Enantioselective copper-catalyzed conjugate addition using chiral diaminocarbene ligands

Article abstract of DOI:10.1016/S0957-4166(01)00387-1

Chiral diaminocarbene ligands, generated by in-situ deprotonation of the corresponding chiral imidazolinium salts, are shown to be efficient ligands in the asymmetric copper-catalyzed 1,4-conjugate addition of diethylzinc to enones, allowing enantiomeric

Full text of DOI:10.1016/S0957-4166(01)00387-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2083–2086
Enantioselective copper-catalyzed conjugate addition using chiral
diaminocarbene ligands
Fre´de´ric Guillen, Caroline L. Winn and Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, 30, quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
Received 6 July 2001; accepted 3 September 2001
Abstract—Chiral diaminocarbene ligands, generated by in-situ deprotonation of the corresponding chiral imidazolinium salts, are
shown to be efficient ligands in the asymmetric copper-catalyzed 1,4-conjugate addition of diethylzinc to enones, allowing
enantiomeric excesses of up to 51% to be achieved. © 2001 Elsevier Science Ltd. All rights reserved.
Stabilized carbenes, such as diaminocarbenes, are
highly s-donating and low p-accepting species, showing
coordination properties similar to those of basic phos-
phorus-based ligands.1 Their coordination chemistry
has been studied since the early 70’s: diaminocarbene–
transition metal complexes were prepared from tetra-
aminoolefins, which can be considered as the dimeric
form of the diaminocarbene,2 or via in situ generation
of the carbene.3
imidazolium halide salts from the primary amine and
glyoxal,10 or of imidazolinium salts from the corre-
sponding diamine,11 gives ready access to various satu-
rated or unsaturated carbenes via simple deprotonation
of the salt12 or thermal decomposition of the alkoxy-
aminal derivative.13
In order to investigate the influence of several parame-
ters such as the steric bulk of the nitrogen substituents,
the presence of a chiral backbone, of chiral substituents
on the nitrogen atoms and the ring size, the synthesis of
the novel imidazolinium salts 2–6 (Fig. 1) was effected
by a reported procedure11 in good yields, from the
readily available chiral diamines (Scheme 1). Although
the presence of a bulky alkyl or aryl substituent on each
nitrogen is necessary to stabilize the free diaminocar-
bene (especially the saturated imidazolinyl-2-ylidenes),14
The discovery of stable diaminocarbenes by Arduengo4
in 1991 has increased interest in the use of diaminocar-
bene ligands in organonometallic catalysis, especially in
palladium catalyzed coupling reactions5 and ruthenium
catalyzed olefin ring closing metathesis.6 However, only
a
few examples of asymmetric catalysis using
diaminocarbene-based metal complexes have been
reported.7
Interestingly, few diaminocarbene–copper complexes
have been synthesized8 and their catalytic properties
were not investigated. Very recently, Woodward et al.
demonstrated the ability of carbene 1 to accelerate the
copper-catalyzed addition of diethylzinc to cyclo-
hexenone.9 Herein, we describe the first use of chiral
diaminocarbenes as ligands in the copper(I)-catalyzed
1,4-conjugate addition of diethylzinc to enones.
Ph
Ph
Ph
+N
Ph
Ph
Ph
+N
N
N
N
N
Mes
Mes
-
-
BF4
BF4
1
2
3
Ph
+N
Ph
Among the various methods allowing the formation of
diaminocarbenes, deprotonation of imidazolium salts
occupies a prominent place. The direct synthesis of
Ph
Ph
+N
N
Ph
+N
N
Ph
N
Cy
Cy
-
-
BF4
BF4
-
BF4
4
5
6
* Corresponding author. Tel.: +41 (0)22 702 65 22; fax: +41 (0)22 328
73 96; e-mail: alexandre.alexakis@chiorg.unige.ch
Figure 1.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00387-1

