Simple chiral sulfonamide primary amine catalysed highly enantioselective Michael addition of malonates to enones

Article abstract of DOI:10.1039/c2ob07191f

A chiral sulfonamide primary amine-organocatalysed, highly enantioselective Michael addition of malonates to enones has been developed. This reaction afforded the corresponding products in excellent yields (up to 99%) and excellent enantioselectivity (up

Full text of DOI:10.1039/c2ob07191f

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4116
www.rsc.org/obc
PAPER
Simple chiral sulfonamide primary amine catalysed highly enantioselective
Michael addition of malonates to enones†‡
Chunhua Luo, Yu Jin and Da-Ming Du*
Received 29th December 2011, Accepted 22nd March 2012
DOI: 10.1039/c2ob07191f
A chiral sulfonamide primary amine-organocatalysed, highly enantioselective Michael addition of
malonates to enones has been developed. This reaction afforded the corresponding products in excellent
yields (up to 99%) and excellent enantioselectivity (up to 99% ee).
some cases, the need for a large excess of malonate, a narrow
substrate scope, and restriction to a limited combination of
Introduction
The catalytic asymmetric Michael reaction is one of the most
powerful carbon–carbon bond-forming reactions, which provides
access to various optically active compounds or synthons.1
Among the various stabilized carbanion nucleophiles, the versa-
tile nucleophilic enol and related species, such as malonate
esters,2 β-ketoesters,3 1,3-diketones,4 α-nitro or α-cyano esters,5
α-nitroketone6 and malononitrile,7 are very important nucleo-
philes for the asymmetric Michael addition to α,β-unsaturated
systems. The catalytic asymmetric Michael additions of nucleo-
philic enol species to α,β-enones would produce synthetically
useful building blocks in organic synthesis owing to them pos-
sessing various functional groups, such as nitro, ester, carbonyl,
and cyano, for further transformation. As a result, considerable
efforts have been directed towards the development of catalytic
asymmetric Michael addition of malonates to enones in recent
years and many improvements to this reaction have been made.
Many types of chiral catalysts such as chiral metal complexes,8
phase-transfer catalysts,9 metal salts of carboxylic acids,10 orga-
nocatalysts,11 and chiral ionic liquids12 have been developed for
this important carbon–carbon bond forming reaction. Jørgensen
reported the first highly enantioselective organocatalytic Michael
addition of malonates to enones using an imidazoline catalyst in
2003.11a Subsequently, other organocatalysts such as thiour-
eas,11b,c,h proline tetrazole11i and primary–secondary diamine11f,g
were explored to catalyze this reaction. Despite excellent enan-
tioselectivities having been achieved in a few cases, nevertheless
some of the reported methods suffer, to a greater or lesser extent,
from several drawbacks such as reaction times up to weeks in
nucleophile and electrophile type. Therefore, the successful
design of a simple and more efficient organocatalyst remains a
challenging task in order to enable a wide range of nucleophilic
enol species to engage in this reaction.
On the other hand, during the past several years the inspiring
successful applications of sulfonamide derivatives as organocata-
lysts have been reported in catalytic asymmetric Michael
addition.13 To the best of our knowledge, chiral sulfonamide
primary amine-catalysed asymmetric Michael addition of malo-
nates to enones has been rarely reported. We report herein a
highly efficient enantioselective Michael addition of malonates
to enones catalysed by a simple chiral sulfonamide primary
amine; the desired products were obtained with excellent yields
and enantioselectivities (up to 99% ee).
Results and discussion
A series of chiral sulfonamide primary amine organocatalysts
1a–f (Fig. 1) were readily synthesized from chiral primary amino
alcohol or 1,2-diamine in a few steps according to our previous
report.14 These primary amine organocatalysts were evaluated in
the Michael addition of malonates to α,β-unsaturated ketones.
Initially, the Michael reaction of dibenzyl malonate 2a to
School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing 100081, People’s Republic of China. E-mail:
dudm@bit.edu.cn; Tel: +86 10 68914985
†This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
‡Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra of new compounds and HPLC chromatograms of the
Michael addition products. See DOI: 10.1039/c2ob07191f
Fig. 1 Structures of sulfonamide primary amine organocatalysts
(1a–f).
4116 | Org. Biomol. Chem., 2012, 10, 4116–4123
This journal is © The Royal Society of Chemistry 2012

benzylideneacetone 3a was selected as a model reaction. The
model reaction was performed in CHCl3 in the presence of
20 mol% catalyst loading at room temperature. The catalytic
effects of the various primary amine catalysts were examined
and the results are summarized in Table 1. To our delight, amino
alcohol-derived sulfonamide primary amines 1a and 1d gave the
desired products in good yields with high enantioselectivities
(91% ee and 90% ee, respectively) in 72 h (Table 1, entries 1
and 4). Especially, up to 91% yield and 94% ee were obtained
with catalyst 1b (Table 1, entry 2). However, poor results were
obtained when catalyst 1e and 1f derived from 1,2-diamine were
employed (Table 1, entries 5 and 6).
With the best catalyst in hand, optimization of the reaction
conditions was performed. It was found that the reaction
medium had an obvious impact on the catalytic process (Table 1,
entries 7–20). Without solvent, the product was formed in 91%
yield with 91% ee (Table 1, entry 7). As expected, i-PrOH
(Table 1, entry 13, 25% yield and 62% ee), H2O (Table 1, entry
14, 65% yield and 75% ee), MeOH (Table 1, entry 15, 27%
yield and 57% ee) and DMSO (Table 1, entry 16, 62% yield and
68% ee) provided the corresponding product in poor yield with
low enantioselectivity. The low enantioselectivities in protic sol-
vents may be ascribed to the competitive hydrogen bonding
interactions of these protic solvents with the substrates or
catalysts. Common solvents such as CHCl3, Et2O, hexane,
CH2Cl2 and CH2ClCH2Cl gave excellent yields and enantios-
electivities (90–94% ee) (Table 1, entries 2, 9, 12, 17, and 18),
and the best results were obtained with toluene (Table 1, entry
20, 99% yield and 94% ee). When using 10 mol% catalyst
loading, the corresponding product was obtained in lower yield
with maintenance of enantioselectivity (Table 1, entry 21). For
most catalytic systems, moderate conversion could be achieved
at lower reaction temperature within a longer time, but was gen-
erally accompanied by increased enantioselectivity. However,
when this reaction was carried out at 0 °C, a good yield (85%)
and low enantioselectivity (57% ee) were observed after a pro-
longed time (Table 1, entry 22). The decrease in enantioselectiv-
ity of the product at low temperature may be ascribed to a
deficiency in forming the iminium intermediate.
