Catalytic asymmetric Michael reactions with enamides as nucleophiles

Article abstract of DOI:10.1002/anie.200702517

(Chemical Equation Presented) Under its own steam: No external proton source is required for catalytic turnover in the copper-catalyzed title reaction with alkylidenemalonates, as proton transfer occurs rapidly in an intramolecular manner. The desired 1,5-dicarbonyl adducts were formed in moderate to high yield with high enantioselectivity (see scheme). R¹ = alkyl; R² = alkyl, aryl; Tf=trifluoromethanesulfonyl.

Full text of DOI:10.1002/anie.200702517

Angewandte
Chemie
DOI: 10.1002/anie.200702517
Asymmetric Catalysis
Catalytic Asymmetric Michael Reactions with Enamides as
Nucleophiles**
Florian Berthiol, Ryosuke Matsubara, Nobuyuki Kawai, and Shu¯ Kobayashi*
The asymmetric Michael addition reaction is among the most
powerful methods for the generation of enantiomerically
enriched 1,5-dicarbonyl compounds. As these compounds are
of great synthetic interest, many chiral metal complexes have
been developed for their enantioselective synthesis. Evans
et al. reported the Michael addition of silicon enolates to
alkylidenemalonates under the catalysis of a copper(II)–
bisoxazoline complex. Although they observed high yields
and high selectivities when benzylidenemalonate or bulky
alkylidenemalonates were used as electrophiles, the selectiv-
ities were lower when smaller alkylidenemalonates (such as
ethylidene- or propylidenemalonate) were used, and the
presence of an alcohol additive was essential for high catalytic
turnover.[1] Several other methods, including the addition of
nucleophiles to alkylidenemalonates[2] and the addition of
malonates to enones,[3] mainly to chalcone,[3a–o] have been
developed for the preparation of these valuable 1,5-dicar-
bonyl compounds. Whereas high enantioselectivities were
observed when benzylidenemalonate or chalcone derivatives
were used as electrophiles, low to moderate selectivities were
observed with ethylidenemalonate and other enones.
Recently, we reported the first examples of the highly
enantioselective addition of enamides and enecarbamates to
various electrophiles by using complexes of copper with a
chiral diamine or chiral diimine.[4] An advantage of the use of
enamides and enecarbamates is that a proton is transferred
very smoothly from these compounds during the addition
step, and therefore no external proton source is necessary for
high catalyst turnover. Moreover, the final products are
imines, which can be hydrolyzed to carbonyl derivatives or
reduced to provide a variety of valuable nitrogen-containing
compounds. The usefulness of enamides and enecarbamates
as nucleophiles prompted our interest in their use in Michael
reactions. Herein, we describe catalytic asymmetric Michael
reactions of enamides and enecarbamates with alkylidene-
malonates.
First, we investigated the reactivity of several Michael
acceptors toward the acetophenone-derived enecarbamate 3
in the presence of copper(II) triflate (Cu(OTf)2). The
reactions did not proceed at all with chalcone, 2-cyclohexen-
1-one, or ethyl crotonate in the presence of Cu(OTf)2
(10 mol%) at room temperature during a reaction time of
3 h. Moreover, the enecarbamate decomposed completely
under these reaction conditions. However, the use of diethyl
ethylidenemalonate as an electrophile under the same
reaction conditions, followed by hydrolysis, gave the desired
ketone product in 66% yield, although decomposition of the
enecarbamate was observed to some extent. This exception-
ally high reactivity may be attributed to strong coordination
of the copper ion to the diester functionality of the ethyl-
idenemalonate through favorable bidentate chelation.
