Copper-catalyzed asymmetric conjugate addition with Grignard reagents and SimplePhos ligands

Article abstract of DOI:10.1016/j.tetasy.2009.11.016

Herein we report the copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic and acyclic enones, with SimplePhos as chiral ligands. A variety of Grignard reagents can be added to a range of cyclic and acyclic enones, with moderate to good enantioselectivities (ee's up to 86%).

Full text of DOI:10.1016/j.tetasy.2009.11.016

Tetrahedron: Asymmetry 20 (2009) 2866–2870
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Copper-catalyzed asymmetric conjugate addition with Grignard reagents
and SimplePhos ligands
*
Laëtitia Palais, Alexandre Alexakis
University of Geneva, Department of Organic Chemistry, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic and
acyclic enones, with SimplePhos as chiral ligands. A variety of Grignard reagents can be added to a range
of cyclic and acyclic enones, with moderate to good enantioselectivities (ee’s up to 86%).
Ó 2009 Elsevier Ltd. All rights reserved.
Received 2 November 2009
Accepted 19 November 2009
Available online 7 January 2010
1. Introduction
2. Results and discussion
The asymmetric conjugate addition (A.C.A.) of organometallic re-
agents to Michael acceptors is amongst the most important method-
ologiesto createachiralC–Cbond.1 In thisfield, muchefforthasbeen
directed toward the development of copper-catalyzed reactions.2
Organozinc reagents have been the most successful of the organo-
metallic reagents in this respect. Dialkylzinc reagents offer some
advantages because of their low reactivity and their high tolerance
toward functional groups on the substrate, but also on the organo-
zinc itself.3 However, their diversity remains limited and this is
why the use of Grignard reagents is a good option.
The first example of Cu-catalyzed conjugate addition with Grig-
nard reagents as organometallics was reported by Karash in 1941,
in a racemic version.4 Since then, many groups have developed sev-
eral methodologies to afford the chiral version of this reaction via
diastereoselective or enantioselective ways. The first example of
enantioselective Cu-catalyzed conjugate addition of Grignard re-
agentswasreportedbyLippardandco-workersin1988, witha chiral
bidentate N,N0-dialkyl-substituted aminotroponeimin ligand.5 Since
then, various bidentate ligands allowed high regio- and enantiose-
lectivities of this reaction to a large scope of enones.6 The only case
where monodentate ligands were used in copper-catalyzed A.C.A.
wasdescribedby Feringawith phosphoramidite-typeligandsto acy-
clic enones in 2008 (ee’s up to 80%).7 In this respect, we herein report
the use of SimplePhos ligands in the A.C.A. of Grignard reagents to
cyclic and acyclic enones catalyzed by copper salts.
We report herein a full account of our results in the copper-cat-
alyzed A.C.A. of a large scope of Grignard reagents to various enon-
es with SimplePhos ligands.
Cyclohexenone 1 is the archetypical enone in ACA. With this
substrate, we have searched the optimal copper source, solvent,
reaction temperature, ligand, and halide in the Grignard reagent
for the addition of various Grignard reagents (alkyl or aryl). All
the optimizations were carried out with SimplePhos ligand L1
(Fig. 1).
We initially tested the addition of EtMgBr to cyclohexenone 1 in
the presence of several copper salts (2 mol %) and ligand L1
(4 mol %) in ether at ꢀ30 °C. All the results are summarized in Ta-
ble 1. Various copper(I) and (II) salts were screened in this study.
The first promising results were achieved with CuBr2, which gave
54% ee in the addition of EtMgBr to the model substrate 1 (Table 1,
entry 5). Some other copper salts such as CuI, Cu(OAc)2ꢁH2O, and
Cu(acac)2 showed almost the same results, 51% ee (entries 2, 8,
10). All other copper sources gave lower enantioselectivities. In
contrast to diorganozinc or triorganoaluminium reagents, the
1,4-regioselectivity is not perfect. The direct carbonyl addition
product (1,2-addition) is always observed, from negligible (entries
1, 3, 4, 6, 10, and 11) to 50% (entry 7, with CuCN). For the next
experiments, we chose CuBr2 as the best compromise.
Next, we examined the influence on the enantioselectivity of the
copper/ligand ratio as well as the catalyst loading in the addition of
EtMgBr to cyclohexenone 1 (Table 2). No improvement in enantiose-
lectivity was observed with a ratio of CuBr2/ligand ranging from 1/
1.5 to 1/3 and 1/6 (Table 2, entries 1–3, 5–6). From these results,
we concluded that the best results in terms of asymmetric induction
were obtained with the copper to ligand ratio of 1/4 with 61% ee.