We further evaluated the effect of several acid and base addi-
tives, because acid additives were beneficial for the Michael
addition of malonates to enones in Zhao and Yang’s report,11f
whereas base additives were used by Ley et al.11i It was noted
that the acid and base additives had an obvious effect on the
reactivity of the Michael addition in our catalytic system, and the
results are summarized in Table 2. Among the acids screened,
the reaction rate, yield, and enantiomeric excess were decreased
when a carboxylic acid additive was added, such as 2-nitroben-
zoic acid (Table 2, entry 3; 41% yield, 81% ee), p-toluenesulfo-
nic acid (Table 2, entry 6; 25% yield, 87% ee), p-
hydroxybenzoic acid (Table 2, entry 10; 49% yield, 88% ee). In
the presence of CF3CO2H (20 mol%) and CF3SO3H, no product
was obtained (Table 2, entries 7 and 9). Furthermore, base addi-
tives such as Et3N, DMAP and pyridine were also evaluated, and
no significant improvements were obtained (Table 2, entries
Table 1 Catalyst and reaction solvent screen for the asymmetric
Michael addition of dibenzyl malonate 2a to benzylideneacetone 3aa
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
Table 2 The effect of additivesa
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Neat
CH3CN
Et2O
EtOAc
DMF
Hexane
i-PrOH
H2O
MeOH
DMSO
CH2Cl2
ClCH2CH2Cl
THF
81
94
91
87
33
31
91
51
73
58
50
95
25
65
27
62
92
86
51
99
79
85
91
94
75
90
57
39
91
88
91
90
91
91
62
75
57
68
94
94
83
94
94
57
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
Entry Additive
Loading (mol%) Yieldb (%) eec (%)
9
1
2
3
4
5
6
7
8
—
—
20
20
20
20
20
20
10
20
20
99
89
41
77
72
25
—
41
—
49
65
39
41
—
45
94
91
81
89
83
87
—
79
—
88
94
83
86
—
89
10
11
12
13
14
15
16
17
18
19
20
21d
22e
C6H5CO2H
2-O2NC6H4CO2H
CH3CO2H
4-CH3C6H4CO2H
TsOH
CF3SO3H
CF3CO2H
CF3CO2H
4-HOC6H4CO2H
4-HO2CC6H4CO2H 20
4-O2NC6H4OH
Et3N
9
10
11
12
13
14
15
Toluene
Toluene
Toluene
20
100
100
100
DMAP
Pyridine
a Unless otherwise specified, all reactions were carried out with
benzylideneacetone 3a (36.5 mg, 0.25 mmol), dibenzyl malonate 2a
(142 mg, 0.50 mmol), and catalyst 1 (0.05 mmol, 20 mol%) in the
solvent (1 mL) at room temperature for 72 h. b Yield of the isolated
product after chromatography on silica gel. c Determined by HPLC
using Daicel Chiralpak AS-H column, the configuration was assigned
according to literature.11a d The catalyst was loaded at 10 mol%. e The
reaction was run for 96 h at 0 °C.
a Unless otherwise specified, all reactions were carried out with
benzylideneacetone 3a (36.5 mg, 0.25 mmol), dibenzyl malonate 2a
(142 mg, 0.50 mmol), catalyst 1b (13.5 mg, 0.05 mmol, 20 mol%), and
the additive in toluene (1 mL) at room temperature for 72 h. b Yield of
the isolated product after chromatography on silica gel. c Determined by
chiral HPLC analysis, the configuration was assigned according to
literature.11a
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4116–4123 | 4117

Table 3 Substrate scope of the catalytic asymmetric Michael addition
of dibenzyl malonate 2a to enones 3a
phenyl, no reaction take place at all (Table 3, entries 15 and 16).
Meanwhile, other enones such as trans-chalcone (Table 3, entry
17), rigid enone 2-benzylidene-3,4-dihydronaphthalen-1(2H)-
one (Table 3, entry 18) were also evaluated, but also no reactions
were observed. These results may be ascribed to the lower reac-
tivity for iminium formation of the carboxyl group in chalcone,
rigid or sterically hindered enones than in methyl enones.
It is known that the ester group has a large effect on the asym-
metric induction of the reaction. To our great delight, the reac-
tions of the symmetrical malonates 2a–d all proceeded with
excellent yields and enantioselectivities. Especially, a high yield
was observed for the diisopropyl malonate 2d, with up to 99%
ee (Table 4, entry 4). Using diisopropyl malonate 2d as the
reagent, investigation of substrates 3g, 3i, 3j and 3n, which gave
only moderate to good ee when using 2a as reagent, were further
investigated. Diisopropyl malonate 2d reacted with enone 3g for
eight days at room temperature to afford the corresponding
product 4dg in 53% yield and 95% ee. The corresponding reac-
tion of the other three enones 3i, 3j and 3n did not take place at
all.15
Yieldb
(%)
eec
(%)
Entry
R1
R2
Product
1
2
3
4
5
6
7
8
Ph
4-BrC6H4
4-ClC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
4ao
4ap
4aq
4ar
99
99
99
98
94
99
62
99
84
99
75
90
70
61
—
—
—
—
94
97
98
94
94
94
87
94
80
83
94
91
95
18
—
—
—
—
4-CH3C6H4
4-MeOC6H4
4-NO2C6H4
4-N(CH3)2C6H4
3-NO2C6H4
2-MeOC6H4
2-BrC6H4
3,4-(MeO)2C6H3
1-Naphthyl
i-Pr
2-Cyclohexenone (3n)
Ph
t-Bu
Ph
9
10
11
12
13
14
15
16
17
18
On the basis of the experimental results described above, we
suggest a possible catalytic activation mode for the asymmetric
induction in this catalytic system. This catalytic activation mode
has no significant difference with those previously reported.11a,f
The two substrates involved in the reaction are activated simul-
taneously by catalyst 1b, as shown in Fig. 2. The carbonyl group
Cyclohexyl
Ph
Ph
2-Benzylidene-3,4-
dihydronaphthalen-1(2H)-one
(3r)
a Unless otherwise specified, all reactions were carried out with enones 3
(0.25 mmol), dibenzyl malonate 2a (142 mg, 0.50 mmol), and catalyst
1b (13.5 mg, 0.05 mmol, 20 mol%) in toluene (1 mL) at room
temperature for 72 h. b Yield of the isolated product after
chromatography on silica gel. c Determined by HPLC using Daicel
Chiralpak AS-H column, the configuration was assigned according to
literature.11a,f
Table 4 Catalytic asymmetric Michael addition of malonates 2a–d to
benzylideneacetone 3aa
13–15). Thus, the reaction was best performed using catalyst 1b
in toluene with no any additive.
