New bidentate alkoxy-NHC ligands for enantioselective copper-catalysed conjugate addition

Article abstract of DOI:10.1016/j.tetasy.2005.01.015

Chiral alkoxy-imidazolinium salts are easily available via a five-step procedure starting from β-aminoalcohols. This new family of alkoxy-N-heterocyclic carbene (NHC) precursors is shown to be highly active in the enantioselective copper-catalysed conjugate addition to cyclic enones. Complete conversion with low catalyst loading and good enantiomeric excesses up to 93% were obtained at room temperature.

Full text of DOI:10.1016/j.tetasy.2005.01.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 921–924
New bidentate alkoxy-NHC ligands for enantioselective
copper-catalysed conjugate addition
*
´
Herve Clavier, Ludovic Coutable, Jean-Claude Guillemin and Marc Mauduit
` ´ ´
UMR CNRS 6052, Laboratoire de Syntheses et Activations de Biomolecules, Ecole Nationale Superieure de Chimie de Rennes,
Institut de Chimie de Rennes, 35700 Rennes, France
Received 9 December 2004; accepted 10 January 2005
Abstract—Chiral alkoxy-imidazolinium salts are easily available via a five-step procedure starting from b-aminoalcohols. This new
family of alkoxy-N-heterocyclic carbene (NHC) precursors is shown to be highly active in the enantioselective copper-catalysed con-
jugate addition to cyclic enones. Complete conversion with low catalyst loading and good enantiomeric excesses up to 93% were
obtained at room temperature.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tivities (up to 98% ee) in copper catalysed allylic
alkylations.
Since the first isolation and characterisation of stable
N-heterocyclic carbenes (NHC) by Arduengo 13 years
ago,1 NHCÕs have become extremely popular ligands
in organometallic reactions. Indeed, many complexes
bearing NHCÕs have been used for several synthetic
transformations including the C–C and C–N cross-cou-
pling2 and metathesis reactions.3 Several applications of
chiral NHC in asymmetric catalysis have been reported
with moderate to high enantiomeric excess.4
Herein, we report the synthesis of a new class of chiral
alkoxy-imidazolinium salts 4 (Fig. 1) derived from com-
mercially available b-aminoalcohols. These salts have
been evaluated as chiral bidentate NHC ligand precur-
sors and lead to an efficient copper(II)-alkoxy-NHC cat-
alyst for the enantioselective copper-catalysed conjugate
addition to cyclic enones.
In the area of copper-catalysed reaction, Alexakis and
co-workers5 have described the synthesis of chiral
NHC precursors 1 derived from C2 symmetric diamines
and their use in the enantioselective copper-catalysed
conjugate addition.6 Recently, Okamoto and co-work-
ers7 have used the same ligands 1 in copper catalysed
allylic alkylations and obtained moderate enantioselec-
tivity. In the development of chelating alkoxy-NHC
ligands,8a Arnold et al. have reported the isolation of
the first chiral copper(II) alkoxy-NHC complex based
on salt 38b and obtained moderate enantioselectivity in
the copper conjugate addition of diethylzinc to cyclo-
hexenone (up to 51% ee). At the same time, Hoveyda
and co-workers9 described a chiral bidentate alkoxy-
NHC precursor 2 derived from axial symmetric amino-
hydroxybinaphthalene and obtained high enantioselec-
2. Results and discussion
A simple procedure for synthesising alkoxy-imidazolin-
ium salts 4a–f from enantiopure aminoalcohols is
described in Scheme 1.10 Ethyloxalylchloride 5 is
condensed onto substituted aniline to give the corre-
sponding oxanilinic diethylester 6. Treatment with the
desired aminoalcohol in refluxing dichloromethane
provided oxalamide 7 in pure form. After LiAlH4
reduction, the resulting diamine 8 was treated with
anhydrous HCl followed by condensation with trimeth-
ylorthoformate to provide the desired imidazolinium
chloride. The salt was easily purified by a simple anion
exchange to give the corresponding potassium hexa-
flurophosphate alkoxy-imidazolinium salts 4a–d in pure
form with high overall yields (59% to 76%). Impor-
tantly, all salts are air stable and easy to handle and
can be synthesised on a multigram scale without further
purification.
*
Corresponding author. Tel.: +33 2 23 23 81 12; fax: +33 2 23 23 81
08; e-mail: marc.mauduit@ensc-rennes.fr
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.015