Unfortunately, at the same time, a decrease of the 1,4-adduct pro-
duction was observed (1,4:1,2 70:30) (Table 2, entry 4).
Monodentate SimplePhos ligands have already shown their effi-
ciency in various asymmetric copper-catalyzed reactions, such as
the conjugate addition of dialkylzinc or trialkylaluminium to di-
and trisubstituted enones8–10 or the allylic alkylation,7 in kinetic
resolution of vinyloxiranes10 but also in desymmetrization of meso
compounds.11
The addition of EtMgBr to 1 was next studied at different tem-
peratures and in different solvents (Table 3). Performing the
* Corresponding author. Tel.: +41 22 379 65 22; fax: +41 22 379 32 15.
E-mail address: alexandre.alexakis@unige.ch (A. Alexakis).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.016

L. Palais, A. Alexakis / Tetrahedron: Asymmetry 20 (2009) 2866–2870
2867
Ar1
Ar3
R
P
N
P
N
P
N
Ar3
R
Ar2
L2 : Ar1=Ar2=Ph, R=Et
L1
L7 : Ar3=m-CF3(C6H4)
L8 : Ar3=m-OMe(C6H4)
L9 : Ar3=3,5-Me(C6H4)
L10 : Ar3=2-naphthyl
L11 : Ar3=o-furyl
L3 : Ar1=Ar2=o-OMe(C6H4), R=Me
L4 : Ar1=Ar2=2-naphthyl, R=Me
L5 : Ar1=Ar2=1-naphthyl, R=Me
L6 : Ar1=Ph, Ar2=o-pyridine, R=Me
CF3
O
O
P
N
P
N
CF3
L12
L13
Figure 1. SimplePhos ligands used in this study.
Table 1
Table 2
Optimizations of copper salts
Optimization of the copper/ligand ratio
O
O
O
O
CuX (2 mol%)
L1 (4 mol%)
CuBr2
L1
+ EtMgBr
(2 equiv.)
+ EtMgBr
(2 equiv.)
ether, -30ºC, 2h
(R)
(R)
ether, -30ºC, 2h
1
2
1
2
Entry
CuX
Conv.a (%)
1,4:1,2a
eeb (%)
Entry
Ratio CuBr2/L1 (mol %/mol %)
Conv.a (%)
1,4:1,2a
eeb (%)
1
2
3
4
5
6
7
8
9
CuTC
CuI
CuCl
CuBr
100
98
99
97
98
99
95
98
98
98
99
99:1
79:21
97:3
96:4
84:16
97:3
49:51
92:8
76:24
93:7
45
51
47
47
54
46
31
51
49
51
41
1
2
3
4
5
6
1/1.5 (2/3)
1/2 (2/4)
1/3 (2/6)
1/4 (2/8)
1/5 (2/10)
1/6 (2/12)
98
99
99
91
98
96
84:16
84:16
81:09
70:30
75:25
69:31
51
54
55
61
42
54
CuBr2
CuBrꢁMe2S
CuCN
a
Determined by GC–MS.
Determined by chiral GC.
Cu(OAc)2ꢁH2O
Cu(CH3CN)4BF4
Cu(acac)2
Cu(OTf)2
b
10
11
98:2
proved regioselectivity (93:7) and enantioselectivity of 67% (Ta-
ble 4, entry 4). Furthermore, the slow addition of the Grignard
reagent over 1 h could increase the asymmetric induction to 72%
ee (Table 4, entry 5). In other applications of SimplePhos ligands,
we have often seen the importance of the steric bulkiness on the
chiral amine part of the ligand in improving the enantioselectivi-
a
Determined by GC–MS.
Determined by chiral GC.
b
reaction in dichloromethane or in 1-methyl-THF at ꢀ30 °C allowed
an increase in the regioselectivity (1,4-addition vs 1,2-addition)
but a high decrease in the enantioselectivity from 27% and 22%,
respectively (Table 3, entries 2 and 3). Different temperatures were
evaluated in diethylether but both lower and higher temperatures
produced a decrease in enantioselectivity (Table 3, entries 4–7).
To finish the optimizations of experimental conditions, several
SimplePhos ligands were tested (Table 4)
ty.8–12 The ligand L3, with
a
chelating group (Ar1 = Ar2 = o-
OMe(C6H4)), also showed good enantioselectivities up to 69% but
with a decrease in the regioselectivity (83:17) (Table 4, entry 3).
The enantioselectivities observed with the other ligands were con-
sistently poorer.
