Highly enantioselective michael addition of ketone to alkylidene malonates catalyzed by binaphthyl sulfonimides in water

Article abstract of DOI:10.1002/cjoc.201200910

Binaphthyl sulfonimides have been developed to catalyze the asymmetric Michael addition of ketone to alkylidene malonates, affording the corresponding Michael products in good to high yields (up to 98%) with good to excellent diastereoselectivity (up to 9

Full text of DOI:10.1002/cjoc.201200910

FULL PAPER
DOI: 10.1002/cjoc.201200910
Highly Enantioselective Michael Addition of Ketone to
Alkylidene Malonates Catalyzed by Binaphthyl
Sulfonimides in Water
Jia, Shengjian(贾胜见)
Luo, Chunhua(罗春华)
Du, Daming*(杜大明)
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, China
Binaphthyl sulfonimides have been developed to catalyze the asymmetric Michael addition of ketone to alky-
lidene malonates, affording the corresponding Michael products in good to high yields (up to 98%) with good to
excellent diastereoselectivity (up to 99∶1 dr) and enantioselectivity (up to 92% ee) under mild conditions using
environmentally benign water as the solvent.
Keywords asymmetric catalysis, organocatalysis, Michael addition, malonates, sulfonimides
compounds by Tang, Wang, Feng and so on.[2,3,9]
Introduction
Many chiral sulfonamide catalysts have been exten-
sively applied in asymmetric catalysis. The strong elec-
tron withdrawing effect of sulfonyl can improve the
acidity of sulfonamide, enhance hydrogen bond donor
ability. Meanwhile, it also can provide lone pair of elec-
tions for coordination, which is conducive to raise enan-
tioseletivity in asymmetric reactions. Sulfonamide or-
ganocatalysts are amazingly used in many asymmetric
reaction such as asymmetric Michael addition, asym-
metric Aldol reaction and asymmetric Mannich reaction.
Wang et al.[3h,10] reported pyrrolidine-based sulfonamide
organocatalyst in asymmetric Michael addition of alde-
hydes to nitroalkenes, asymmetric Aldol reaction of
α,α-dialkyl substituted aldehydes with aromatic alde-
hydes, asymmetric Mannich reaction of ketones with
α-imino esters. Tang et al.[2] devoted the same catalyst
for the asymmetric Michael addition of ketones to alky-
lidene manolates with the additive n-butyric acid in or-
ganic solvent. Imai et al.[11] reported direct asymmetric
Aldol reactions of aldehyde with ketones in brine using
the novel sulfonamide catalysts, which give the desired
adducts in high yields with modest enantioselectivities.
Recently, we have developed L-proline-based
binaphthyl sulfonimides and sulfonamides 1 (Figure 1)
as highly efficient and stereoselective organocatalysts
for the asymmetric Michael addition of ketones to nitro-
alkenes with the additive PhCO2H in organic solvent or
in water.[12] We assumed that catalysts 1 should be also
a well organocatalyst and tried to apply them to catalyze
the Michael addition reaction of ketones to alkylidene
malonates. Herein, we present the application of
L-proline-based binaphthyl sulfonimides and sulfona-
In the past decades, the asymmetric Michael addition
reaction as an important asymmetric carbon-carbon
bond formation reaction obtained great development in
organic synthesis of bifunctional products.[1] The direct
organocatalytic asymmetric Michael addition of ketones
or aldehydes to α,β-unsaturated compounds provides a
particularly attractive atom-economical manner.[2] Al-
though there are many types of substrates and donors
for Michael reaction, many efforts have been made to
achieve catalytic enantioselective conjugate addition
and great progress can be seen. On one hand, the Mi-
chael acceptors have been extended from nitroalkenes[3]
to α,β-unsaturated aldehydes,[4] ketones,[5] sulfones,[6]
and phosphate[7] etc. electronic deficiency systems. On
the other hand, many new types of catalysts have been
developed, such as L-porline-based catalysts, primary
amines, thioureas etc. The asymmetric Michael addition
of ketones to alkylidene manolates has been reported
only in a few case compared with other Michael donors,
this was ascribed to the low reactivity of alkylidene
manolates. The pioneering work of using pyrrolidine
based diamine as highly efficient and stereoselective
organocatalysts for the asymmetric Michael addition of
ketones to alkylidene manolates was reported by Barbas
and co-workers.[8] Although the catalytic effect was un-
satisfactory, it provided a new idea for the chemical
researchers to investigate those reactions and design
new catalysts. In recent years, great efforts have been
devoted to the L-porline-based catalysts or primary-
secondary diamine catalysts for asymmetric Michael
addition of ketones or aldehydes to α,β-unsaturated
*
E-mail: dudm@bit.edu.cn; Tel.: 0086-010-68914985; Fax: 0086-010-68914985
Received September 17, 2012; accepted November 1, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200910 or from the author.