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
Bn
Me
Et
4aa
4ba
4ca
4da
99
98
94
99
94
94
92
99
With the optimized reaction conditions in hand, the substrate
scope of this catalytic asymmetric Michael reaction was
explored. As shown in Table 3, a series of α,β-unsaturated
enones 3a–n were reacted with dibenzyl malonate 2a in the pres-
ence of 20 mol% of catalyst 1b. This catalytic system was well
applicable to various β-aryl-substituted butenones, and the con-
jugate addition products were obtained with very high yields and
enantioselectivities; 3- or 4-substituted aryl enones with elec-
tron-withdrawing or electron-donating groups all gave excellent
yields and enantioselectivities. These results demonstrate that
the substitution position and the electronic properties of the
substituents on the aromatic rings have limited effects on the
enantioselectivities. The exceptions to the generally high
enantioselectivities with aromatic enones were the sterically
more hindered 2-OMe substituted substrate 3i (Table 3, entry 9;
80% ee) and 2-Br substituted substrate 3j (Table 3, entry 10;
83% ee). Low reactivity was observed for the alkyl-substituted
enone 3m, with which only moderate yields were obtained,
although excellent enantioselectivity was obtained (Table 3,
entry 13; 70% yield, 95% ee). Cyclic enone was also evaluated,
but poor results were obtained when cyclohex-2-enone (3n) was
employed (Table 3, entry 14; 61% yield, 18% ee). If the R2 sub-
stituent is a group other than methyl, such as cyclohexyl or
iPr
a Unless otherwise specified, all reactions were carried out with
benzylideneacetone 3a (36.5 mg, 0.25 mmol), malonates 2 (0.50 mmol),
and catalyst 1b (13.5 mg, 0.05 mmol, 20 mol%) in toluene (1 mL) at
room temperature for 72 h. b Yield of the isolated product after
chromatography on silica gel. c Determined by chiral HPLC analysis, the
configuration was assigned according to literature.11a,f
Fig. 2 Proposed catalytic activation mode for the observed enantio-
selectivity of the catalysis of 1b.
4118 | Org. Biomol. Chem., 2012, 10, 4116–4123
This journal is © The Royal Society of Chemistry 2012

of the enones is assumed to be activated by the primary amine
moiety of catalyst 1b via an iminium ion formation, while the
sulfonamide activates the nucleophile malonate 2 through hydro-
gen bond.13c The Re face of the enone is shielded by the bulky
tert-butyl group of the chiral catalyst, and the malonate
approaches the open Si face of the enone to afford the desired R
product.
stirred at given temperature for 72 h and then the solvent was
removed under vacuum. The residue was purified by column
chromatography on silica gel to yield the desired addition
product 4.
(R)-Dibenzyl 2-(3-oxo-1-phenylbutyl)malonate (4aa)
Compound 4aa was obtained according to the general procedure
as a white solid; yield: 99%; mp 85–87 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 15.6 min,
major enantiomer tR = 17.2 min, 94% ee; [α]2D5: −5.64 (c 2.06,
Conclusions
In summary, we have developed a highly enantioselective orga-
nocatalysed Michael addition of malonates to enones by using
simple chiral sulfonamide primary amine. A series of simple
chiral sulfonamide primary amine organocatalysts is readily
available from chiral primary amino alcohol or 1,2-diamine,
making this methodology cheap and facile in practice. These
organocatalysts have been successfully applied to promoting the
asymmetric Michael addition of malonates to enones and the
corresponding products were obtained in excellent yields (up to
99%) with excellent enantioselectivities (up to 99% ee). Further
investigation of the application of this catalyst in other asym-
metric catalytic reactions is in progress.
1
CH2Cl2), Lit.11a [α]Drt = −7.1 (c 1.0, CHCl3, 99% ee). H NMR
(400 MHz, CDCl3): δ = 1.95 (s, 3H, CH3), 2.88 (d, J = 6.4 Hz,
2H, CH2), 3.82 (d, J = 9.6 Hz, 1H, CH), 3.97–4.03 (m, 1H,
CH), 4.89 (s, 2H, CH2), 5.13 (s, 2H, CH2), 7.04–7.07 (m, 2H,
ArH), 7.19–7.32 (m 13H, ArH) ppm. MS (EI): m/z (% rel. inten-
sity) 430 (M+, 1), 339 (4), 261 (9), 91 (100).
(R)-Dibenzyl 2-(1-(4-bromophenyl)-3-oxobutyl)malonate (4ab)
Compound 4ab was obtained according to the general procedure
as a white solid; yield: 99%; mp 79–81 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 16.6 min,
major enantiomer tR = 17.8 min, 96% ee; [α]2D5: −2.83 (c 1.84,
Experimental
General methods
Commercially available compounds were used without further
purification. Solvents were dried according to standard pro-
cedures. Column chromatography was carried out using silica
gel (200–300 mesh). Melting points were measured with a
XT-4 melting point apparatus. The 1H NMR spectra were
recorded with Varian Mercury-plus 400 MHz spectrometers,
while the 13C NMR spectra were recorded at 100 MHz. Infrared
spectra were obtained with a Perkin Elmer Spectrum One spec-
trometer. The EI mass spectra were obtained with VG-ZAB-HS
mass spectrometer. The ESI-HRMS spectra were obtained with
Bruker APEX IV mass spectrometer. Optical rotations were
measured with a WZZ-3 polarimeter. The enantiomeric excesses
(ee values) of the products were determined by chiral HPLC
analysis using an Agilent HP 1200 instrument (n-hexane–
2-propanol as eluent).
1
CH2Cl2), Lit.11f [α]D24 = −6.9 (c 1.0, CHCl3, 99% ee). H NMR
(400 MHz, CDCl3): δ = 1.95 (s, 3H, CH3), 2.84 (d, J = 6.0 Hz,
2H, CH2), 3.77 (d, J = 9.6 Hz, 1H, CH), 3.91–3.97 (m, 1H,
CH), 4.92 (s, 2H, CH2), 5.13 (s, 2H, CH2), 7.03–7.07 (m, 4H,
ArH), 7.28–7.33 (m, 10H, ArH) ppm. MS (EI): m/z (% rel.
intensity) 510 (M+, 1.2, 81Br), 508 (M+, 1.2, 79Br), 419 (4),
357 (6), 91 (100).
(R)-Dibenzyl 2-(1-(4-chlorophenyl)-3-oxobutyl)malonate (4ac)
Compound 4ac was obtained according to the general procedure
as a white solid; yield: 99%; mp 83–85 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 16.2 min,
major enantiomer tR = 17.5 min, 98% ee; [α]2D5: −9.14 (c
1.75 mL, CH2Cl2), Lit.11a [α]Drt = −8.1 (c 1.0, CHCl3, 98% ee).
1H NMR (400 MHz, CDCl3): δ = 1.95 (s, 3H, CH3), 2.84 (d, J =
6.0 Hz, 2H, CH2), 3.78 (d, J = 9.6 Hz, 1H, CH), 3.93–3.99 (m,
1H, CH), 4.92 (s, 2H, CH2), 5.14 (s, 2H, CH2), 7.05–7.16 (m,
6H, ArH), 7.27–7.33 (m, 8H, ArH) ppm. MS (EI): m/z (% rel.
intensity) 464 (M+, 0.6), 313 (4), 295 (4), 91 (100).