With these optimized conditions in hand, we decided to use
2 mol % of CuBr2 and 8 mol % of L4 in ether to screen several Grig-
nard reagents with a range of enones (cyclic or acyclic), to deter-
mine if the new system was viable (Table 5). Thus, various alkyl
The copper-catalyzed A.C.A. of EtMgBr to cyclohexenone 1 in
the presence of ligand SimplePhos L4 (with the 2-naphthyl group
on the chiral amine) gave the corresponding adduct 2 in an im-

2868
L. Palais, A. Alexakis / Tetrahedron: Asymmetry 20 (2009) 2866–2870
Table 3
Table 4
Optimizations of the temperature and the solvent of the reaction
Optimization of SimplePhos ligands
O
O
O
O
CuBr2 (2 mol%)
CuBr2 (2 mol%)
L1 (8 mol%)
L* (8 mol%)
+ EtMgBr
(2 equiv.)
+ EtMgBr
(2 equiv.)
(R)
(R)
Et2O, -30ºC, 2h
solvent, TºC, 2h
1
2
1
2
Entry
Temperature (°C)
Solvent
Conv.a (%)
1,4:1,2a
eeb (%)
Entry
Ligand
Conv.b (%)
1,4:1,2b
eec (%)
1
2
3
4
5
6
7
ꢀ30
ꢀ30
ꢀ30
ꢀ78
ꢀ45
ꢀ10
0
Et2O
91
100
100
100
100
100
100
70:30
99.5:0.5
98:2
89:11
78:22
90:10
99:1
61
27
22
32
52
52
52
1
2
3
L1
L2
L3
L4
L4
L5
L6
L7
L8
L9
L10
L11
L12
91
97
95
95
100
93
98
72
95
95
70:30
93:7
83:17
93:7
61
39
69
67
72
39
20
5
46
9
20
36
29
CH2Cl2
1-Me–THF
Et2O
Et2O
Et2O
4
5a
6
93:7
69:31
58:42
83:17
85:15
93:7
86:14
94:36
94:6
Et2O
7
8
9
10
11
12
13
a
Determined by GC–MS.
Determined by chiral GC.
b
98
100
95
and aryl Grignard reagents were added to cyclohexenone 1. When
linear alkyl Grignard reagents (MeMgBr, EtMgBr, n-BuMgBr, n-
Hex-5-enylMgBr, and n-octylMgBr) were used as nucleophiles,
the corresponding adducts 2–6 were obtained with 51–86% ee (Ta-
ble 5, entries 1–3, 6–7). We observed an improvement in the
enantioselectivity with the length of the alkyl chain being added.
The halide of the Grignard reagent was also important. A decrease
in both the regio- and enantioselectivity was observed by using n-
BuMgCl (1,4/1,2 66:34, 69% ee) instead of n-BuMgBr (80% ee) (Ta-
ble 5, entry 5). For the sake of comparison, phosphoramidite ligand
L13 (Fig. 1) was also tested for the addition of n-BuMgBr to 1.
Unfortunately only 69% ee was obtained, with a slightly higher reg-
ioselectivity for the 1,4 adduct (Table 5, entry 4).
Other primary alkyl Grignard reagents were also screened with-
out any increase in the asymmetric induction (ee’s up to 72%) (Ta-
ble 5, entries 8 and 9). For secondary alkyl Grignard reagents, i-
PrMgBr and c-HexMgBr, enantioselectivities were found to be
64% and 76%, respectively (Table 5, entries 10 and 11). For the
bulky Grignard reagents t-BuMgBr, only the racemate adduct was
obtained (Table 5, entry 12). Finally, the addition of an aryl Grig-
a
b
c
Addition of EtMgBr over 1 h.
Determined by GC–MS.
Determined by chiral GC.
nard reagent, PhMgBr, proceeded in a moderate regioselectivity
(77:23) and with a moderate enantioselectivity (60%) (Table 5, en-
try 13).
Next, the addition of EtMgBr was investigated with various cyc-
lic enones with 5-, 7-, and 15-membered ring systems (Table 6). In
comparison with cyclohexenone 1, enones with a smaller ring,
such as 13, or a larger cycle, such as 14 or 15, showed lower enanti-
oselectivities: 44%, 55%, and 4%, respectively (Table 6, entries 1, 3
and 4).
Finally, we studied the addition of EtMgBr to alkyl linear and
aryl acyclic
a,b-unsaturated ketones (Table 7). However, regardless
of which substrate was used, very low enantioselectivities were re-
ported with at best 36% ee for the adduct 23 (Table 7, entry 1). Only
racemate adducts were found with an aryl substrate (Table 7,
Table 5
Screening of Grignard reagents to 1
O
O
CuBr2 (2 mol%)
L4 (8 mol%)
+ RMgX
(2 equiv.)