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2676—2680

Highly Enantioselective Michael Addition of Ketone to Alkylidene Malonates
mides 1 in the asymmetric Michael addition of ketone to
alkylidene malonates to give the desired products in
good to high yields with good to excellent enantioselec-
Table 1 Optimization of solvents and additivea
NO2
tivities and diastereoselectivities (up to 98% yield, 92%
ee, 99∶1 dr) under mild conditions in water.
O
EtO2C
+
CO2Et
O
1c (10 mol%)
CO2Et
additive (10 mol%)
r.t.
O
O
NO2
CO2Et
O
2
O
S
N
H
3a
4a
N
S
S
H
N
N
H
N
H
H
dr (syn/
anti)c
—
Additive Solvent Time/h Yieldb/%
eed/%
N
Entry
S
O
O
O
O
O
1
2
3
4
5
6
7
8
9
—
—
—
72
72
0
—
93
88
90
90
89
90
90
89
1a
1b
PhCO2H
PhCO2H CH2Cl2 72
PhCO2H CH3CN 72
PhCO2H
PhCO2H
PhCO2H i-PrOH 72
PhCO2H
PhCO2H
2-O2NC6H4-
CO2H
50
35
47
25
30
37
35
53
93∶7
93∶7
92∶8
91∶9
91∶9
92∶8
91∶9
96∶4
O
O
O
S
N
S
S
N
H
THF
Et2O
72
72
H
N
N
H
H
H
N
N
S
O
O
O
O
DMF
H2O
72
48
1c
1d
Figure 1 Binaphthyl sulfonimide and sulfonamide organo-
catalysts 1a—1d.
10
H2O
48
30
90∶10
89
11
12
13
14
15
16
17
18e
CF3SO3H
CF3CO2H
CF3CO2H Brine
DMAP
DMAP
—
H2O
H2O
48
48
48
48
48
48
48
48
0
0
0
35
40
88
86
98
—
—
—
—
89
88
90
90
92
—
Results and Discussion
—
H2O
Brine
H2O
Brine
H2O
94∶6
95∶5
97∶3
97∶3
97∶3
Initially, the Michael reaction of cyclohexanone 2
with 2-(4-nitrobenzylidene)malonate (3a) catalyzed by
catalyst 1c (10 mol%) was selected as a model reaction
at room temperature. The results are listed in Table 1. It
was found that no desired product was observed under
solvent-free reaction conditions without additive. To our
delight, the reaction proceeded smoothly when PhCO2H
was added as the additive; high diastereoselectivity (dr)
and enantioselectivity were obtained (Table 1, Entry 2;
93% ee, 93∶7 dr). A series of solvents were then in-
vestigated, and the results are listed in Table 1. As ex-
pected, CH2Cl2, CH3CN, THF, Et2O, i-PrOH and DMF
were employed as the solvent in the reaction, and the
product was obtained in high diastereoselectivities and
enantioselectivities but with poor yields (Table 1, En-
tries 3—8; 88%—90% ee, 25%—47% yield). Particu-
larly, the optimal procedure was to perform the reaction
in water (Table 1, Entry 16), which gave 88% yield with
97∶3 diastereoselectivity and 90% ee (major) in a
shorter time. The reaction rate, yield, and enantioselec-
tivity were decreased when acids PhCO2H (Table 1,
Entry 9; 89% ee, 53% yield) and 2-O2NC6H4CO2H (Ta-
ble 1, Entry 10; 89% ee, 30% yield) were added in wa-
ter. No product was observed in the presence of
CF3SO3H and CF3CO2H (Table 1, Entries 11 and 12).