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F. Guillen et al. / Tetrahedron: Asymmetry 12 (2001) 2083–2086
14% (Table 1, entry 1). The use of 2 equiv. of the
ligand, which usually improves the selectivity when
using phosphorus-based ligands, induced a dramatic
decrease of the reactivity, the addition product being
obtained in 15% yield (Table 1, entry 2).
R1
R1
R2
NH
R1
R2
HC(OEt)3, NH4BF4
120°C, 15 min - 2h
N
-
BF4
n
n
NH
R2
N+
R2
R1
n = 0, 1
2: 95 % 3: 88 %
4: 96 % 5: 80 %
6: 79 %
In situ generation of the diaminocarbene gave enhanced
enantioselectivity when compared to the use of the
pre-formed diaminocarbene (Table 1, entry 3). For this
reason, along with the simplified experimental proce-
dure, in situ carbene preparation was used throughout
the rest of this study.
Scheme 1. Synthesis of imidazolinium tetrafluoroborates 2–6.
it was thought that in situ trapping of the carbene
derived from 3 should give access to the corresponding
copper complex.
In order to ascertain the formation of the diaminocar-
bene–copper complex, several control experiments were
carried out. No enantioselectivity was observed in the
addition of diethylzinc to cyclohexenone when no
deprotonating agent was added to the Cu(OTf)2/2 mix-
ture (Scheme 3, equation 1); this experiment also
showed that diethylzinc alone is not basic enough to
deprotonate the imidazolinium salt 2, confirming the
need for an added base. Alternatively, the use of
diamine 7 as ligand for copper afforded a reduced
conversion and e.e. as compared to the diaminocar-
bene–copper system (Scheme 3, equation 2). These two
experiments, along with the results in Table 1, clearly
indicate that a diaminocarbene–copper complex is
involved in the catalytic cycle.
Determination of the optimum experimental conditions
was conducted using the salt 2, bearing chiral sub-
stituents on the nitrogen in addition to the chiral back-
bone, and the reactive cyclohexenone (Scheme 2).
Addition of 1 equiv. of previously deprotonated 2 to a
suspension of copper(II) triflate in dry degassed tolu-
ene, followed by diethylzinc and the cyclohexenone
afforded, after 14 h at −20°C, the expected ethylcyclo-
hexanone in quantitative yield with a modest e.e. of
O
O
L* / CuX (4%)
*
Et2Zn 1.5 eq., -20°C, 2 h
Different copper(I) or copper(II) salts can be used as
precursors of the active copper(I) catalyst (Table 1,
entries 4–6). However, only copper(II) triflate-based
catalysts lead to high conversions and e.e.s above 10%.
Scheme 2. Conjugate addition of diethylzinc on cyclo-
hexenone.
Table 1. Conjugate addition of diethylzinc to cyclohexenone
Entry
Imidazolinium salt
Copper salt
Solvent
Duration
Yield (%)a
E.e. (%)b
1d
2d
3
4
5
2 (4%)
2 (8%)
2 (4%)
2 (4%)
2 (4%)
2 (4%)
2 (4%)
2 (4%)
2 (4%)
3 (4%)
4 (4%)
5 (4%)
6 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
CuCN (4%)
CuBF4.CH3CN (4%)
CuPF6.CH3CN (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Cu(OTf)2 (4%)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
14 h
14 h
2 h
2 h
2 h
2 h
2 h
2 h
15 min
2 h
\99
15
92
93
63
26
90
24
97
\99
97
\99
\99
14 (S)
20 (S)
22 (S)
0
11(S)
11 (S)
27 (S)
3 (S)
19 (S)
4 (S)
7 (R)
13 (S)
13 (R)
6
7c
8
9
Ether
10
11
12
13
Toluene
Toluene
Toluene
Toluene
2 h
2 h
2 h
Representative procedures: (i) Pre-formed ligand: A solution of n-BuLi (1.6 M solution in hexane, 150 mL, 0.24 mmol) was slowly added at −78°C
to a suspension of salt 2 (104 mg, 0.2 mmol) in dry, degassed toluene (5 mL) under argon and the reaction mixture allowed to warm to room
temperature. A 1 mL aliquot of the resulting cloudy yellow solution was then added to a suspension of copper(II) triflate (14 mg, 39 mmol) in
toluene (2 mL) at −20°C. After 30 min, diethylzinc (15% solution in hexane, 1.7 mL, 1.5 mmol) and cyclohex-2-enenone (98 mL, 1.0 mmol) were
added at this temperature. After stirring the mixture for 2 h, the reaction mixture was hydrolyzed with aqueous 2 M HCl solution (2 mL),
extracted with ether and filtered through a short plug of silica gel. (ii) In situ ligand formation: A solution of n-BuLi (1.6 M solution in hexane,
31 mL, 50 mmol) was added to a suspension of salt 2 (21 mg, 40 mmol), copper(II) triflate (14 mg, 39 mmol) and cyclododecane (50 mg, internal
standard) in the appropriate dried, degassed solvent (3 mL) at −78°C. The temperature was then allowed to rise slowly to −20°C, then diethylzinc
(15% solution in hexane, 1.7 mL, 1.5 mmol) and cyclohex-2-enenone (98 mL, 1.0 mmol) were added at this temperature.
a Determined by GC/MS.
b Determined by chiral GC (Lipodex E).
c Deprotonation was conducted in 1 ml of toluene, then, after addition of the diethylzinc solution, 3 ml of CH2Cl2 was added.
d Pre-formed ligand.