*
ether, -30ºC, 3h
R
3
2-12
Entry
RMgX
Adduct
Conv.b (%)
1,4:1,2b
eec (%) (Abs. Conf.)
1
2
EtMgBr
MeMgBr
2
3
4
4
4
5
6
7
8
100
100
100
100
80
100
100
100
100
100
100
100
91
93:7
93:7
92:8
72 (R)
51 (R)
80 (R)
68 (R)
69 (R)
80
86 (R)
54 (S)
72 (S)
64
3
n-BuMgBr
n-BuMgBr
n-BuMgCl
n-Hex-5-enylMgBr
n-OctylMgBr
i-BuMgBr
Ph(CH2)2MgBr
i-PrMgBr
c-HexMgBr
t-BuMgBr
4a
5
94:6
66:34
73:27
83:17
93:7
100:0
100:0
98:2
6
7
8
9
10
11
12
13
9
10
11
12
76
0
60
100:0
77:23
PhMgBr
a
b
c
With phosphoramidite ligand L13.
Determined by GC–MS.
Determined by chiral GC.

L. Palais, A. Alexakis / Tetrahedron: Asymmetry 20 (2009) 2866–2870
2869
Table 6
by the addition of a saturated NH4Cl solution. All the conjugate ad-
ducts are described in the literature. Enantiomeric excesses were
determined by chiral GC or SFC.
Addition of EtMgBr to various cyclic enones
O
O
CuBr2 (2 mol%)
L4 (8 mol%)
4.2. Determination of enantiomeric excesses
+ EtMgBr
(2 equiv.)
(R) *
ether, -30ºC, 3h
4.2.1. (R)-3-Ethyl-cyclohexanone 2
n
n
Enantiomeric excess was measured by chiral GC: LIPODEX E,
isotherm T = 60 °C, Rt1 = 16.8 (R), Rt2 = 20.5 (S).
13 : n=0
16 : n=0
2 : n=1
17 : n=2
18 : n=10
1 : n=1
14 : n=2
15 : n=10
4.2.2. (R)-3-Methyl-cyclohexanone 3
Enantiomeric excess was measured by chiral GC: HYDRODEX
TBDM, T: 60 °C—flow rate 1 °C/min, Rt1 = 19.58 (R), Rt2 = 20.35 (S).
Entry
n
Conv.a (%)
1,4:1,2a
eeb (%)
1
2
3
4
0
1
2
100
100
100
100
94:6
93:7
75:25
81:19
44
72
55
4
4.2.3. (R)-3-Butyl-cyclohexanone 4
Enantiomeric excess was measured by chiral GC: HYDRODEX
TBDM, T: 60 °C—flow rate 1 °C/min, Rt1 = 52.77 (S), Rt2 = 53.03 (R).
10
a
Determined by GC–MS.
Determined by chiral GC.
b
4.2.4. 3-(Hex-5-enyl)-cyclohexanone 5
Enantiomeric excess was measured by chiral GC: LIPODEX E,
T = 60 °C, flow rate 1 °C/min, Rt1 = 41.92, Rt2 = 42.40.
entries 3 and 4). These results showed the limitations of the system
with SimplePhos ligands.
4.2.5. (R)-3-Octyl-cyclohexanone 6
3. Conclusion
Enantiomeric excess was measured by chiral GC: HYDRODEX
TBDM, T: 60 °C—flow rate 1 °C/min, Rt1 = 98.16 (R), Rt2 = 98.5 (S).
In conclusion, we have demonstrated that monodentate Simple-
Phos ligands could efficiently perform the copper-catalyzed asym-
metric conjugate addition of Grignard reagents to cyclohexenone 1,
with at best 86% ee. Lower results were observed with other cyclic
4.2.6. (S)-3-Isobutyl-cyclohexanone 7
Enantiomeric excess was measured by chiral GC: LIPODEX E, T:
60 °C—flow rate 1 °C/min, Rt1 = 16.85 (S), Rt2 = 17.93 (R).
and acyclic a,b-unsaturated ketones.
4.2.7. (S)-3-Phenethyl-cyclohexanone 8
Enantiomeric excess was measured by chiral SFC: Chiralcel AD-
H column (2% MeOH flow rate 2 mL/min), Rt1 = 6.82 (S), Rt2 = 7.87
(R).
4. Experimental section
4.1. General procedure
4.2.8. 3-Isopropyl-cyclohexanone 9
Enantiomeric excess was measured by chiral GC: HYDRODEX
TBDM, isotherm T: 90 °C, Rt1 = 29.03, Rt2 = 29.51.