Furthermore, the results of reaction were not better by
using brine instead of water (Table 1, Entry 17). To our
delight, increasing the catalyst loading increased the
yield from 86% to 98% and enantioselectivity from 90%
ee to 92% ee (Table 1, Entries 16 and 18).
—
—
a All reactions were carried out using cyclohexanone (2, 196 mg,
2.0 mmol), additive (10 mol%) and catalyst 1c (10 mol%) in sol-
vent (0.2 mL) with stirring at room temperature for 15 min. Then
2-(4-nitrobenzylidene) malonate (33 mg, 0.125 mmol) was added.
b Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC on Chiracel IA column with
n-hexane and 2-propanol as eluents. Determined by chiral
HPLC analysis. e The catalyst was loading at 15 mol%.
c
d
catalyst 1c gave the best result: 98% yield and 92% ee
(Table 2, Entry 3) for the syn diastereomer (97∶3 dr).
It was observed that, by changing the chirality of the
binaphthyl part as in 1a, the results were equally good
with enantioselectivity of 91% ee (Table 2, Entry 1).
Slight higher yields and enantioselectivities catalyzed
by sulfonimides 1a and 1c were observed than sulfona-
mides 1b and 1d.
Under the optimized conditions, a variety of alky-
lidene malonate substrates were investigated to test the
generality of the present reaction and the results are
summarized in Table 3. Various alkylidene malonates
can react smoothly with cyclohexanone in the presence
of the catalyst 1c (15 mol%), leading to the corres-
ponding adducts in moderate to high yields and with
good to excellent diastereoselectivities and high enantio-
selectivities in water (Table 3, Entries 1—9, 11 and 12).
It was observed that substituents on aryl groups had no
obvious influence on the diastereoselectivities and
Encouraged by these results, other chiral catalysts
were screened by using water as solvent without addi-
tive, and the results are summarized in Table 2. The
Chin. J. Chem. 2012, 30, 2676—2680
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2677

Jia, Luo & Du
FULL PAPER
Table 2 Screening of catalystsa
enantioselectivities but affected strongly the yields (Ta-
ble 3, Entries 1—12). Alkylidene malonates with elec-
tron-donating groups gave poor yields than those with
electron-withdrawing groups (Table 3, Entries 1—9 vs.
10, 11). 4-Methylphenyl or phenyl substituted substrate
has very low reactivity, no reaction was occurred at all
(Table 3, Entries 10 and 14—17).
Furthermore, the asymmetric Michael addition of
other ketones such as cyclopentanone, cycloheptanone,
acetone were also carried out in the presence of catalyst
1c. Unfortunately, the reactions for cyclopentanone,
cycloheptanone or acetone with alkylidene malonates in
water did not afford corresponding product.
Based on the configuration of the product, we pro-
pose the putative transition state for the 1c-catalyzed
asymmetric Michael addition of cyclohexanone to alky-
lidene malonates as shown in Figure 2. The pyrrolidine
ring first reacts with the carbonyl compound to form the
enamine. The oxygen atom of the sulfonimides group,
via a H-bond with water, directs the alkyliene manolates
so that the enamine will attack the alkyliene manolates
from the Re face to give product with high enantio- and
diastereoselectivity.
