reaction was run as
under the same reaction conditions as shown in Table 1, entry 7 or
b
c
entry 15. Isolated yield. 6: 2-Cyclohepten-1-one; 4: Et2Zn; 8: Me2Zn;
3: 2-cyclohexen-1-one; 11: 4,4-dimethyl-2-cyclohexen-1-one; 13: 2-
cyclopenten-1-one. d For 24 h.
conformational difference between the ve-membered ring in
13 and six-membered ring in 3.11 Furthermore, the ACA reaction
of acyclic enone was examined. Although the switching of
enantioselectivity was observed in the reactions of 3-nonen-2-
one with Et2Zn, the 1,4-adducts were obtained with low enan-
tioselectivities (see Scheme S2 in ESI†).12
Mauduit and Alexakis proposed a reaction mechanistic
model in the NHC–Cu-catalyzed ACA of a Grignard reagent to an
enone. The enantioselectivity of the reaction was signicantly
affected by the order of addition of the substrates.5d,13 The
present Cu-catalyzed ACA reaction may have proceeded through
a similar reaction pathway. When dialkylzinc was added to
a mixture of Cu salt, chiral ligand and enone in the ACA reaction
of enone 3 and Et2Zn (4) (method A), an alkylcuprate species A
might be generated, affording 1,4-adduct with R-conguration.
In contrast, when the enone is added as the last component
(method B), a higher-order cuprate B might be formed, probably
because of the presence of an excess amount of dialkylzinc.
Presumably, the reaction of dialkylzinc with NHC–Cu species in
the presence of an enone affords cuprate A, whereas higher-
order cuprate B is produced in the absence of enone. The
resulting higher-order cuprate B would promote the ACA reac-
tion, affording 1,4-adduct with the opposite conguration.
In summary, a switchable enantioselectivity was achieved in
a Cu-catalyzed ACA reaction. The hydroxyamide-functionalized
NHC–Ag complex, readily accessible from a chiral b-amino
alcohol, was found to be a versatile chiral ligand precursor for
a dual enantioselective control.
A dual enantioselective control was also observed in the
reactions of 4,4-dimethyl-2-cyclohexen-1-one (11) with Et2Zn (4),
affording 3-ethyl-4,4-dimethylcyclohexanone (12) (entries 10–
13). Despite a good yield, the reaction of 2-cyclopenten-1-one
(13) and 4 using method A afforded 1,4-adduct 14 with a poor
enantioselectivity (entry 14). This is probably because of the
Acknowledgements
This work was nancially supported by a Grant-in-Aid for
Scientic Research (C) (26410127) from Japan Society for the
Promotion of Science (JSPS).
Fig. 1 Chiral amplification phenomenon in ACA reaction.
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‡ Procedure for method A: the reaction was performed under argon atmosphere. A
ask, under argon atmosphere, was charged with (CuOTf)2$C6H6 (15 mg, 0.03
mmol) and NHC–Ag complex 2b (23 mg, 0.04 mmol). Then, a solution of 3 (96 mg,
1 mmol) in anhydrous THF (9 mL) was added. The resulting mixture was stirred at
room temperature for 1 h. Aer the mixture was cooled to ꢀ20 ꢂC, a solution of 4
(3 mmol, 1 M in hexanes, 3 mL) was added dropwise over a period of 10 min. The
reaction mixture was stirred at ꢀ20 ꢂC for 3 h. The reaction was quenched by
adding 10% aq. HCl. The resulting mixture was extracted with diisopropyl ether
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