922
H. Clavier et al. / Tetrahedron: Asymmetry 16 (2005) 921–924
R
R
Cl
N
N
BF4
N
Mes
Ar
N
Ar
R1
R1
HO
2
1
R
Cl
R
H2N
HO
N
N
N
N
Me
Mes
PF6
HO
HO
3
4
Figure 1.
R
O
O
H2N
OH
Ar-NH2
OEt
OEt
Cl
ArHN
pyridine, CH2Cl2
0˚C
CH2Cl2, reflux
O
O
6
5
1) HCl:MeOH
then HC(OMe)3
toluene 90˚C
R
O
R
LiAlH4
NH
HO
HN HN
ArHN
Ar
THF, reflux
2) KPF6/H2O
O
HO
Ar
7
8
R
overall yield
4a
4b
4c
4d
4e
4f
Mes
Mes
Mes
Mes
Ph
iBu
76%
73%
71%
66%
67%
59%
PF6
R
iPr
Me
tBu
iPr
iPr
N
N
Y
HO
4a-f
DIPP
DIPP = 2,6-diisopropylphenyl
Scheme 1. Synthesis of alkoxy-imidazolinium salts.
We then evaluated their potential in the enantioselective
copper-conjugate addition of diethylzinc to cyclohexe-
none (Table 1). When formed in situ the desired
copper(II)-alkoxy-NHC catalyst, and 2 equiv of n-
butyllithium were used to produce the carbene ligand
and generate the alkoxylate. Under these conditions,
using 3 mol% of imidazolinium salt 4a as ligand and
2 mol% of copper(II) triflate (Cu(OTf)2) as precatalyst,
complete conversion was obtained in diethyl ether after
4 h at ꢀ50 °C with 75% ee (entry 1). Replacement of the
precatalyst by a more soluble copper complex, such as
copper(II) ethylacetoacetate [Cu(eaa)2] accelerates the
reaction allowing the addition to be carried out at a lower
temperature (ꢀ78 °C) with complete conversion in 4 h
(entry 2). Curiously, in this case, the enantioselectivity
decreased to 70% ee. We then decided to perform the
reaction at a higher temperature. Whereas at ꢀ25 °C,
the enantioselectivity increased to 78% ee (entry 3),
86% ee was observed at room temperature with a com-
plete conversion after only 30 min (entry 4). Similar
enantioselectivity was obtained when the reaction was
performed at 40 °C (entry 5). Hoveyda and co-workers11
and Krauss and Leighton12 have recently observed a
similar unusual relationship between temperature and
enantioselectivity in the copper-catalysed enantioselec-
tive conjugate addition using chiral phosphine ligands.
Replacement of the mesityl unit by phenyl (imidazolin-
ium 4e) or the 2,6-(i-Pr)-C6H3 group (imidazolinium
4f) produced a dramatic effect on the enantioselectivity
(54% and 29%, respectively, entries 9 and 10). Finally,
the influence of the alkyl group bearing the imidazolin-
ium alkoxy-side chain was examined. Except for the
methyl group (imidazolinium 4c, 79% ee, entry 7), we
observed only 1–2% difference in the enantioselectivity
between the more hindered tert-butyl group (4d, 87%
ee, entry 8) and the other alkyl groups (4a, b entries 4
and 6). With the aim of developing efficient and inexpen-
sive ligands, this result becomes important because
valine and leucine a-aminoacid are less expensive than
tert-leucine.
The hydroxymethylene side chain in the NHC ligand is
probably crucial for the enantiocontrol of the conjugate

H. Clavier et al. / Tetrahedron: Asymmetry 16 (2005) 921–924
Table 1. Optimisation of reaction conditions and ligand
923
PF6
R
O
O
N
N
3 mol%
Y
HO
4
Et2Zn
+
8 mol% nBuLi, 2 mol% CuX2
Et2O, T˚C
Et
Yielda
(1.5 equiv)
Entry
Ligand
CuX2
Temp (°C)
Time
Ee (%)b
1
2
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
Cu(OTf)2
Cu(eaa)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
ꢀ50 °C
ꢀ78 °C
ꢀ25 °C
RT
4 h
4 h
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
75 (R)
70 (R)
78 (R)
86 (R)
84 (R)
85 (R)
79 (R)
87 (R)
54 (R)
29 (R)
3
4 h
4
30 min
30 min
30 min
30 min
30 min
30 min
30 min
5
40 °C
RT
RT
6
7
8
RT
RT
9
10
RT
a Determined by GC analysis.
b Determined by chiral GC analysis (Lipodex E).
addition. To prove this, we protected the hydroxyl func-
tion by a tert-butyldimethylsilyl group. The protected
imidazolinium 4g was isolated in excellent yield from
imidazolinium 4a under standard conditions (Scheme
2). Its use in conjugate addition of diethylzinc to cyclo-
hexenone at room temperature involved an important
loss of enantioselectivity to 24% ee. The requirement
of the hydroxyl function for high enantioselectivity
strongly suggests that these alkoxy-NHC ligands have
served as a LX bidentate ligand.
ated the activity of the ligand 4a with other dialkylzinc
and cyclic enones (Table 2). In the case of a more hin-
dered enone, such as 4,4-dimethylcyclohexenone, com-
plete conversion was obtained after 12 h at room
temperature with 93% ee (entry 2). 2-Cyclohexenone
may be alkylated with diisopropylzinc in complete
conversion after 1 h with 79% ee (entry 3). Addition
of Et2Zn on 2-cycloheptenone (entry 4) was achieved
in 1 h at room temperature with 90% ee. Lastly, we
tried to alkylate the a,b-unsaturated lactone with Et2Zn
(entry 5) and obtained total conversion after 1 h. How-
ever, only moderate enantioselectivity was observed
(72% ee).
Having established the optimal conditions for the use
of these salts in the conjugate addition, we then evalu-
PF6
PF6
TBDMSCl
N
N
N
N
Mes
Mes
Et3N, DMAP
CH2Cl2, 12h, rt
TBDMSO
HO
4g
4a
94%
Scheme 2.
Table 2. Enantioselective copper-catalysed conjugate addition of dialkylzinc to cyclic enones
PF6
O
O
N
N
3 mol%
X
HO
X
4a
R'2Zn
(1.5 equiv)
+
8 mol% nBuLi, 2 mol% Cu(OTf)2
n
R'
n
R
R
R
R
Et2O, RT
Entry
n
R
R0
X
Time
Yielda
Ee (%)b
1
2
3
4
5
1
1
1
2
1
H
Et
Et
CH2
CH2
CH2
CH2
O
30 min
12 h
1 h
>99
>99
>99
>99
>99
85 (R)
93 (R)
79 (R)
90 (R)
72 (R)
Me
H
i-Pr
Et
H
30 min
1 h
H
Et
a Determined by GC analysis.
b Determined by chiral GC analysis (Lipodex E).