NO2
EtO2C
+
CO2Et
O
1 (15 mol%)
O
CO2Et
H2O, r.t., 48 h
NO2
CO2Et
2
3a
4a
Entry Catalyst
Yieldb/%
dr (syn/anti)c
eed/%
1
2
3
4
1a
1b
1c
1d
91
88
98
87
96∶4
93∶7
97∶3
90∶10
91
86
92
85
a All reactions were carried out using cyclohexanone (2, 196 mg,
2.0 mmol) and catalyst 1 (15 mol%) in water (0.2 mL) with stir-
ring at room temperature for 15 min. Then 2-(4-nitrobenzylidene)
malonate (33 mg, 0.125 mmol) was added. Yield of the isolated
product after chromatography on silica gel. Determined by
b
c
chiral HPLC on Chiracel IA column with n-hexane and
2-propanol as eluents. d Determined by chiral HPLC analysis.
Table 3 Catalytic asymmetric Michael addition of cyclohexan-
one to alkylidene malonatesa
O
H
O
R1
CO2R2
CO2R2
CO2R2
CO2R2
O
O
1c (15 mol%)
+
H
S
O
R1
H2O, r.t.
EtO
N
O
4
S
2
3
O
O
N
EtO
Entry
R1
R2 Product Yieldb/%
drc
eed/%
H
O
4a
4b
4c
4d
4e
4f
1
2
4-NO2C6H4 Et
4-NO2C6H4 Me
3-NO2C6H4 Et
3-NO2C6H4 Me
2-NO2C6H4 Et
2-NO2C6H4 Me
98
97
95
88
80
85
69
64
68
—
49
61
—
—
—
—
97∶3
96∶4
96∶4
98∶2
99∶1
92
91
90
88
91
H
NO2
3
4
5
6
＞99∶1 92
7e
8e
9e
10e
4-FC6H4
4-ClC6H4
4-BrC6H4
Me
Me
Me
97∶3
97∶3
97∶3
—
88
88
88
—
92
87
—
—
—
—
—
4g
4h
4i
O
S
N
O
4j
4-MeC6H4 Me
S
N
O
11e 4-CH3OC6H4 Me
86∶14
80∶20
—
OEt
4k
4l
O
O
H
OEt
12f
13 f
14f
15f
16f
17f
3-Pyridineyl Me
Cyclohexyl Me
Re
O
4n
4o
4p
4q
4r
O
H
Ph
Ph
Ph
Ph
Me
i-Pr
Ph
—
—
—
O2N
Bn
—
Figure 2 A proposed transition state.
a
Unless otherwise noted, the reactions were carried out using
cyclohexanone 2 (196 mg , 2.0 mmol) and catalyst 1c (15 mol%)
in water (0.2 mL). The mixture was stirred at room temperature
for 15 min, then alkylidene malonate 3 (0.20 mmol) was added
and stirred at room temperature for 72 h. b Yield of the isolated
Conclusions
In summary, we have developed an L-proline-based
binaphthyl sulfonamide-catalyzed asymmetric Michael
addition of cyclohexanone to alkylidene malonates, and
the corresponding products were obtained in good to
high yields (up to 98%) with good to excellent di-
astereoselectivity (up to 99∶1 dr) and high enantio-
c
product after chromatography on silica gel. Determined by
chiral HPLC. d Determined by chiral HPLC analysis, the con-
e
figuration was assigned according to literature. The reaction
time was 8 d. f The reaction time was 12 d.
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Chin. J. Chem. 2012, 30, 2676—2680

Highly Enantioselective Michael Addition of Ketone to Alkylidene Malonates
selectivity (up to 92% ee) under mild conditions in wa-
ter. Meanwhile, the putative transition state for the
1c-catalyzed asymmetric Michael addition of cyclo-
hexanone to alkylidene malonates was proposed.
syn diastereomer tR(minor)＝17.6 min, tR(major)＝24.9
min; syn/anti＝96/4, 90% ee.
2-[(2-Oxocyclohexyl)-3-nitrophenylmethyl]malonic
acid dimethyl ester (4d)[9b]: The product 4d was ob-
tained as a white solid (69.0 mg, 96% yield) according
to the general procedure after reacted for 72 h. HPLC
analysis (Chiralpak IA column, n-hexane/ 2-propanol,
V∶V＝70∶30, flow rate 0.80 mL/min, detection at 254
nm): syn diastereomer tR(minor)＝9.4 min, tR(major)＝
11.1 min; syn/anti＝98/2, 88% ee.