Materials
Dimethyl malonate, diethyl malonate, dibenzyl malonate were
commercially available and used as received. 2-Cyclohexanone
were purchased from Acros and other α,β-unsaturated enones
were prepared according to literature.16 The chiral sulfonamide
primary amine catalysts 1a–1e were prepared following the pre-
viously reported procedure.14
(R)-Dibenzyl 2-(1-(4-methylphenyl)-3-oxobutyl)malonate (4ad)
General procedure for the enantioselective Michael addition
reaction
Compound 4ad was obtained according to the general procedure
as a white solid; yield: 98%; mp 87–89 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 14.2 min,
To a solution of toluene (1.0 mL) was added α,β-unsaturated
ketone 3 (0.25 mmol), malonate 2 (0.50 mmol), catalyst 1b
(13.5 mg, 0.05 mmol, 20 mol%). The reaction mixture was
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4116–4123 | 4119

major enantiomer tR = 15.5 min, 94% ee; [α]2D5: −5.20 (c 2.04,
CH2Cl2), Lit.11f [α]D25 = −8.1 (c 1.0, CHCl3, >99% ee). 1H NMR
(400 MHz, CDCl3): δ = 1.94 (s, 3H, CH3), 2.78 (s, 3H, CH3),
2.85 (d, J = 6.8 Hz, 2H, CH2), 3.79 (d, J = 9.6 Hz, 1H, CH),
3.92–3.99 (m, 1H, CH), 4.90 (s, 2H, CH2), 5.13 (s, 2H, CH2),
7.00–7.06 (m, 6H, ArH), 7.26–7.32 (m, 8H, ArH) ppm. MS
(EI): m/z (% rel. intensity) 444 (M+, 1.8), 353 (4), 293 (5), 275
(20), 227 (5), 91 (100).
(R)-Dibenzyl 2-(1-(3-nitrophenyl)-3-oxobutyl)malonate (4ah)
Compound 4ah was obtained according to the general procedure
as a white solid; yield: 99%; mp 123–125 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak IA
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.75 mL
min−1, detection at 254 nm): minor enantiomer tR = 19.4 min,
major enantiomer tR = 15.7 min, 94% ee; [α]2D5: −8.58 (c 2.12,
1
CH2Cl2); H NMR (400 MHz, CDCl3): δ = 1.97 (s, 3H, CH3),
2.92 (d, J = 6.4 Hz, 2H, CH2), 3.85 (dd, J = 2.0, 9.4 Hz, 1H,
CH), 4.06–4.12 (m, 1H, CH), 4.93 (AB, J = 12.6 Hz, 2H, CH2),
5.15 (AB, J = 12.8Hz, 2H, CH2), 7.08 (d, J = 6.8 Hz, 2H, ArH),
7.22–7.34 (m, 9H, ArH), 7.55 (d, J = 7.6 Hz, 1H, ArH),
7.96–7.99 (m, 1H, ArH), 8.04 (d, J = 1.6 Hz, 1H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 204.9, 167.3, 166.9, 148.0,
142.4, 135.0, 134.8, 134.6, 129.2, 128.52, 128.47, 128.38,
128.27, 122.7, 122.2, 67.4, 67.2, 56.4, 46.5, 39.6, 30.0 ppm. IR
(KBr): ν 3067, 3034, 2958, 2922, 1739, 1727, 1702, 1529,
1458, 1354, 1266, 1182, 749, 701 cm−1. HRMS (ESI): m/z
calcd for C27H26NO7 [M + H]+ 476.17038, found 476.17082.
(R)-Dibenzyl 2-(1-(4-methoxyphenyl)-3-oxobutyl)malonate (4ae)
Compound 4ae was obtained according to the general procedure
as a white solid; yield: 94%; mp 55–57 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 20.5 min,
major enantiomer tR = 21.8 min, 94% ee; [α]2D5: −6.41 (c 1.37,
1
CH2Cl2), Lit.11f [α]D25 = −10.2 (c = 1.0, CHCl3, >99% ee). H
NMR (400 MHz, CDCl3): δ = 1.94 (s, 3H, CH3), 2.83 (d, J =
6.8 Hz, 2H, CH2), 3.75 (s, 3H, OCH3), 3.77 (d, J = 9.6 Hz, 1H,
CH), 3.91–3.97 (m, 1H, CH), 4.90 (s, 2H, CH2), 5.14 (s, 2H,
CH2), 6.74 (d, J = 4.4 Hz, 2H, ArH), 7.06–7.11 (m, 4H, ArH),
7.26–7.32 (m, 8H, ArH) ppm. MS (EI): m/z (% rel. intensity)
460 (M+, 2.4), 369 (4), 291 (10), 265 (6), 243 (6), 91 (100).
(R)-Dibenzyl 2-(1-(2-methoxyphenyl)-3-oxobutyl)malonate (4ai)
Compound 4ai was obtained according to the general procedure
as a colorless oil; yield: 84%. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AS-H column (n-
hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL min−1, detec-
tion at 254 nm): minor enantiomer tR = 13.1 min, major enantio-
(R)-Dibenzyl 2-(1-(4-nitrophenyl)-3-oxobutyl)malonate (4af)
1
mer tR = 15.1 min, 80% ee; [α]2D5: −3.83 (c 1.62, CH2Cl2); H
Compound 4af was obtained according to the general procedure
as a yellow solid; yield: 99%; mp 68–69 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 29.0 min,
major enantiomer tR = 33.1 min, 94% ee; [α]2D5: −7.33 (c 1.83,
NMR (400 MHz, CDCl3): δ = 1.96 (s, 3H, CH3), 2.85 (dd, J =
3.4, 16.6 Hz, 1H, CH), 3.00–3.07 (m, 1H, CH), 3.76 (s, 3H,
OCH3), 4.15–4.23 (m, 2H, CH2), 4.86 (s, 2H, CH2), 5.12 (AB, J
= 12.4 Hz, 2H, CH2), 6.76–6.82 (m, 2H, ArH), 7.05–7.19 (m,
4H, ArH), 7.23–7.33 (m, 8H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 206.6, 168.2, 167.7, 157.1, 135.2, 135.1, 130.2,
128.4, 128.34, 128.28, 128.20, 128.1, 128.0, 127.5, 120.4,
110.8, 67.0, 66.8, 55.1, 54.8, 45.3, 37.1, 29.8 ppm. IR (KBr): ν
3066, 3033, 2951, 1733, 1716, 1602, 1542, 1496, 1456, 1356,
1244, 1145, 1023, 903, 752, 697 cm−1. HRMS (ESI): m/z calcd
for C28H29O6 [M + H]+ 461.19587, found 461.19635.
