Asymmetric conjugate addition to cyclic enone catalyzed by Cu-NHC complexes with C2 symmetry

Article abstract of DOI:10.1002/cjoc.201190198

A series of chiral, C₂ symmetric tridentate N-heterocyclic carbene precursors, containing two N-functionalized hydroxyl or alkoxyl groups, were synthesized. They were applied to catalyze the asymmetric conjugate addition of diethylzinc to cyclo

Full text of DOI:10.1002/cjoc.201190198

FULL PAPER
Asymmetric Conjugate Addition to Cyclic Enone Catalyzed by
Cu-NHC Complexes with C2 Symmetry
Shan, Fengjuna(单凤军)
Li, Zhengning*,a,b(李争宁)
Jiang, Lana,c(姜岚)
Zhao, Defengc(赵德峰)
a College of Environmental and Chemical Engineering, Dalian University, Dalian, Liaoning 116622, China
b Liaoning Key Laboratory of Bioorganic Chemistry, Dalian University, Dalian, Liaoning 116622, China
c State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning 116012, China
A series of chiral, C2 symmetric tridentate N-heterocyclic carbene precursors, containing two N-functionalized
hydroxyl or alkoxyl groups, were synthesized. They were applied to catalyze the asymmetric conjugate addition of
diethylzinc to cyclohex-2-enone and cyclopent-2-enone. Enantioselectivity of corresponding reactions can be
accomplished with up to 76% ee, and 65% ee, respectively. Flip of major enantiomer was observed when different
bases or copper sources were utilized.
Keywords asymmetric catalysis, copper-NHC, imidazolinium salt, C2 symmetry, Michael addition
Introduction
ity with up to 87% ee. Furthermore, Katsuki13 has re-
ported that 97% ee was achieved when chiral imida-
zolinium salt 7-Cu(II) was used in the conjugate addi-
tion of dialkyl zinc to acyclic enones. However, very
poor enantioselectivity (3% ee) was observed in the case
of using cyclohex-2-enone.
Asymmetric reactions catalyzed by chiral N-hetero-
cyclic carbene (NHC)-metal complexes have attracted
broad attention in recent years.1 NHC has displayed
strong σ-donor capacity, and its corresponding com-
plexes with transition metals have been used as efficient
catalysts in asymmetric olefin metathesis,2 conjugate
addition,3 cross-coupling reaction,4 hydrosilylation,5 and
hydrogenation.6 In phosphorous ligand-participating
enantioselective reactions, bidentate phosphorus ligands,
especially those with C2 symmetry, were generally fur-
nished with higher ee’s and they were superior to
monodentate phosphines. It was also found in asymmet-
ric reactions that those bidentate NHCs derived from
chelating imidazolium or imidazolinium salts afforded
better enantioselectivity when compared with mono-
dentate NHC ligands.7 For instance, imidazolinium salts
1 was successfully prepared by Hoveyda’s group,8,9 and
later it was applied to olefin metathesis and allylic alky-
lation affording high enantioselectivities (up to 98% ee).
Cu-NHC complex, derived from biphenyl 2, demon-
strated good selectivities in catalytic asymmetric conju-
gate additions, i.e. asymmetric Michael addition, of al-
kylzinc, arylzinc or alkyl aluminum reagents to the
β-substituted cyclic enones.10 Cu-NHC complex, de-
rived from imidazolium salt 3 by Arnold,11 was used in
the reaction of cyclohex-2-enone with diethylzinc fur-
nishing 3-ethylcyclohexanone [Eq. (1)] with ee up to
51%. Recently, Mauduit and coworkers12 have reported
that in the copper-catalyzed Eq. (1), NHC precursors 4
— 6 and their analogues resulted in high enantioselectiv-
Even though C2 symmetry in the catalyst and ligand
is well recognized as an important structural element in
the catalytic enantioselective reactions, there were only
a few reports to date regarding asymmetric reactions
using chiral multidentate NHC with C2 symmetry.14
Recently, Wilhelm et al.15 prepared C2-symmetric imi-
dazolinium salts 8, and related analogues containing two
hydroxyl groups, and employed their NHCs as ligand in
the diethylzinc addition to aldehydes resulting in up to
80% ee. The NHC precursor 9 also demonstrated good
enantioselectivity (80% ee) in the asymmetric conjugate
addition of Grignard reagents to 3-alkylcyclohex-2-
enone.16 Structures of imidazol(in)ium salts 1— 9 are
listed in Figure 1. We envisioned that 8 might have po-
tential in the transition metal-catalyzed asymmetric
transformation based on its symmetrical dihydroxyl
imidazolinium structural features. To this end we are
reporting that high enantioselectivity was obtained in
the Eq. (1) when utilizing 10, oxygen atom tethered tri-
dentate imidazolinium salts with C2-symmetry.