Experimental
Materials
Commercially available compounds were used
without further purification. Column chromatography
was carried out using silica gel (200—300 mesh). Melt-
ing points were measured with an XT-4 melting point
apparatus. The NMR spectra were recorded with Varian
Mercury-plus 400 MHz or Bruker Avance III 400 MHz
spectrometer. Optical rotations were measured with a
WZZ-3 polarimeter. The enatiomeric excesses (ee val-
ues) of the products were determined by chiral HPLC
analysis using an Aglient HP 1200 instrument
(n-hexane/2-propanol as eluent). High resolution mass
spectra (HRMS) were recorded on a Bruker PEX IV
Fourier-Transform mass spectrometer with electrospray
ionization (ESI). L-Proline-based binaphthyl sulfonim-
ides and sulfonamides 1 were prepared according to our
previous report.[12]
2-[(2-Oxocyclohexyl)-2-nitrophenylmethyl]malonic
acid diethyl ester (4e): The product 4e was obtained as a
brown oil (54.0 mg, 69% yield) according to the general
procedure after reacted for 72 h. [α]2D0 －32.7 (c 0.51,
CH2Cl2); 1HNMR (400 MHz, CDCl3) δ: 7.75 (d, J＝8.4
Hz, 1H, ArH), 7.52—7.50 (m, 2H, ArH), 7.37—7.33 (m,
1H, ArH), 4.06 (t, J＝8.4 Hz, 1H, CH), 4.16—3.91 (m,
5H, CH＋2CH2), 3.18—3.12 (m, 1H, CH), 2.48—2.34
(m, 2H, CH2), 2.05—2.02 (m, 1H, CH2), 1.82—1.78 (m,
2H, CH2), 1.74—1.66 (m, 2H, CH2), 1.60—1.53 (m, 1H,
CH2), 1.50—1.43 (m, 1H, CH2), 1.19 (t, J＝7.2 Hz, 3H,
CH3), 1.07 (t, J＝7.2 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ: 211.4, 168.2, 168.0, 134.3, 132.1,
130.9, 128.8, 127.7, 124.3, 61.7, 61.3, 55.3, 53.1, 42.5,
32.7, 29.6, 28.3, 25.3, 13.8, 13.7; IR (KBr) ν: 2939,
2866, 1728, 1530, 1448, 1358, 1243, 1178, 1032, 854,
General procedure for asymmetric Michael addition
of hexanone to alkylidene malonates
－
1
788 cm ; HRMS (ESI) calcd for C20H25NaO7 [M＋
Na]＋ 414.15232, found 414.15303. HPLC analysis
(Chiralpak IA column, n-hexane/2-propanol, V∶V＝
70∶30, flow rate 0.80 mL/min, detection at 254 nm):
syn diastereomer tR(minor)＝9.1 min, tR(major)＝16.6
min; syn/ant＞99/1, 90% ee.
The organocatalyst 1c (14.7 mg, 0.03 mmol) was
added to cyclohexanone 2 (196 mg, 2.0 mmol) in H2O
(0.2 mL) and stirred for 15 min. Then alkylidene malo-
nates 3 (0.2 mmol) was added, and the resulting mixture
was stirred at room temperature for indicated time until
the reaction was complete (monitered by TLC). The
corresponding Michael addition product was isolated by
flash chromatography on silica gel using petroleum
ether-ethyl acetate (10∶1 to 5∶1) as eluent.
2-[(2-Oxocyclohexyl)-4-nitrophenylmethyl]malonic
acid diethyl ester (4a)[9b]: The product 4a was obtained
as a white solid (76.6 mg, 98% yield) according to the
general procedure after reacted for 72 h. HPLC (Chiral-
pak IA, hexane/i-PrOH, V∶V＝70∶30, flow rate 0.80
mL/min, detection at 230 nm): syn diastereomer
tR(minor)＝13.5 min, tR(major)＝22.9 min; syn/ant＝
97/3, 92% ee.