1
CH2Cl2), Lit.11a [α]Drt = −9.3 (c 1.0, CHCl3, 89% ee). H NMR
(400 MHz, CDCl3): δ = 1.96 (s, 3H, CH3), 2.89 (d, J = 8.8 Hz,
2H, CH2), 3.82 (d, J = 9.6 Hz, 1H, CH), 4.04–4.10 (m, 1H,
CH), 4.93 (s, 2H, CH2), 5.15 (s, 2H, CH2), 6.74 (d, J = 4.4 Hz,
2H, ArH), 7.07 (d, J = 6.4 Hz, 2H, ArH), 7.21–7.34 (m, 10H,
ArH), 7.96 (d, J = 4.4 Hz, 2H, ArH) ppm. MS (EI): m/z (% rel.
intensity) 445 (M+, 0.3), 260 (5), 220 (4), 107 (24), 91 (100).
(R)-Dibenzyl 2-(1-(2-bromophenyl)-3-oxobutyl)malonate (4aj)
Compound 4aj was obtained according to the general procedure
as a colorless oil; yield: 84%. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak IA column (n-
hexane–2-propanol 70 : 30 v/v, flow rate 0.75 mL min−1, detec-
tion at 254 nm): minor enantiomer tR = 11.9 min, major enantio-
mer tR = 10.0 min, 83% ee; [α]2D5: +6.38 (c 1.97 mL, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ = 1.96 (s, 3H, CH3), 2.94–3.07
(m, 2H, CH2), 4.09 (d, J = 7.6 Hz, 1H, CH), 4.45–4.52 (m, 1H ,
CH), 4.99 (s, 2H, CH2), 5.08 (s, 2H, CH2), 6.69–7.03 (m, 1H,
ArH), 7.10–7.28 (m, 12H, ArH), 7.49 (d, J = 7.6 Hz, 1H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 205.9, 167.8, 167.5,
139.3, 135.2, 133.5, 128.9, 128.7, 128.6, 128.55, 128.47,
128.35, 128.2, 127.6, 124.8, 67.3, 55.0, 45.2, 39.3, 30.1 ppm.
IR (KBr): ν 3065, 3034, 2956, 2924, 1732, 1606, 1587, 1567,
1498, 1455, 1147, 1022, 908, 751, 697 cm−1. HRMS (ESI): m/z
calcd for C27H26BrO5 [M + H]+ 509.50981, found 509.09617.
(R)-Dibenzyl 2-(1-(4-dimethylaminophenyl)-3-oxobutyl)-
malonate (4ag)
Compound 4ag was obtained according to the general procedure
as yellow oil; yield: 62%. The enantiomeric excess was deter-
mined by HPLC with a Daicel Chiralpak IA column (n-hexane–
2-propanol 70 : 30 v/v, flow rate 0.75 mL min−1, detection at
254 nm): minor enantiomer tR = 19.1 min, major enantiomer tR
= 13.0 min, 87% ee; [α]2D5: −9.03 (c 1.15, CH2Cl2), Lit.11a [α]rDt
1
= −2.9 (c 1.0, CHCl3, 77% ee). H NMR (400 MHz, CDCl3): δ
= 1.94 (s, 3H, CH3), 2.82 (d, J = 7.2 Hz, 2H, CH2), 2.89 (s, 6H,
NCH3), 3.77 (d, J = 10.0 Hz, 1H, CH), 3.87–3.94 (m, 1H, CH),
4.90 (s, 2H, CH2), 5.13 (s, 2H, CH2), 6.57 (d, J = 8.4 Hz, 2H,
ArH), 7.03–7.07 (m, 4H, ArH), 7.24–7.31 (m, 8H, ArH) ppm.
MS (EI): m/z (% rel. intensity) 473 (M+, 22), 190 (55), 148 (36),
107 (100), 91 (100).
4120 | Org. Biomol. Chem., 2012, 10, 4116–4123
This journal is © The Royal Society of Chemistry 2012

7.34–7.27 (m, 10H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ
= 207.1, 168.8, 168.5, 135.2, 128.5, 128.3, 128.2, 67.1, 67.0,
53.5, 42.7, 38.9, 30.1, 29.8, 20.5, 18.8 ppm.
(R)-Dibenzyl 2-(1-(3,4-dimethoxyphenyl)-3-oxobutyl)malonate
(4ak)
Compound 4ak was obtained according to the general procedure
as a white solid; yield: 75%; mp 78–80 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 18.8 min,
major enantiomer tR = 21.8 min, 94% ee; [α]2D5: −7.68 (c 1.46,
(R)-Dibenzyl 2-(3-oxocyclohexyl)malonate (4an)
Compound 4an was obtained according to the general procedure
as a white solid; yield: 61%; mp 54–56 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 25.8 min,
major enantiomer tR = 29.8 min, 18% ee; [α]2D5: −2.15 (c 1.02,
1
CH2Cl2); H NMR (400 MHz, CDCl3): δ = 1.94 (s, 3H, CH3),
2.84 (d, J = 6.8 Hz, 2H, CH2), 3.75 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 3.83 (br s, 1H, CH), 3.91–3.97 (m, 1H, CH), 4.91 (AB
q, J = 12.2 Hz, 2H, CH2), 5.14 (AB q, J = 12.2 Hz, 2H, CH2),
6.67–6.73 (m, 3H, ArH), 7.03–7.06 (m, 2H, ArH), 7.23–7.33
(m, 8H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 205.9,
167.8, 167.3, 148.6, 147.9, 135.1, 134.9, 132.6, 128.5, 128.3,
128.1, 128.0, 119.8, 111.5, 110.9, 67.2, 67.0, 57.4, 55.7, 55.6,
47.3, 40.2, 30.2 ppm. IR (KBr): ν 3034, 3008, 2957, 2940,
2836, 1745, 1714, 1591, 1516, 1469, 1457, 1448, 1374, 1358,
1263, 1195, 1148, 1025, 900, 817, 762, 750, 698 cm−1. HRMS
(ESI): m/z calcd for C29H31O7 [M + H]+ 491.20643, found
491.20709.
CH2Cl2), Lit.11a [α]Drt = −1.4 (c 1.0, CHCl3, 83% ee). H NMR
1
(400 MHz, CDCl3): δ = 1.42–1.51 (m, 1H, CH2), 1.58–1.68 (m,
1H, CH2), 1.91 (d, J = 12.4 Hz, 1H, CH2), 2.00–2.04 (m, 1H,
CH2), 2.15–2.27 (m, 2H, CH2), 2.35–2.46 (m, 2H, CH2),
2.51–2.58 (m, 1H, CH), 3.14 (d, J = 7.6 Hz, 1H, CH), 5.15 (s,
4H, CH2), 7.26–7.34 (m, 10H, ArH) ppm. MS (EI): m/z (% rel.
intensity) 289 (M+, 4), 183 (12), 139 (5), 107 (22), 91 (100).
