Copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted enones. Construction of all-carbon quaternary chiral centers

Article abstract of DOI:10.1021/ja0629920

The copper-catalyzed asymmetric conjugate addition of Grignard reagents to trisubstituted cyclic enones affords enantioenriched all-carbon quaternary centers with up to 96% ee. The chiral ligand is a diaminocarbene, directly generated in situ. The combination of Grignard reagent and diaminocarbene is unprecedented in conjugate addition, and the additon of the phenyl group, on such enones, cannot be done by other conjugate addition methods. Copyright

Full text of DOI:10.1021/ja0629920

Published on Web 06/14/2006
Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents to
Trisubstituted Enones. Construction of All-Carbon Quaternary Chiral Centers
David Martin,† Stefan Kehrli,† Magali d’Augustin,† Herve´ Clavier,‡ Marc Mauduit,*,‡ and
Alexandre Alexakis*,†
De´partement de Chimie Organique, UniVersite´ de Gene`Ve, 30, quai Ernest Ansermet CH-1211 Gene`Ve 4,
Switzerland, and UMR CNRS 6226 “Sciences Chimiques de Rennes”, Ecole Nationale Supe´rieure de Chimie de
Rennes, AV. du Ge´ne´ral Leclerc, 35700 Rennes, France
Received April 29, 2006; E-mail: alexandre.alexakis@chiorg.unige.ch
Table 1. Comparison of Organometallics
The creation of enantioenriched all-carbon quaternary centers is
still a synthetic challenge.1 Solutions to this problem through the
asymmetric conjugate addition2 have been recently disclosed. We
have found that the enhanced Lewis acidity of R3Al allows the
copper-catalyzed conjugate addition to proceed on simple trisub-
tituted cyclic enones.3 On the other hand, more reactive substrates,
such as nitro-alkenes,4 or doubly activated enones5,6 are able to
react with R2Zn. However, there is also another way to tackle the
problem: this is to use a more reactive primary organometallic
reagent.
It has been long known that lithium dialkyl cuprates, or copper-
catalyzed Grignard reagents, are able to undergo conjugate addition
to trisubstituted Michael acceptors, thus creating an all-carbon
quaternary center.7 Therefore, we focused our attention on the use
of Grignard reagents. It was recently reported that ferrocene-based
ligands were appropriate for the enantioselective conjugate addition
of Grignards onto several classes of Michael acceptors; however,
none of them was trisubstituted.8 Our attempts to use such ligands
with trisubstituted enones were disappointing, the ee’s were low
and the regioselectivity (1,2 versus 1,4 addition) was poor. On the
other hand, all the attempts to use known phosphoramidite ligands
gave poor ee’s, despite an excellent 1,4 regiocontrol. Our efforts
were then focused on finding the right chiral ligands to copper that
could induce high levels of enantioselectivity.
entry
ImH+
“EtM”
time (h)
conv.a (%)
eeb (%)
1
2
3
4
6
7
8
1b
1b
2a
3b
1b
2a
3b
Et2Zn
Et3Al
Et3Al
Et3Al
EtMgBr
EtMgBr
EtMgBr
16
16
16
16
0.5
0.5
0.5
1
85
94
94
86
92
96
9 (-)S
54 (-)S
0
17 (+)R
68 (-)S
61 (+)R
a After 16h; determined by GC-MS. b Determined by chiral GC Lipodex
E.
Scheme 1. Conjugate Addition of Et Grignard and Chiral Ligands
Scheme 2. Transfer of the Chiral Information to the Reacting
Center
Among the recently described ligands for the copper-catalyzed
conjugate addition, the class of diaminocarbenes (or NHCs for
N-heterocyclic carbenes)9 has emerged as a viable alternative to
phosphorus-based ligands. They do afford an acceleration of the
reaction rate,10 and they also afford high levels of enantioselectiv-
ity.11 The combination of Grignard reagents and NHCs as ligands
is unprecedented in the conjugate addition, although an example
has been disclosed in the copper-catalyzed allylic substitution.12
To begin this study, we performed preliminary tests by reacting
different organometallic compounds with 3-methylcyclohex-2-enone
4 (Table 1). The copper-NHC catalyst was prepared in situ by
deprotonating the corresponding imidazolidinium salt (ImH+) with
butyllithium in the presence of copper(II) triflate. Three families
of chiral ImH+ were considered (Scheme 1).