*
E-mail: znli@dl.cn
Received October 29, 2010; revised December 2, 2010; accepted January 21, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20672016, 20972020).
Chin. J. Chem. 2011, 29, 973— 977
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
973

Shan et al.
FULL PAPER
Figure 1 Typical NHC precursors containing oxygen atom(s) on the N-side chain.
Results and discussion
Initially, ether was used as the solvent according to the
literature result.12a Here (R) isomer of the conjugate ad-
duct was observed as the major enantiomer and this re-
sult is in agreement with Mauduit’s report using mono-
hydroxyl imidazolinium salt 4.12a As it can be seen from
Table 1, both the conversion of cyclohex-2-enone and
the ee of the 3-ethylcyclohexanone were greatly influ-
enced by reaction temperatures employed for the cata-
lyst preparation as well as alkylation reaction. The best
result was obtained when deprotonation of imidazolin-
ium salt 10a was carried out at 0—5 ℃, followed by
the Eq. (1) at －30 ℃. The reaction was furnished in
98% yield with 71% ee (Entry 5). Lowering the depro-
tonation temperature (－30 ℃) led to significant de-
crease of conversion. Accordingly, reaction conditions
in Entry 5 were used for the further investigation.
Chiral imidazolinium salts 10a—10i were readily
prepared in two to three steps from commercially avail-
able enantiopure β-amino alcohols (Scheme 1). This
protocol is very straightforward compared to the prepa-
ration of 4 by Mauduit,12 which needed five steps from
related amino alcohol.
With these NHC ligands precursors in hand, we set
to explore their potential application to the Eq. (1). Cata-
lysts were prepared in situ by adding base to the mixture
of copper salt and imidazolinium salts 10a—10i. The
resulting catalysts were directly used for next step of
catalytic Eq. (1) without further purification. Reaction
conditions were optimized with the imidazolinium salts
10a. First, 10a-Cu(OTf)2 and n-BuLi were used to pre-
pare corresponding catalyst under different temperatures.
Scheme 1 Synthetic routes of imidazolinium salts 10a—10i
974
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 973— 977

Asymmetric Conjugate Addition to Cyclic Enone Catalyzed by Cu-NHC Complexes
Table 1 Influence of the temperature on Eq. (1) with 10aa
Table 3 Scan of copper salts for Eq. (1) with NHC ligand de-
rived from 10aa
Entry
T1/℃
T2/℃
Conv.b/%
eec/%
51 (R)
58 (R)
57 (R)
62 (R)
71 (R)
65 (R)
58 (R)
—
Entry
CuX
Cu(OTf)2
CuCl
Conv./%
99
ee/%
1
2
3
4
5
6
7
8
r.t.
r.t.
99
98
98
99
99
90
90
10
1
2
3
4
5
6
7
71 (R)
24 (R)
58 (R)
63 (R)
37 (R)
64 (R)
26 (R)
0
r.t.
90
－5—0
－5—0
－5—0
－5—0
－10—－5
－30
r.t.
CuCl2
98
－20
－30
－40
－30
－30
CuBr
99
CuI
99
Cu(acac)2
99
Cu(OAc)2•H2O
95
a Reaction conditions are the same as those of Entry 5 in Table 1
unless noted.
a
Reaction conditions: cyclohex-2-enone 0.5 mmol, diethylzinc
0.75 mmol, 3 mol% NHC ligand, 4 mol% Cu(OTf)2, 18 mol%
n-BuLi, ether, 2 h. n-BuLi and diethylzinc were added at T1, and
cyclohex-2-enone was added and reaction was performed at T2.
b Determined by GC analysis. c Determined by chiral GC analysis,
major isomer is indicated in parenthesis.
ratio of n-BuLi to 10a resulted in low enone conversion
and ee of the product (Entry 4). Reducing amount of
pre-catalyst led to almost identical ee though with de-
creased yield. Replacement of n-BuLi with KHMDS
gave the highest ee with 3 mol% 10a, 4 mol% Cu(OTf)2
and 18 mol% base (Entry 5). Further increasing the
amount of base, either n-BuLi or KHMDS, reduced en-
antioselectivity (Entries 6—10).