4.1.1. Typical procedure for enantioselective copper-catalyzed
conjugate addition with Grignard reagents
A
flame-dried Schlenk tube was charged with CuBr2
(0.01 mmol) and the chiral ligand (0.04 mmol). Ether (1 ml) was
added and the mixture was stirred at room temperature for
30 min. Then the Michael acceptor (0.5 mmol) in ether (1 ml)
was added at room temperature and the reaction mixture was stir-
red for a further 5 min before being cooled to ꢀ30 °C. Then, the
Grignard reagent (2 equiv) dissolved in 2 mL of Et2O was intro-
duced dropwise over 1 h. Once the addition was completed, the
reaction was left at ꢀ30 °C for 2 h. The reaction was hydrolyzed
4.2.9. 3-Cyclohexyl-cyclohexanone 10
Enantiomeric excess was measured by chiral GC: HYDRODEX
TBDM, T: 60 °C—flow rate 1 °C/min, Rt1 = 72.86, Rt2 = 73.01.
4.2.10. 3-tert-Butyl-cyclohexanone 11
Enantiomeric excess was measured by chiral GC: LIPODEX E, T:
60 °C—flow rate 1 °C/min, Rt1 = 17.99, Rt2 = 18.84.
Table 7
Addition of EtMgBr to various cyclic enones
CuBr2 (2 mol%)
L4 (8 mol%)
O
O
Et
+ EtMgBr
(2 equiv.)
R1
R2
R1
R2
ether, -30ºC, 3h
19 : R1=Me, R2=i-Pr
20 : R1=Me, R2=C5H11
21 : R1=Me, R2=Ph
22 : R1=Ph, R2=Ph
23 : R1=Me, R2=i-Pr
24 : R1=Me, R2=C5H11
25 : R1=Me, R2=Ph
26 : R1=Ph, R2=Ph
Entry
Substrate
Conv.a (%)
1,4:1,2a
eeb (%) (Abs. Conf.)
1
5
6
7
19
20
21
22
100
94
100
100
97:3
36 (R)
15 (S)
0
3
66:34
100:0
100:0
a
Determined by GC–MS.
Determined by chiral GC.
b

2870
L. Palais, A. Alexakis / Tetrahedron: Asymmetry 20 (2009) 2866–2870
4.2.11. 3-Phenyl-cyclohexanone 12
Acknowledgments
Enantiomeric excess was measured by chiral SFC: Chiralcel AD-
H column (2% MeOH flow rate 2 mL/min), Rt1 = 5.97, Rt2 = 6.64.
The authors thank the Swiss National Research Foundation
(Grant No. 200020-113332) and COST action D40 (SER Contract
No. C07.0097) for their financial support, as well as Stephane Ros-
set for his help in chiral separations and BASF for a generous gift of
chiral amines.
4.2.12. (R)-3-Ethylcyclopentanone 16
Enantiomeric excess was measured by chiral GC: HYDRODEX B-
3P isotherm T = 60 °C, Rt1 = 27.79, Rt2 = 28.57.
4.2.13. (R)-3-Ethyl-cycloheptanone 17
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4.2.14. (R)-3-Ethylcyclopentadecanone 18
Enantiomeric excess was determined by chiral GC: HYDRODEX
B-3P, isotherm T: 140 °C, Rt1 = 62.8 (R), Rt2 = 64.3 (S).
4.2.15. (R)-4-Ethyl-5-methylhexan-2-one 23
Enantiomeric excess was measured by chiral GC: LIPODEX E, T:
60 °C—flow rate 1 °C/min, Rt1 = 5.88 (R), Rt2 = 7.29 (S).
4.2.16. (R)-4-Ethylnonan-2-one 24
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isotherm 75 °C, Rt1 = 38.21 (S), Rt2 = 41.37 (R).
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4.2.17. (R)-1,3-Diphenylpentan-1-one 25
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column(26%MeOH flowrate2 mL/min), Rt1 = 5.87(S), Rt2 = 6.63(R).
4.2.18. (R)-1,3-Diphenylbutan-1-one 26
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12. (a) Millet, R.; Bernardez, T.; Palais, L.; Alexakis, A. Tetrahedron Lett. 2009, 26,
3474–3477.; (b) Millet, R.; Gremaud, L.; Bernardez, T.; Palais, L. Synthesis 2009,
12, 2101–2112.
Enantiomeric excess was measured by chiral SFC: Chiralcel OD-H
column (2% MeOH flow rate 2 mL/min), Rt1 = 5.85 (R), Rt2 = 6.25 (S).