924
H. Clavier et al. / Tetrahedron: Asymmetry 16 (2005) 921–924
PF6
N
N
O
O
HO
4a
0.15 mol%
Et2Zn
(1.5 equiv)
+
0.20 mol% nBuLi
0.10 mol% Cu(OTf)2
Et2O, RT, 1h
Et
>99%
83% ee
Scheme 3. Optimisation of catalytic process.
2. For recent reviews, see: (a) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1290; (b) Hillier, A. C.; Nolan,
S. P. Platinium Metals Rev. 2002, 46, 50.
To optimise the catalytic process, the catalyst loading
was decreased from 2% to 0.10 mol% in the conjugate
addition to 2-cyclohexenone. Total conversion was ob-
served after 1 h without significant loss of enantioselec-
tivity (Scheme 3).
3. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
´
4. For recent reviews, see: (a) Cesar, V.; Bellemin-Laponnaz,
S.; Gade, L. H. Chem. Soc. Rev. 2004, 33, 619; (b) Perry,
M. C.; Burgess, K. Tetrahedron: Asymmetry 2003, 14, 951;
For recent examples, see: (c) Gade, L. H.; Cesar, V.;
Bellemin-Laponnaz, S. Angew. Chem., Int. Ed. 2004, 43,
1014; (d) Ma, Y.; Song, C.; Ma, C.; Chai, Q.; Andrus, M.
B. Angew. Chem., Int. Ed. 2003, 42, 5871; (e) Bappert, E.;
Helmchen, G. Synlett 2004, 1789.
3. Conclusion
In conclusion, this work shows the design of a new fam-
ily of chiral alkoxy-NHC ligands easily synthesised in a
five-step procedure. High reactivity and good enantiose-
lectivity were obtained at room temperature in the cop-
per-conjugate addition with low loading of catalyst (up
to 0.10 mol%). A study of their use in conjugate addi-
tions with acyclic substrates is currently under progress.
Replacement of the alkoxy group by other chelating
groups (such as S-Ar or PPh2) for cross-coupling and
hydrogenation reactions will be also studied and re-
ported in due course.
5. (a) Guillen, F.; Winn, C. L.; Alexakis, A. Tetrahedron:
Asymmetry 2001, 12, 2083; (b) Pytkowics, J.; Roland, S.;
Mangeney, P. Tetrahedron: Asymmetry 2001, 12, 2087; (c)
Alexakis, A.; Winn, C. L.; Guillen, F.; Pytkowics, J.;
Roland, S.; Mangeney, P. Adv. Synth. Catal. 2003, 345,
345.
6. For a review on enantioselective Cu-catalysed conjugate
addition, see: (a) Alexakis, A.; Benhaim, C. Eur. J. Org.
Chem. 2002, 3221; For the first use of NHC ligand in
Cu-catalysed conjugate addition, see: (b) Fraser, P. K.;
Woodward, S. Tetrahedron Lett. 2001, 42, 2747.
7. Tominiga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S.
Tetrahedron Lett. 2004, 45, 5585.
8. (a) Arnold, P. L.; Scarisbrick, A. C.; Blake, A. J.; Wilson,
C. Chem. Commun. 2001, 2340; (b) Arnold, P. L.; Rodden,
M.; Davis, K. M.; Scarisbrick, A. C.; Blake, A. J.; Wilson,
C. Chem. Commun. 2004, 1612.
9. Larsen, A. O.; Leu, W.; Oberhuber, C. N.; Campbell, J.
E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130.
10. During the preparation of this paper, a similar synthesis
using aminophenol was reported: Waltman, A. W.;
Grubbs, R. H. Organometallics 2004, 23, 3105.
Acknowledgements
This work was supported by the CNRS and the Min-
`
istere de la Recherche et de la Technologie (Grant to
H.C.). We thank Professor A. Alexakis for helpful
discussion.
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