Next, solvent and base effects were also investigated
(Table 2). Less favorable yield and/or ee were observed
in dichloromethane or THF (Entries 1 and 2). Toluene
improved the ee to 66% (Entry 3), however it was still
lower than that obtained in ether (Entry 4). With ether as
the solvent, switching the base to KHMDS resulted in
the best ee (76%). However overall low ee’s were ob-
served with t-BuOK, DBU or K2CO3 as the base (En-
tries 6—8).
Table 4 Optimization of the ratio of ligand, CuX and the base
with 10a in Eq. (1)a
Entry
Base
10a Cu(OTf)2 Base Conv./% ee/%
1
2
n-BuLi
n-BuLi
n-BuLi
n-BuLi
KHMDS
n-BuLi
KHMDS
n-BuLi
KHMDS
n-BuLi
2
3
6
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
12
18
36
12
18
24
24
30
30
24
75
99
99
75
95
99
99
99
99
99
16 (R)
71 (R)
54 (R)
60 (R)
76 (R)
68 (R)
44 (R)
60 (R)
34 (R)
64 (R)
Table 2 Effect of the solvent and base with NHC ligand 10a in
Eq. (1)a
3
4
Entry
Base
n-BuLi
n-BuLi
n-BuLi
n-BuLi
KHMDS
t-BuOK
DBU
Solvent
CH2Cl2
THF
Conv./%
50
ee/%
38 (R)
38 (R)
66 (R)
71 (R)
76 (R)
60 (R)
20 (R)
0
5
1
2
3
4
5
6
7
8
6
99
7
Toluene
Et2O
85
8
99
9
Et2O
99
10
Et2O
84
a Reaction conditions are the same as those of Entry 5 in Table 1
unless noted.
Et2O
92
K2CO3
Et2O
60
a Reaction conditions are the same as those of Entry 5 in Table 1
unless noted.
Based on aforementioned discussion, optimal condi-
tions were applied to the Eq. (1), and the results are
listed in Table 5 with different imidazolinium salts 10b—
10i. Compared to Mauduit’s results using monohydroxyl
based ligand 4, lower ee’s were obtained with using
bi-hydroxyl ligand 10a — 10i.12a However, these
pre-ligands are still attractive due to their preparation
easiness. When the hydroxyl group in 10a was replaced
by methoxyl group, both conversion and ee value were
decreased (Entry 3 vs. Entry 1). A similar phenomenon
was observed in the case of 10c and 10d (Entry 6 vs.
Entry 4). Neutral oxygen has inferior coordinative abil-
ity compared to anionic oxygen atom derived from hy-
droxyl and a strong base. Therefore, it can be concluded
that strong coordinative oxygen atom in a NHC moiety
which served as a di- or multidentate chelating ligand,
Various copper salts were also examined, and related
results are summarized in Table 3. Cu(OTf)2 gave satis-
fied results in terms of yield and ee. Cu(acac)2 also af-
forded high yield but with lower ee. Both CuCl2 and
CuBr gave reasonable ee, but the other copper salts were
inferior (Entries 2, 5, 7).
Further optimization of the reaction conditions was
carried out and related results are summarized in Table 4.
When initially using 2 mol% ligand 10a, 4 mol%
Cu(OTf)2 and 12 mol% n-BuLi, the reaction conversion
and selectivity were lower (Entry 1) and this can be im-
proved by adding more ligand (Entry 2). However, large
excess ligand led to decreased ee (Entry 3). Lowing the
Chin. J. Chem. 2011, 29, 973— 977
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
975

Shan et al.