2-[(2-Oxocyclohexyl)-4-nitrophenylmethyl]malonic
acid dimethyl ester (4b)[9b]: The product 4b was ob-
tained as a white solid (70.0 mg, 97% yield) according
to the general procedure after reacted for 72 h. HPLC
analysis (Chiralpak AS-H column, n-hexane/ 2-propanol,
V∶V＝96∶4, flow rate 1 mL/min, detection at 254
nm): syn diastereomer tR(minor)＝46.1 min, tR(major)
＝58.9 min; syn/anti＝96/4, 91% ee.
2-[(2-Oxocyclohexyl)-3-nitrophenylmethyl]malonic
acid diethyl ester (4c)[9b]: The product 4c was obtained
as a colorless oil (75.0 mg, 95% yield) according to the
general procedure after reacted for 72 h. HPLC analysis
(Chiralpak IA column, n-hexane/2-propanol, V∶V＝
90∶10, flow rate 0.80 mL/min, detection at 254 nm):
2-[(2-Oxocyclohexyl)-2-nitrophenylmethyl]malonic
acid dimethyl ester (4f)[9c]: The product 4f was obtained
as a light yellow solid (61.0 mg, 85% yield) according
to the general procedure after reacted for 72 h. HPLC
analysis (Chiralpak IA column, n-hexane/2-propanol,
V∶V＝90∶10, flow rate 1.0 mL/min, detection at 254
nm): syn diastereomer tR(minor)＝15.1, tR(major)＝24.3
min; syn/ant＞99/1, 92% ee.
2-[(2-Oxocyclohexyl)-4-fluorophenylmethyl]malonic
acid dimethyl ester (4g): The product 4g was obtained
as a white solid (46.0 mg, 69% yield) according to the
general procedure after reacted for 8 d. m.p. 91—93 ℃;
1
[α]2D0 －17.5 (c 0.80, CH2Cl2); HNMR (400 MHz,
CDCl3) δ: 7.25—7.21 (m, 2H, ArH), 6.98—6.94 (m, 2H,
ArH), 4.00—3.95 (m, 2H, 2CH), 3.67 (s, 3H, CH3), 3.49
(s, 3H, CH3), 2.94—2.88 (m, 1H, CH), 2.48—2.43 (m,
1H, CH2), 2.40—2.32 (m, 1H, CH2), 2.01—1.98 (m, 1H,
CH2), 1.78—1.73 (m, 2H, CH2), 1.65—1.58 (m, 2H,
CH2), 1.20—1.10 (m, 1H, CH2); 13C NMR (100 MHz,
1
CDCl3) δ: 211.9, 168.8, 168.4, 161.7 (d, JC-F＝244.2
3
2
Hz), 134.3, 130.9 (d, JC-F＝7.8 Hz), 115.0 (d, JC-F
＝
21.2 Hz), 55.5, 53.0, 52.5, 52.2, 43.1, 42.1, 31.9, 27.9,
24.6; IR(KBr) ν: 3040, 3000, 2950, 2863, 1756, 1702,
1603, 1512, 1456, 1435, 1310, 1266, 1224, 1150, 1015,
－
979, 848, 788 cm 1. HRMS (ESI) calcd for
C18H21FNaO5 [M＋Na]＋ 359.12652, found 359.12725.
Chin. J. Chem. 2012, 30, 2676—2680
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2679

Jia, Luo & Du
FULL PAPER
HPLC analysis (Chiralpak IA column, n-hexane/
2-propanol, V∶V＝90∶10, flow rate＝0.80 mL/min,
detection at 254 nm): syn diastereomer tR(minor)＝12.7,
tR(major)＝13.8 min; syn/ant＝97/3, 88% ee.
tinguished Young and Middle-aged Teachers of Beijing
Institute of Technology.