From Hermann’s-type ligands 1a-c,9c we already knew that 1b
was very efficient in the conjugate addition of Et2Zn to cyclohex-
enone (89% ee).11c However, with 4, no reaction took place with
Et2Zn.
With Et3Al and EtMgBr, the conversions were good and a small
enantioselectivity was observed (entries 2 and 6). These results were
not discouraging, because it is well-accepted that these standard
chiral-NHCs often feature low chiral inductions, mainly because
of the rapid internal rotation of the chiral substituents around the
C-N axis. Thus, considering the possible strategies to lock the N-
substituents in fixed conformations, we focused on the C2-symmetric
imidazolidinium 2a-d, bearing chirality on the heterocycle. Their
interest lies in the ability of the chiral centers to transfer the chiral
information directly in R-position of nitrogens through steric
interactions with the a priori achiral N-substituents (Scheme 2).11d,13
Interestingly, in this series, the Cu-2a complex afforded a
promising 54% ee with Et3Al and 68% ee with EtMgBr (entries 3
and 7). Yet, another strategy is to use bidentate ligands such as the
alkoxy-NHCs 3a-f that have demonstrated their efficiency on
cyclohexenone and Et2Zn.11e-g The Cu-3b complex afforded 61%
ee with EtMgBr but no ee with EtAl3 (entries 4 and 8).
We then optimized the experimental conditions for the conjugate
addition of EtMgBr to 3-methylcyclohexenone in the presence of
a Cu-2a complex. The results are summarized in Table 2 of the
Supporting Information. The choice of the solvent appeared to be
critical. Indeed the best ee (68%; entry 1) is obtained in pure Et2O,
whereas no ee was observed in THF (entry 2). The best temperature
for this reaction is 0 °C (entries 1, 6, and 7). Cu(OTf)2 or Cu(CN)4-
PF6 appeared to be appropriate copper sources (entries 1 and 8-11).
Having in hand these operating conditions, we tried to optimize
the structure of the chiral ligands. (Table 3 of the Supporting
† Universite´ de Gene`ve.
‡ Ecole Nationale Supe´rieure de Chimie de Rennes.
9
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J. AM. CHEM. SOC. 2006, 128, 8416-8417
10.1021/ja0629920 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Additions of Grignards to 4
Table 3. Variation of the Enone
entry
ImH+
R
T (
°
C)
product
conv.a (%)
eeb (%)
entry ImH+ enone
n
R1
R2
R3
prod.
conv.a (%) eeb (%)
1
2
3
4
5
6
7
8
9
2a
3d
3d
3d
3d
3d
3d
3d
3d
3d
ethyl
ethyl
butyl
butenyl
i-butyl
i-propyl
c-pentyl
c-hexyl
t-butyl
Ph
0
0
0
ent-5a
5a
5b
5c
5d
5e
5f
5g
5h
5i
96(90)
99(81)
100
91(80)
100(72)
100(77)
100(80)
100(79)
0
73(S)
80(R)
77(R)
90(S)
96(S)
77(R)
85(R)
74(R)
1
2
3
4
5
6
7
8
2a
3d
3d
3d
3d
3d
3d
3d
6
6
7a
7b
7c
7d
8
1
1
1
1
1
1
0
2
Me,Me methyl Et
Me,Me methyl Et
ent-10 93(57)
10 100(85) 82(R)
71(S)
-30
-30
-18
-30
-30
-30
-30
H,H
H,H
H,H
H,H
H,H
H,H
ethyl
Me 11a
98(67)
98(69)
98(87)
99(84)
98(90)
99
68(S)
81(S)
72(S)
69(R)
46(R)
82(R)
i-butyl Et
phenyl Et
butenyl Et
methyl Et
methyl Et
11b
11c
11d
12
9
13
10
72(61)
66(R)
a Conversion determined by GC-MS. Isolated yields in parentheses.
a Conversion determined by GC-MS. Isolated yields are in parentheses.
b Determined by chiral GC (Lipodex E).
b Determined by chiral GC (Lipodex E).