FULL PAPER
led to higher enantioselectivity. It was also found that
the reactivity and selectivity of Eq. (1) can be affected
by the steric effect of N-substituents as well as the loca-
tion of chiral center along the side chain. Increasing the
steric hindrance of branch β-carbon atom relative to N
atom reduced the enantioselectivity significantly even
though the chiral centers were closer to metal atom (En-
tries 8, 9). It is noteworthy that replacement of n-BuLi
with KHMDS resulted in stereochemistry flip of the
major product from (R) to (S) in the presence of ligand
10c only (Entry 5). Previously, Katsuki13 has reported
that different bases (t-BuONa, n-BuLi) induced reversed
enantioselectivity in asymmetric conjugate addition of
acyclic enones. Sakaguchi7 also reported that replacing
Cu(OTf)2 with Cu(acac)2 led to different major enanti-
omers in copper-catalyzed asymmetric conjugate addi-
tion of diethylzinc to cyclic enones, in which the same
chiral NHC ligand was employed. Additionally, it was
found that the results of Eq. (1) were sensitive to the
addition order of the reactants and the base. Higher ee’s
were obtained if adding base to the mixture of copper
salt and 10a — 10i followed by cyclohex-2-enone,
whereas poor enantioselectivities (ca. 2% ee) were ob-
served if deprotonation of imidazolinium salts were car-
ried out prior to the addition of a Cu source, even
though in this case high yield (99%) can be obtained.
Among the imidazolinium salts 10a—10i studied, 10a is
the most efficient one.
We speculated that major product chirality flip might be
due to different catalytic species involved as a result of
altering bases. Related reaction results are summarized
in Table 6.
Table 6 Conjugate addition of Et2Zn to cyclopent-2-enone
promoted by Cu(II)-base-10a
Entry
L
CuX
Base
Conv.a/%
eeb/%
14 (R)
7 (S)
1
2
3
4
5
6
10a Cu(OTf)2
10a Cu(acac)2
10a Cu(OTf)2
10c Cu(OTf)2
10c Cu(OTf)2
10d Cu(OTf)2
n-BuLi
n-BuLi
KHMDS
n-BuLi
KHMDS
n-BuLi
95
94
96
64
91
63
65 (S)
9 (R)
42 (S)
9 (R)
a Reaction conditions are the same as those of Entry 5 in Table 1
except that 2-cyclopent-2-enone was used as the substrate and
reaction was carried out at －30 ℃. b Determined by chiral GC.
Conclusion
In conclusion, imidazolinium salts 10a—10i of C2
symmetry with two ancillary oxygen atoms on the
N,N'-side chains were readily prepared from corre-
sponding enantiopure amino alcohols. Deprotonation of
these salts in the presence of copper salts led to
Cu-NHC complexes. The resulting Cu-NHCs are effi-
cient in catalyzing enantioselective conjugate addition to
cyclohex-2-enone and cyclopent-2-enone. Adduct of
conjugate addition was obtained with up to 76% ee and
99% yield for cyclohex-2-enone, and up to 65% ee for
the 5-membered ring substrate. Enantioselectivity flip of
the major isomer was observed in some examples when
the base or copper sources were changed.
Table 5 Evaluation of the NHC ligands derived from 10a—10i
in Eq. (1)a
Entry
L
Base
n-BuLi
KHMDS
n-BuLi
n-BuLi
KHMDS
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
Conv./%
99
ee/%
71 (R)
76 (R)
22 (R)
51 (R)
40 (S)
36 (R)
50 (S)
28 (S)
10 (S)
48 (R)
50 (R)
1
2
10a
10a
10b
10c
10c
10d
10e
10f
10g
10h
10i
95
3
85
Acknowledgment
4
90
Ms. Huiying Chen is thanked for recording the NMR
spectra.
5
98
6
85
7
90
References
8
80
1
(a) César, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem.
Soc. Rev. 2004, 33, 619.
9
94
10
95
(b) Crudden, C. M.; Allen, D. P. Coord. Chem. Rev. 2004,
248, 2247.
(c) Gade, L. H.; Bellemin-Laponnaz, S. Coord. Chem. Rev.
2007, 251, 718.
11
93
a Reaction conditions are the same as those of Entry 5 in Table 1
unless noted.
(d) Dez-Gonzalez, S.; Marionand, N.; Nolan, S. P. Chem.
Rev. 2009, 109, 3612.
(a) Colacino, E.; Martinez, J.; Lamaty, F. Coord. Chem. Rev.
2007, 251, 726.
(b) Dragutan, V.; Dragutan, I.; Delaude, L.; Demonceau, A.
Coord. Chem. Rev. 2007, 251, 765.
(a) Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.;
Mangeney, P.; Alexakis, A. J. Organomet. Chem. 2005, 690,
5672.
Ligands derived from 10a—10d were also tested in
conjugate addition of diethylzinc to cyclopentene-2-one.