References
2-[(2-Oxocyclohexyl)-4-chlorophenylmethyl]malonic
acid dimethyl ester (4h)[9c]: The product 4h was ob-
tained as a white solid (45.0 mg, 64% yield) according
to the general procedure after reacted for 8 d. HPLC
analysis (Chiralpak IA column, n-hexane/ 2-propanol,
V∶V＝90∶10, flow rate＝0.80 mL/min, detection at
230 nm): syn diastereomer tR(minor)＝13.7, tR(major)＝
14.9 min; syn/anti＝97/3, 88% ee.
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Org. Chem. 2007, 1701; (e) Christoffers, J.; Koripelly, G.; Rosiak,
A.; Rössle, M. Synthesis 2007, 1279; (f) Vicario, J. L.; Badía, D.;
Carrillo, L. Synthesis 2007, 2065; (g) Almaşi, D.; Alonso, D. A.;
Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299; (h) Hawner, C.;
Alexakis, A. Chem. Commun. 2010, 46, 7295.
2-[(2-Oxocyclohexyl)-4-bromophenylmethyl]malonic
acid dimethyl ester (4i)[9c]: The product 4i was obtained
as a white solid (54.0 mg, 68% yield) according to the
general procedure after reacted for 8 d. HPLC analysis
(Chiralpak IA column, n-hexane/2-propanol, V∶V＝
95∶5, flow rate 0.80 mL/min, detection at 230 nm): syn
diastereomer tR(minor)＝21.7, tR(major)＝23.8 min;
syn/anti＝97/3, 88% ee.
2-[(2-Oxocyclohexyl)-4-methoxyphenylmethyl]-
malonic acid dimethyl ester (4k)[9b]: The product 4k was
obtained as a white solid (34.0 mg, 49% yield) accord-
ing to the general procedure after reacted for 8 d. HPLC
analysis (Chiralpak AS-H column, n-hexane/ 2-propanol,
V∶V＝95∶5, flow rate 0.50 mL/min, detection at 230
nm): syn diastereomer tR(minor)＝40.4 min, tR(major)
＝46.0 min; syn/anti＝86/14, 92% ee.
[2] Cao, C. L.; Sun, X. L.; Zhou, J. L.; Tang, Y. J. Org. Chem. 2007, 72,
4073.
[3] (a) Ishii, T.; Fujioka, S.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126,
9558; (b) List, B.; Pojarlier, P.; Martin, H. J. Org. Lett. 2001, 3,
2423; (c) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005,
44, 1369; (d) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem., Int. Ed. 2005, 44, 4212; (e) Luo, S. Z.; Mi, X. L.; Zhang, L.;
Liu, S.; Xu, H.; Cheng, J. P. Angew. Chem., Int. Ed. 2006, 45, 3093;
(f) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624;
(g) Cao, C. L.; Ye, M. C.; Sun, X. L.; Tang, Y. Org. Lett. 2006, 8,
2901; (h) Zu, L. S.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8,
3077; (i) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.
Eur. J. 2006, 12, 4321; (j) Andrey, O.; Alexakis, A. Org. Lett. 2003,
5, 2559; (k) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611;
(l) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, III. C. F. J. Am. Chem.
Soc. 2001, 123, 5260; (m) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu,
X. F.; Guo, C. Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed.
2005, 44, 105; (n) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem.
Soc. 2006, 128, 1454.
[4] (a) Hong, B. C.; Wu, M. F.; Tseng, H. C.; Liao, J. H. Org. Lett. 2006,
8, 2217; (b) Marigo, M.; Bertelsen, S.; Jørgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 5475.
[5] (a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151;
(b) Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed.
2004, 43, 3958; (c) Peelen, T. J.; Chi, Y. G.; Gellman, S. H. J. Am.