Information). Concerning Hermann’s-type ImH+ 1a-c, better
results were obtained with the smaller 1-phenyl ethyl substituents
(ee up to 55%, entries 1 and 3), rather than 2-ethylnaphthyl (17%
ee, entry 2). The case of the imidazolidiniums 2a-d is more tricky;
the enantioselectivity decreased following the order 1-naphthyl
(68%) > o-MeC6H4 (63%) . 2-naphthyl (17%) > o-i-PrC6H4
(10%; entries 4-7). With bidentates ImH+ 3a-f (entries 8-13),
the enantioselectivity logically increased with the size of the
substituent on the chiral center. Slightly better conversions were
obtained by adding the substrate on the Grignard reagent slowly.
Finally, when adding first the substrate and then the Grignard, the
ee drops down, and only 2% ee was obtained (entry 14) with ImH+
2a. This may indicate that the active asymmetric species, in the
present reaction, is an ate-complex (or higher-order cuprate) such
as the type [(NHC)CuEt2]. This is in contrast with the copper-
catalyzed asymmetric allylic substitution, where the Grignard
reagent is added very slowly to the substrate to avoid the formation
of cuprate species.14 A last practical modification was made: instead
of deprotonating ImH+ with BuLi, we just did it with the Grignard
reagent used for the conjugate addition (entry 18). Although the
observed ee is slightly lower, this procedure is more convenient
and more reproducible.
Next, we explored the scope and limitation of this new
methodology. First, a screening of the various Grignard reagents
was made with 3-methylcyclohex-2-enone 4 (Table 2). Primary
Grignards gave high ee’s, up to 96% with i-Bu (entry 5). Secondary
Grignards behaved as well, particularly when the reaction temper-
ature was lowered to -30 °C. However, t-BuMgBr did not react
at all, even at a higher temperature. Finally, PhMgBr gave 66% ee
of an adduct that cannot be obtained by the Rh-catalyzed conjugate
addition of aryl boronic acids.2c
Complementary, the addition of EtMgBr was done on various
trisubstituted cyclohexenones (Table 3). In all cases, the reaction
afforded the desired product in good to moderate ee’s. It should be
pointed out that even poorly reactive enones, such as isophorone
or phenyl cyclohexenone, gave good yields and ee’s.
Turning to five- (10) and seven-membered rings (11), we only
tested the addition of EtMgBr, with 3d as chiral ligand. Although
the ee is moderate, this promising result should be improved with
better ligands. In conclusion, we have found an efficient way to
create, enantioselectively, all-carbon quaternary centers, by the
unprecedented asymmetric conjugate addition of Grignard reagents
associated with a copper catalyst and a chiral diaminocarbene ligand.
There is no need to use specially activated trisubstituted enones,
and the scope of the reaction seems wider because many Grignard
reagents are easily or commercially available. We strongly believe
that new chiral diaminocarbenes, from these laboratories or
elsewhere, will improve these first generation ligands.
Acknowledgment. The authors thank Stephane Rosset for the
help, the Swiss National Research Foundation (Grant No. 200020-
105368) and COST action D24/0003/01 (OFES Contract No.
C02.0027) for financial support.
Note Added in Proof. After submission of our manuscript, a
Communication related to our work appeared: Lee, K. S.; Brown,
M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128,
7182.
Supporting Information Available: Tables 2 and 3, full experi-
mental data, all chromatograms, and NMR spectra of all new conjugate
adducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
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