(R)-Dimethyl 2-(3-oxo-1-phenylbutyl)malonate (4ba)
Compound 4ba was obtained according to the general procedure
as a white solid; yield: 98%; mp 44–45 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 14.6 min,
major enantiomer tR = 18.3 min, 94% ee; [α]2D5: −13.33 (c 1.20,
(R)-Dibenzyl 2-(1-(naphthalen-1-yl)-3-oxobutyl)malonate (4al)
Compound 4al was obtained according to the general procedure
as a colorless oil; yield: 90%. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AS-H column (n-
hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL min−1, detec-
tion at 254 nm): minor enantiomer tR = 15.3 min, major enantio-
1
CH2Cl2), Lit.11a [α]Drt = −9.7 (c 1.0, CHCl3, 73% ee). H NMR
1
mer tR = 17.0 min, 91% ee; [α]2D5: +19.0 (c 1.12, CH2Cl2); H
(400 MHz, CDCl3): δ = 2.03 (s, 3H, CH3), 2.88–3.03 (m, 2H,
CH2), 3.50 (s, 3H, CH3), 3.72 (s, 3H, CH3), 3.74 (d, J = 7.6 Hz,
1H, CH), 3.94–4.01 (m, 1H, CH), 7.20–7.27 (m, 5H, ArH) ppm.
MS (EI): m/z (% rel. intensity) 278 (M+, 10), 215 (16), 187 (28),
176 (34), 147 (58), 132 (13), 115 (14), 91 (6), 43 (100).
NMR (400 MHz, CDCl3): δ = 1.93 (s, 3H, CH3), 3.09 (d, J =
4.8 Hz, 2H, CH2), 4.09 (d, J = 7.6 Hz, 1H, CH), 4.82 (s, 2H,
CH2), 4.97 (br s, 1H , CH), 5.10 (s, 2H, CH2), 6.88–6.97 (m,
2H, ArH), 7.17–7.30 (m, 10H, ArH), 7.45–7.51 (m, 2H, ArH),
7.69 (d, J = 3.2 Hz, 1H, ArH), 7.81 (d, J = 7.2 Hz, 1H, ArH),
8.25 (d, J = 7.6 Hz, 1H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 205.9, 168.0, 167.5, 136.9, 135.1, 134.9, 134.0,
131.2, 128.8, 128.5, 128.3, 128.22, 128.16, 128.08, 127.98,
127.8, 126.4, 125.7, 125.1, 123.1, 109.6, 67.2, 67.1, 56.6, 46.7,
30.1 ppm. IR (KBr): ν 3060, 3035, 2956, 2923, 1759, 1722,
1598, 1509, 1498, 1454, 1149, 1003, 905, 796, 780, 751,
696 cm−1. HRMS (ESI): m/z calcd for C31H29O5 [M + H]+
481.20095, found 481.20146.
(R)-Diethyl 2-(3-oxo-1-phenylbutyl)malonate (4ca)
Compound 4ca was obtained according to the general procedure
as a white solid; yield: 94%; mp 41–42 °C. The enantiomeric
excess was determined by HPLC with a Daicel Chiralpak AS-H
column (n-hexane–2-propanol 70 : 30 v/v, flow rate 0.5 mL
min−1, detection at 254 nm): minor enantiomer tR = 11.8 min,
major enantiomer tR = 13.2 min, 92% ee; [α]2D5: −17.61 (c 1.42,
CH2Cl2), Lit.11a [α]Drt = −12.1 (c 1.0, CHCl3, 91% ee). 1H NMR
(400 MHz, CDCl3): δ = 1.01 (t, J = 7.2 Hz, 3H, CH3), 1.25 (t, J
= 7.2 Hz, 3H, CH3), 2.02 (s, 3H, CH3), 2.87–2.99 (m, 2H, CH2),
3.69 (d, J = 9.6 Hz, 1H, CH), 3.91–3.99 (m, 3H, CH + CH2),
4.16–4.20 (m, 2H, CH2), 7.20–7.26 (m, 5H, ArH) ppm. MS
(EI): m/z (% rel. intensity) 306 (M+, 15), 215 (26), 187 (56), 160
(22), 147 (45), 145 (22), 91 (8), 43 (100).
(R)-Dibenzyl 2-(1-isopropyl-3-oxobutyl)malonate (4am)
Compound 4am was obtained according to the general pro-
cedure as a colorless oil; yield: 70%. The enantiomeric excess
was determined by HPLC with a Daicel Chiralpak IA column
(n-hexane–2-propanol 95 : 5 v/v, flow rate 1.0 mL min−1, detec-
tion at 254 nm): minor enantiomer tR = 11.1 min, major enantio-
mer tR = 9.9 min, 95% ee; [α]2D5: −4.3 (c 3.10, CH2Cl2), Lit.11a
[α]rDt = −9.7 (c 1.0, CHCl3, 84% ee). 1H NMR (400 MHz,
CDCl3): δ = 0.79 (d, J = 6.8 Hz, 3H, CH3), 0.87 (d, J = 6.8 Hz,
3H, CH3), 1.72–1.64 (m, 1H, CH), 2.06 (s, 3H, COCH3), 2.48
(dd, J = 5.6, 18 Hz, 1H, COCH2), 2.66 (dd, J = 4.2, 18 Hz, 1H,
COCH2), 2.77–2.71 (m, 1H, CH), 3.63 (d, J = 6.8 Hz, 1H,
CO2CHCO2), 5.10 (s, 2H, OCH2), 5.11 (s, 2H, OCH2),
(R)-Diisopropyl 2-(3-oxo-1-phenylbutyl)malonate (4da)
Compound 4da was obtained according to the general procedure
as a colorless oil; yield: 99%. The enantiomeric excess was
determined by HPLC with a Daicel Chiralpak AS-H column (n-
hexane–2-propanol 80 : 20 v/v, flow rate 0.5 mL min−1, detec-
tion at 254 nm): minor enantiomer tR = 10.1 min, major
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4116–4123 | 4121

enantiomer tR = 11.4 min, 99% ee; [α]2D5: −20.02 (c 1.76,
CH2Cl2), Lit.11a [α]Drt = −13.6 (c 1.0, CHCl3, 71% ee). 1H NMR
(400 MHz, CDCl3): δ = 0.97 (d, J = 6.0 Hz, 3H, CH3), 1.04 (d,
J = 6.0 Hz, 3H, CH3), 1.22–1.24 (m, 6H, CH3), 2.01 (s, 3H,
CH3), 2.84–2.97 (m, 2H, CH2), 3.64 (d, J = 10.0 Hz, 1H, CH),
3.91–3.97 (m, 1H, CH), 4.74–4.81 (m, 1H, CH), 5.01–5.08 (m,
1H, CH), 7.20–7.25 (m, 5H, ArH) ppm. MS (EI): m/z (% rel.
intensity) 334 (M+, 15), 233 (18), 214 (36), 187 (32), 162 (17),
147 (76), 104 (18), 43 (100).