Chem. Soc. 2005, 127, 11598; (d) Wang, J.; Li, H.; Zu, L. S.; Wang,
W. Adv. Synth. Catal. 2006, 348, 425.
2-[(2-Oxocyclohexyl)-3-pyridinylmethyl]malonic
acid dimethyl ester (4l): The product 4l was obtained as
a red oil (39.0 mg, 69% yield) according to the general
procedure after reacted for 12 d. [α]2D0 －80.2 (c 1.95,
1
CH2Cl2); HNMR (400 MHz, CDCl3-d6) δ: 8.52 (br s,
2H, ArH), 7.69 (d, J＝8.0 Hz, 1H, ArH), 7.25 (s, 1H,
ArH), 4.07 (d, J＝8.4 Hz, 1H, CH), 4.01 (t, J＝8.0 Hz,
1H, CH), 3.68 (s, 3H, CH3), 3.52 (s, 3H, CH3), 3.01—
2.95 (m, 1H, CH), 2.46—2.33 (m, 2H, CH2), 2.04—
2.01 (m, 1H, CH2), 1.83—1.76 (m, 2H, CH2), 1.65—
1.55 (m, 2H, CH2), 1.21—1.12 (m, 1H, CH2); 13C NMR
(100 MHz, CDCl3-d6) δ: 211.3, 168.6, 168.2, 150.6,
148.3, 137.1, 130.8, 128.7, 54.7, 52.6, 52.30, 52.29,
42.2, 41.5, 31.8, 27.6, 24.8; IR (KBr) ν: 2951, 2862,
[6] Mossé, S.; Alexakis, A. Org. Lett. 2005, 7, 4361.
[7] Sulzer-Mossé, S.; Tissot, M.; Alexakis, A. Org. Lett. 2007, 9, 3749.
[8] (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, III. C.
F. Tetrahedron Lett. 2001, 42, 4441; (b) Betancort, J. M.; Sakthivel,
K.; Thayuman-avan, R.; Tanaka, F.; Barbas, III. C. F. Synthesis
2004, 9, 1509.
[9] (a) Zhao, G. L.; Vesely, J.; Sun, J. L.; Christensen, K. E.; Bonneau,
C.; Córdova, A. Adv. Synth. Catal. 2008, 350, 657; (b) Liu, J.; Yang,
Z. G.; Liu, X. H.; Weng, Z.; Liu, Y. L.; Bai, S.; Lin, L. L.; Feng, X.
M. Org. Biomol. Chem. 2009, 7, 4120; (c) Magar, D. R.; Chang, C.;
Ting, Y. F.; Chen, K. Eur. Org. Chem. 2010, 11, 2062.
[10] (a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44,
1369; (b) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett. 2005, 46,
5077; (c) Wei, K.; Zhang, S.; He, S.; Li, P.; Jin, M.; Xue, F.; Luo, G.;
Zhang, H.; Song, L.; Duan, W.; Wang, W. Tetrahedron Lett. 2008,
49, 2681; (d) Zu, L. S.; Xie, H. X.; Li, H.; Wang, J.; Wang, W. Org.
Lett. 2008, 10, 1211; (e) Wang, W.; Wang, J.; Li, H. Tetrahedron
Lett. 2004, 45, 7243.
－
1
1732, 1435, 1147, 1012, 738 cm ; HRMS (ESI) calcd
for C17H22NO5 [M＋H]＋ 320.14925, found 320.14954.
HPLC analysis (Chiralpak AD-H column, n-hexane/
2-propanol, V∶V＝90∶10, flow rate＝0.80 mL/min,
detection at 254 nm): syn diastereomer tR(minor)＝28.7,
tR(major)＝29.7 min; syn/anti＝80/20, 87% ee.
Acknowledgment
We are grateful for financial support from the Na-
tional Natural Science Foundation of China (No.
21072020), the Science and Technology Innovation
Program of Beijing Institute of Technology (No.
2011CX01008) and the Development Program for Dis-
[11] Miura, T.; Yasaku, Y.; Koyata, N.; Murakami, Y.; Imai, N.
Tetrahedron Lett. 2009, 50, 2632.
[12] (a) Ban, S. R.; Du, D. M.; Liu, H.; Yang, W. Eur. J. Org. Chem.
2010, 5160; (b) Luo, C. H.; Du, D. M. Synthesis 2011, 1968.
(Zhao, C.)
2680
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Chin. J. Chem. 2012, 30, 2676—2680