With a combination of 10a (or 10c or 10d)-Cu(OTf)2-
n-BuLi, low ee in favor of (R)-isomer, was obtained. In
the presence of 10a, (S)-isomer was obtained as the ma-
jor enantiomer under either a combination of Cu(acac)2-
n-BuLi or Cu(OTf)2-KHMDS, and 65% ee was obtained
in the later case. A similar result was observed for 10c,
as the enantioselectivity was reversed with KHMDS as
the base yielding (S)-isomer as the preferred product.
2
3
(b) Guillen, F.; Winn, C. L.; Alexakis, A. Tetrahedron:
976
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 973— 977

Asymmetric Conjugate Addition to Cyclic Enone Catalyzed by Cu-NHC Complexes
Asymmetry 2001, 12, 2083.
Chem., Int. Ed. 2008, 47, 7358.
(c) Yu, Y. F.; Shan, F. J.; Li, Z. N.; Jiang, L. Chin. J. Org.
Chem. 2011, 31, 443 (in Chinese).
(c) Veldhuizen, J. J. V.; Campbell, J. E.; Giudici, R. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877.
11 (a) Arnold, P. L.; Scarisbrick, A. C.; Blake, A. J.; Wilson, C.
Chem. Commun. 2001, 2340.
4
5
(a) Pytkowicz, J.; Roland, S.; Mangeney, P.; Meyer, G.; Ju-
tand, A. J. Organomet. Chem. 2003, 678, 166.
(b) Shi, M.; Qian, H.-X. Tetrahedron 2005, 61, 4949.
(c) Xu, Q.; Duan, W.-L.; Lei, Z.-Y.; Zhu, Z.-B.; Shi, M.
Tetrahedron 2005, 61, 11225.
(a) Herrmann, W. A.; Goossen, L. J.; Kocher, C.; Artus, G.
R. Angew. Chem., Int. Ed. 1996, 35, 2805.
(b) Chianese, A. R.; Crabtree, R. H. Organometallics 2005,
24, 4432.
(c) Song, C.; Ma, C.; Ma, Y.; Feng, W.; Ma, S.; Chai, Q.;
Andrus, M. B. Tetrahedron Lett. 2005, 46, 3241.
Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui, X.; Burgess,
K. J. Am. Chem. Soc. 2001, 123, 8878.
Okamoto, M.; Yamamoto, Y.; Sakaguchi, S. Chem. Com-
mun. 2009, 7363.
Veldhuizen, J. J. V.; Garber, S. B.; Kingsbury, J. S.; Hov-
eyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954.
Larsen, A. O.; Leu, W.; Oberhuber, C. N.; Campbell, J. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130.
(b) Arnold, P. L.; Rodden, M.; Davis, K. M.; Scarisbrick, A.
C.; Blake, A. J.; Wilson, C. Chem. Commun. 2004, 1612.
12 (a) Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J.-C.;
Mauduit, M. J. Organomet. Chem. 2005, 690, 5237.
(b) Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J.-C.;
Mauduit, M. Tetrahedron: Asymmetry 2005, 16, 921.
(c) Clavier, H.; Boulanger, L.; Audic, N.; Toupet, L.;
Mauduit, M.; Guillemin, J.-C. Chem. Commun. 2004, 1224.
(d) Rix, D.; Labat, S.; Toupet, L.; Crévisy, C.; Mauduit, M.
Eur. J. Inorg. Chem. 2009, 1989.
6
7
8
9
13 Uchida, T.; Katsuki, T. Tetrahedron Lett. 2009, 50, 4741.
14 Jia, Y.-X.; Katayev, D.; Bernardinlli, G.; Seidel, T.; Kündig,
E. P. Chem. Eur. J. 2010, 16, 6300.
15 (a) Jurčík, V.; Gilani, M.; Wilhelm, R. Eur. J. Org. Chem.
2006, 5103.
(b) Gilani, M.; Wilhelm, R. Tetrahedron: Asymmetry 2008,
19, 2346.
10 (a) Lee, K.-S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H.
J. Am. Chem. Soc. 2006, 128, 7182.
16 Matsumoto, Y.; Yamada, K.-I.; Tomioka, K. J. Org. Chem.
2008, 73, 4578.
(b) May, T. L.; Brown, M. K.; Hoveyda, A. H. Angew.
(E1010291 Cheng, B.; Zheng, G.)
Chin. J. Chem. 2011, 29, 973— 977
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
977