F. Guillen et al. / Tetrahedron: Asymmetry 12 (2001) 2083–2086
2085
enantioselectivity to 50% when the reaction was
allowed to run for 16 h (Table 2, entry 3).
O
O
2 (4%), (CuOTf)2 (4%)
(1)
Et2Zn 1.5 eq., CH2Cl2
-20˚C, 2 h
A study of the influence of the ligand structure was
conducted using the standard conditions (Table 1, entry
10–13). Compounds 3–4, lacking a chiral nitrogen sub-
stituent, afforded the lowest e.e. Table 1, entry 10–11).
The presence of the chiral 1-phenylethyl substituent on
the nitrogen increased the e.e., with no influence of the
ring size (Table 1, entry 12–13). The imidazolinium salt
2, possessing a chiral backbone and chiral nitrogen
substituents, gave the best e.e. values.
>99% (e.e. 0%)
O
O
7 (4%), (CuOTf)2 (4%)
(2)
Et2Zn 1.5 eq.
toluene, -20˚C, 2h
5% (e.e. 6%)
In order to ascertain the scope of the catalytic system,
several enones, covering a wide range of structural
features (Fig. 2), were submitted to the two sets of
conditions determined previously (i.e. imidazolium salt
2, copper(II) triflate in either toluene/dichloromethane
at −20°C for 16 h, or in Et2O at −78°C for 16 h).
Ph
Ph
Ph
Ph
NHHN
7
Scheme 3. Control experiments.
The results are presented in Table 3. Both reactivity
and selectivity depend heavily on the substrate struc-
ture. At −78°C, every substrate that was tested exhib-
ited lower reactivity than the cyclohexenone. In the case
of the cycloheptenone 8 (entry 1) and the decenone 11
(entry 7), this lowered reactivity toward the diethylzinc
addition induced a large increase in the reaction of the
intermediate zinc enolate with the starting enone,
whereas steric hindrance appears to prohibit this reac-
tion for 5-methyl-3-hexen-2-one 9 (entry 3). Only 3-
nonen-2-one 12 reached 20% e.e., with a 75% yield
(entry 9). At −78°C however, there was no evidence for
the formation of a double addition product and
although the 1,4 addition reaction did not occur for
every substrate (entries 4 and 6 show results for 5-
methyl-3-hexen-2-one 9 and benzylacetone 10, respec-
tively), it was possible to achieve an e.e. of 51% using
decen-4-one 11 as a substrate in excellent yield (entry
8). This was a vast improvement on the result obtained
using the original conditions. Both cycloheptanone 8
and 3-nonen-2-one 12 also gave better yields and enan-
tioselectivities at low temperature than could be
achieved using toluene/dichloromethane at −20°C.
The use of dichloromethane as co-solvent leads to an
increased product e.e. (Table 1, entry 7). However, the
need for a solvent compatible with n-BuLi for the
deprotonation step prohibits the use of dichloro-
methane alone. Whereas THF, as expected for a Lewis
basic solvent, displays the lowest enantioselectivity and
activity (Table 1, entry 8), an increase in activity was
observed in ether without significant loss of selectivity
(Table 1, entry 9: the reaction rate is one order of
magnitude higher than in toluene). Lowering the tem-
perature to −50°C did not improve the enantioselectiv-
ity of the reaction, whilst at −78°C the reaction
becomes sluggish although there was an increase in
Table 2. Influence of the reaction temperature in ether
Entry
Temperature
Yield (%)a
E.e. (%)b
1c
2c
3d
−20°C
−50°C
−78°C
\99
97
91
19
20
50
Experimental procedure as in Table 1, the addition of diethylzinc is
carried out at −20°C and the reaction mixture cooled down to the
appropriate temperature before addition of the cyclohexenone.
a See Table 1.
Table 3. 1,4 Addition of diethylzinc on various enones
Entry
Substrate
Yield (%)a
E.e (%)b
Enolate
b See Table 1.
addition (%)
c Yields and e.e. after 2 h.
d Yields and e.e. after 16 h.
1c
8
8
9
55
66
23
0
27
0
40
99
75
99
9 (−)
12 (−)
10
−
11 (+)
–
1 (+)
51 (+)
20 (R)
26 (R)
28
0
0
0
8
0
42
0
9
0
2d
3c
O
O
O
4d
5c
9
10
10
11
11
12
12
Ph
6d
7c
8d
9c
8
9
10
O
10d
O
a See Table 1.
b See Table 1.
11
12
c Toluene/DCM, −20°C, 16 h.
d Et2O, −78°C, 16 h.
Figure 2.

2086
F. Guillen et al. / Tetrahedron: Asymmetry 12 (2001) 2083–2086
The optimisation of the diaminocarbene ligand struc-
ture as well as the study of the diaminocarbene–copper
catalyzed conjugate addition of organozinc reagents on
various Michael acceptors is currently underway. In the
accompanying paper, Mangeney et al. disclose their
results from enantioselective conjugate addition reac-
Siebr, G. Chem. Eur. J. 2000, 6, 10; (c) Huang, J.; Nolan,
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Acknowledgements
The authors thank the Swiss National Science Founda-
tion No. 20-61891.00 and COST action D12/0022/99
for financial support. We also thank Dr. P. Mangeney
and Dr. S. Woodward for fruitful discussions.
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