We then concentrated on this type of electrophile and
examined several catalytic systems with dimethyl ethylidene-
malonate as the electrophile and the acetophenone-derived
enecarbamate 3 as the nucleophile. We screened a variety of
Lewis acid catalysts and found copper(II)–diamine complexes
to be the most promising. Furthermore, higher yields and
selectivities were observed with diaryl ethylidenemalonates
than with dialkyl ethylidenemalonates. We then optimized the
reaction conditions. With ligand 1a, the desired adduct was
formed in high yield with 66% ee (Table 1, entry 1). The
presence of ortho substituents on the aromatic groups of the
amino moieties (as in 1b) led to the same level of enantio-
selectivity, although longer reaction times were required
(Table 1, entry 2). An increase in the bulkiness of the
diphenyl ethylene backbone (as in 1g) did not improve the
enantioselectivity (Table 1, entry 3), and the presence of alkyl
substituents on the benzylic carbon atoms inhibited the
reaction (entry 4). With the ligand 1i, the reaction was
sluggish, and no asymmetric induction was observed (Table 1,
entry 5). The use of the 2-naphthyl-substituted ligand 1c
(Table 1, entry 6) and the 2-anthracenyl-substituted ligand 1d
(entry 7) led to improved enantioselectivity, and even higher
enantioselectivity was observed with the bulkier 1-naphthyl-
substituted ligand 1e (entry 8). Finally, it was found that the
[*] Dr. F. Berthiol, Dr. R. Matsubara, Dr. N. Kawai, Prof. Dr. S. Kobayashi
Graduate School of Pharmaceutical Sciences and
Department of Chemistry
School of Science, The University of Tokyo
The HFRE Division, ERATO, JST
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[**] This research was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science
(JSPS). F.B. thanks the JSPS for a postdoctoral research fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Optimization of the ligand and the ester groups of the
ethylidenemalonate.[a]
Table 2: Catalytic asymmetric Michael reactions of acetyl enamines.[a]
Entry R1
R2
Product t [h] Yield [%][b] ee [%][c]
Entry Ar
Product Ligand t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
Me (2e) C6H5 (5a)
Me (2e) 4-MeC6H4 (5b) 4 f
Me (2e) 4-ClC6H4 (5c) 4g
4e
10 90
24 80
22 92
18 87
10 35
10 88
24 85
46 64
48 57
48 64
24 63
90
88
90
88
80
83
94
93
85
70
80
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
1a
1b
1g
1h
1i
1c
1d
1e
1 f
1 f
1 f
1 f
1 f
1
24
2
48
24
1
2
1
18
48
10
7
89
92
92
0
50
96
83
80
85
80
79
88
98
66
65
À63
–
Me (2e) 2-naphthyl (5d) 4h
Me (2e) Me[d] (5e)
4i
4j
4k
4l
0
Me (2e)[e] iPr[d] (5 f)
76
73
78
82
28
82
80
83
Et (2 f)
Et (2 f)
Et (2 f)
Et (2 f)
C6H5 (5a)
4-ClC6H4 (5c)
2-naphthyl (5d) 4m
2-thienyl (5g)
C6H5 (5a)
C6H5 (2a)
10
4n
4o
2-MeC6H4 (2b)
3-MeC6H4 (2c)
4-MeC6H4 (2d)
11[f] iPr (2g)
[a] The reaction was conducted with 1.1 equivalents of the diaryl
ethylidenemalonate 2 and 1 equivalent of the enamide 5. [b] Yield of
the isolated product. [c] Determined by HPLC analysis on a chiral phase
(see the Supporting Information). [d] The ethyl enecarbamate was used
instead of the acetyl enamine. [e] A mixture of the enecarbamate and
isomerized enecarbamate (84:16) was used (see the Supporting
Information). [f] The reaction was conducted at À408C.