118, 5088; G. Bartoli, M. Bosco, A. Carlone, A. Cavalli, M. Locatelli,
A. Mazznti, P. Ricci, L. Sambri and P. Melchiorre, Angew. Chem., Int.
Ed., 2006, 45, 4966; (b) A. Lattanzi, Tetrahedron: Asymmetry, 2006, 17,
837; (c) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005,
4481; (d) H. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc., 2004,
126, 9906; (e) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto,
J. Am. Chem. Soc., 2005, 127, 119; (f) S. H. McCooey and S. J. Connon,
Angew. Chem., Int. Ed., 2005, 44, 6367; (g) S. Brandau, A. Landa,
J. Franzén, M. Marigo and K. A. Jørgensen, Angew. Chem., 2006, 118,
4415; S. Brandau, A. Landa, J. Franzén, M. Marigo and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2006, 45, 4305; (h) D. A. Evans and D. Seidel,
J. Am. Chem. Soc., 2005, 127, 9958; (i) A. Ma, S. Zhu and D. Ma, Tetra-
hedron Lett., 2008, 49, 3075; ( j) L. Zhou, L. Lin, W. Wang, J. Ji, X. Liu
and X. Feng, Chem. Commun., 2010, 46, 3601; (k) Z. Wang, D. Chen,
Z. Yang, S. Bai, X. Liu, L. Lin and X. Feng, Chem.–Eur. J., 2010, 16,
10130.
(R)-Diisopropyl 2-[1-(4-dimethylaminophenyl)-3-oxobutyl]-
malonate (4dg)
3 For selected examples of asymmetric Michael additions of keto esters,
see: (a) Y. Hoashi, T. Yabuta and Y. Takemoto, Tetrahedron Lett., 2004,
45, 9185; (b) K. Majima, R. Takita, A. Okada, T. Ohshima and
M. Shibasaki, J. Am. Chem. Soc., 2003, 125, 15837; (c) F. Wu, H. Li,
R. Hong and L. Deng, Angew. Chem., Int. Ed., 2006, 45, 947;
(d) M. Watanabe, A. Ikagawa, H. Wang, K. Murata and T. Ikariya, J. Am.
Chem. Soc., 2004, 126, 11148; (e) H.-P. Cui, P. Li, X.-W. Wang, Z. Chai,
Y.-Q. Yang, Y.-P. Cai, S.-Z. Zhu and G. Zhao, Tetrahedron, 2011, 67,
312; (f) Z. Yu, X. Liu, L. Zhou, L. Lin and X. Feng, Angew. Chem., Int.
Ed., 2009, 48, 5195.
Compound 4dg was obtained according to the general procedure
as a colorless oil; yield: 53% (at room temperature for 8 days).
The enantiomeric excess was determined by HPLC with a
Daicel Chiralpak AS-H column (n-hexane–2-propanol 70 : 30
v/v, flow rate 0.75 mL min−1, detection at 254 nm): minor enan-
tiomer tR = 11.4 min, major enantiomer tR = 7.0 min, 95% ee;
1
[α]1D5: −19.8 (c 2.5, CH2Cl2). H NMR (400 MHz, CDCl3): δ =
4 For selected examples of asymmetric Michael additions of diketones, see:
(a) J. Pulkkinen, P. S. Aburel, N. Halland and K. A. Jøgensen, Adv.
Synth. Catal., 2004, 346, 1077; (b) J. Wang, H. Li, W.-H. Duan, L. Zu
and W. Wang, Org. Lett., 2005, 7, 4713; (c) M. Terada, H. Ube and
Y. Yaguchi, J. Am. Chem. Soc., 2006, 128, 1454; (d) Z. Dong, J. Feng,
W. Cao, X. Liu, L. Lin and X. Feng, Tetrahedron Lett., 2011, 52, 3433.
5 For review of catalytic asymmetric Michael addition of α-cyanoacetates,
see: (a) S. Jautze and R. Peters, Synthesis, 2010, 365. For selected
examples of asymmetric Michael additions of α-nitro or α-cyanoesters,
see: (b) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125,
11204; (c) I. T. Raheem, S. N. Goodman and E. N. Jacobsen, J. Am.
Chem. Soc., 2004, 126, 706; (d) T. Ikariya, H. Wang, M. Watanabe and
K. Murata, J. Organomet. Chem., 2004, 689, 1377; (e) A. Prieto,
N. Halland and K. A. Jørgensen, Org. Lett., 2005, 7, 3897; (f) C. Liu
and Y. Lu, Org. Lett., 2010, 10, 2278.
1.00 (d, J = 6.4 Hz, 3H, CH3), 1.07 (d, J = 6.0 Hz, 3H, CH3),
1.22 (d, J = 3.2 Hz, 3H, CH3), 1.24 (d, J = 3.2 Hz, 3H, CH3),
2.00 (s, 3H, CH3), 2.79–2.93 (m, 8H, CH2 + 2CH3), 3.59 (d, J =
10.0 Hz, 1H, CH), 3.81–3.87 (m, 1H, CH), 4.74–4.84 (m, 1H,
CH), 5.00–5.09 (m, 1H, CH), 6.63 (d, J = 8.4 Hz, 2H, ArH),
7.09 (d, J = 8.8 Hz, 2H, ArH). 13C NMR (100 MHz, CDCl3): δ
= 206.8, 168.1, 167.4, 149.7, 128.9, 112.7, 69.1, 68.7, 58.2,
48.1, 40.7, 39.9, 30.4, 21.8, 21.6, 21.51, 21.45 ppm. IR (KBr): ν
2980, 1725, 1614, 1522, 1467, 1353, 1255, 1157, 1103,
821 cm−1. HRMS (ESI): m/z calcd for C21H32NO5 [M + H]+
378.22750, found 378.222710.
6 Y. Gao, Q. Ren, W.-Y. Siau and J. Wang, Chem. Commun., 2011, 47,
5819.
Acknowledgements
7 For selected examples of asymmetric Michael additions of nitriles, see:
(a) Y. Hoashi, T. Okino and Y. Takemoto, Angew. Chem., Int. Ed., 2005,
44, 4032; (b) J. Wang, H. Li, L. Zu, W. Jiang, H. Xie, W. Duan and
W. Wang, J. Am. Chem. Soc., 2006, 128, 12652; (c) X. Li, L. Cun,
C. Lian, L. Zhong, Y. Chen, J. Liao, J. Zhu and J. Deng, Org. Biomol.
Chem., 2008, 6, 349; (d) J. Shi, M. Wang, L. He, K. Zheng, X. H. Liu, L.
L. Lin and X. M. Feng, Chem. Commun., 2009, 4711; (e) A. Russo,
A. Perfetto and A. Lattanzi, Adv. Synth. Catal., 2009, 351, 3067;
(f) A. Russo, A. Capobianco, A. Perfetto, A. Lattanzi and A. Peluso,
Eur. J. Org. Chem., 2011, 1922.
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21072020), the Science
and Technology Innovation Program of Beijing Institute of
Technology (Grant No. 2011CX01008) and the Development
Program for Distinguished Young and Middle-aged Teachers of
Beijing Institute of Technology.
8 For selected examples, see: (a) N. End, L. Macko, M. Zehnder and
A. Pfaltz, Chem.–Eur. J., 1998, 4, 818; (b) Y. S. Kim, S. Matsunaga,
J. Das, A. Sekine, T. Ohshima and M. Shibasaki, J. Am. Chem. Soc.,
2000, 122, 6506; (c) H. Sasai, T. Arai, Y. Satow, K. N. Houk and
M. Shibasaki, J. Am. Chem. Soc., 1995, 117, 6194; (d) M. Agostinho and
S. Kobayashi, J. Am. Chem. Soc., 2008, 130, 2430; (e) D. Chen,
Z. Chen, X. Xiao, Z. Yang, L. Lin, X. Liu and X. Feng, Chem.–Eur. J.,
2009, 15, 6807.
9 (a) D. Y. Kim, S. C. Huh and S. M. Kim, Tetrahedron Lett., 2001, 42,
6299; (b) R. T. Dere, R. R. Pal, P. S. Patil and M. M. Salunkhe, Tetrahe-
dron Lett., 2003, 44, 5351; (c) T. Ooi, D. Ohara, K. Fukumoto and
K. Maruoka, Org. Lett., 2005, 7, 3195.
10 (a) M. Yamaguchi, T. Shiraishi and M. Hirama, Angew. Chem., Int. Ed.
Engl., 1993, 32, 1176; (b) M. Yamaguchi, T. Shiraishi and M. Hirama, J.
Org. Chem., 1996, 61, 3520.
11 (a) N. Halland, P. S. Aburel and K. A. Jørgensen, Angew. Chem., Int. Ed.,
2003, 42, 661; (b) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem.
Soc., 2003, 125, 12672; (c) J. Wang, H. Li, L. Zu, W. Jiang, H. Xie,
W. Duan and W. Wang, J. Am. Chem. Soc., 2006, 128, 12652;
(d) V. Wascholowski, K. R. Knudsen, C. E. T. Mitchell and S. V. Ley,
Chem.–Eur. J., 2008, 14, 6155; (e) Z. Jiang, W. Ye, Y. Yang and
C.-H. Tan, Adv. Synth. Catal., 2008, 350, 2345; (f) Y.-Q. Yang and
Notes and references
1 P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Perga-
mon, Oxford, 1992. For selected reviews of asymmetric Michael
additions, see: (a) O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org.
Chem., 2002, 1877; (b) D.-M. Du and W.-T. Hua, Chin. J. Org. Chem.,
2002, 22, 164; (c) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701;
(d) J. Christoffers, G. Koripelly, A. Rosiak and M. Rössle, Synthesis,
2007, 1279; (e) S. Sulzer-Mossé and A. Alexakis, Chem. Commun.,
2007, 3123; (f) J. L. Vicario, D. Badía and L. Carrillo, Synthesis, 2007,
2065; (g) D. Almaşi, D. A. Alonso and C. Nájera, Tetrahedron: Asymme-
try, 2007, 18, 299; (h) D. Enders, C. Wang and J. X. Liebich, Chem.–Eur.
J., 2009, 15, 11058; (i) C. Hawner and A. Alexakis, Chem. Commun.,
2010, 46, 7295; ( j) M. Thirumalaikumar, Org. Prep. Proced. Int., 2011,
43, 67; (k) J. L. Vicario, D. Badía, L. Carrillo and E. Reyes, Organocata-
lytic Enantioselective Conjugate Additions: A Powerful Tool for the
Stereocontrolled Synthesis of Complex Molecules, RSC Publishing,
Cambridge, 2010.
2 For selected examples of asymmetric Michael additions of malonates,
see: (a) G. Bartoli, M. Bosco, A. Carlone, A. Cavalli, M. Locatelli,
A. Mazznti, P. Ricci, L. Sambri and P. Melchiorre, Angew. Chem., 2006,
4122 | Org. Biomol. Chem., 2012, 10, 4116–4123
This journal is © The Royal Society of Chemistry 2012

G. Zhao, Chem.–Eur. J., 2008, 14, 10888; (g) Z. Mao, Y. Jia, W. Li and
R. Wang, J. Org. Chem., 2010, 75, 7428; (h) P. Li, S. Wen, F. Yu, Q. Liu,
W. Li, Y. Wang, X. Liang and J. Ye, Org. Lett., 2009, 11, 753; (i) K.
R. Knudsen, C. E. T. Mitchell and S. V. Ley, Chem. Commun., 2006, 66.
12 Z. Wang, Q. Wang, Y. Zhang and W. Bao, Tetrahedron Lett., 2005, 46,
4657.
13 (a) B. K. Ni, Q. Y. Zhang, K. Dhungana and A. D. Headley, Org. Lett.,
2009, 11, 1037; (b) L. Zu, J. Wang, H. Li and W. Wang, Org. Lett., 2006,
8, 3077; (c) J. Wang, H. Li, B. Lou, L. Zu, H. Guo and W. Wang, Chem.–
Eur. J., 2006, 12, 4321; (d) W. Wang, J. Wang and H. Li, Angew. Chem.,
Int. Ed., 2005, 44, 1369; (e) S. R. Ban, D.-M. Du, H. Liu and W. Yang,
Eur. J. Org. Chem., 2010, 5160; (f) C. Luo and D.-M. Du, Synthesis,
2011, 1968.
14 (a) H. Liu and D.-M. Du, Adv. Synth. Catal., 2010, 352, 1113; (b) X. Du,
H. Liu and D.-M. Du, Eur. J. Org. Chem., 2011, 786.
15 These results were obtained at room temperature (about 15 °C in March)
during the revision period; the data in Table 3 were obtained at room
temperature in June last year.
16 (a) S. Paul and M. Gupta, Synth. Commun., 2005, 35, 213; (b) G.-F. Han,
J.-J. Wang and G.-J. Jiang, Chin. J. Org. Chem., 2003, 23, 1004;
(c) M. Wang, L. Lin, J. Shi, X. Liu, Y. Kuang and X. Feng, Chem.–Eur.
J., 2011, 17, 2365.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4116–4123 | 4123