4-MeOC6H4 (2e) 4e
6
[a] The reaction was conducted with 1.1 equivalents of the diaryl
ethylidenemalonate 2 and 1 equivalent of the enecarbamate 3. [b] Yield
of the isolated product. [c] Determined by HPLC analysis on a chiral
phase (see the Supporting Information). Cbz=carbobenzyloxy, MS=
molecular sieves.
product could be obtained with 82% ee when the 9-anthra-
cenyl-substituted ligand 1 f was used (Table 1, entry 9). The
substituents on the benzene rings of the diaryl ethylidene-
malonates were found to influence significantly the reactivity
of the substrates and the selectivity of the reaction (Table 1,
entries 10–13). The presence of a substituent at the ortho
position led to a dramatic decrease in both reactivity and
enantioselectivity (Table 1, entry 10). The best result was
obtained with bis(4-methoxyphenyl) ethylidenemalonate
(2e): the adduct was formed in excellent yield in a relatively
short reaction time with slightly improved enantioselectivity
(Table 1, entry 13).
The scope of this reaction was surveyed under the
optimized reaction conditions. As higher selectivity was
observed with enamides with an acetyl protecting group
than with enecarbamates, N-acetyl enamines were used as the
nucleophile. In most cases high yields and high enantioselec-
tivities were observed, in particular with enamides derived
from aromatic ketones (Table 2). The reaction of the enecar-
bamate prepared from acetone gave the adduct in just 35%
yield with 80% ee (Table 2, entry 5); however, the enecarba-
mate derived from isopropyl methyl ketone reacted well to
afford the product in high yield with high enantioselectivity
(entry 6). Although the reactions of the propylidenemalonate
2 f and the isobutylidenemalonate 2g were slower, high yields
and high enantioselectivities were observed in most cases
(Table 2, entries 7–11).
Scheme 1. Determination of the absolute configuration of the adduct
4e. DMSO=dimethyl sulfoxide.
afford the ketoester 7. The reduction of 7 with LiBH4 gave the
known diol 8 with the S absolute configuration.[5]
An advantage of our system is that the initial adduct
generated in the Michael addition is an imine, which can be
reduced to afford an amino ester. We found that this
reduction occurred simply upon the treatment of the initial
product with NaBH4. In this way, the Michael addition of the
enamide 5 to the ethylidenemalonate 2e followed by reduc-
tion instead of hydrolysis gave the amino ester 9 (Scheme 2).
Thus, the nitrogen atom of the enamide is retained in the
product.
A plausible mechanism for the reaction is shown in
Scheme 3. Initially, the copper–diamine complex coordinates
to an electrophile A, and an enamide then approaches in two
possible ways. The first involves a six-membered-ring tran-
The absolute configuration of the products was deter-
mined by converting an adduct into a known derivative by the
synthetic pathway described in Scheme 1. Thus, transesteri-
fication of the Michael adduct 4e yielded the methyl ester 6,
which underwent hydrolysis followed by decarboxylation to
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Scheme 2. Conversion of the adduct into an aminomalonate.
Scheme 3. A plausible mechanism for the Michael addition of enam-
ides to alkylidenemalonates. It is known whether the copper center
carries a charge or has a counterion.
sition state and leads directly through a concerted pathway to
the adduct E.[6] In the alternative stepwise pathway, the
enamide first attacks the electrophile to generate D, and the
abstraction of the proton from the imine by the negatively
charged carbon atom then occurs in an intramolecular
fashion. Finally, the copper–diamine complex is released
from E to give F. The high enantioselectivity observed is
probably induced by the bulkiness of the 9-anthracenyl
moieties of the diamine ligand. Moreover, p stacking between
the 9-anthracenyl moieties and the aromatic groups on the
ester may be an important effect, as the enantioselectivity
dropped when nonaromatic esters were used.
In summary, we have developed a copper-catalyzed
asymmetric Michael reaction of enamides with alkylidene-
malonates. Enamides derived from both aromatic and ali-
phatic ketones can be used, and the corresponding adducts
are formed in high yields with high enantioselectivities.
Furthermore, no external proton source is necessary for
catalytic turnover, as proton transfer occurs rapidly in an
intramolecular manner.
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Received: June 10, 2007
Published online: September 4, 2007
Keywords: alkylidenemalonates · asymmetric catalysis · copper ·
.
enamides · Michael addition
Angew. Chem. Int. Ed. 2007, 46, 7803 –7805
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7805