Asymmetric Michael addition of aldehydes to nitroalkenes using a primary amino acid lithium salt

Article abstract of DOI:10.1039/c003940c

Enantioselective Michael addition of aldehydes to nitroalkenes was successfully carried out by asymmetric catalysis with l-phenylalanine lithium salt, giving γ-nitroaldehydes in good yields with high enantioselectivity.

Full text of DOI:10.1039/c003940c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric Michael addition of aldehydes to nitroalkenes using a primary
amino acid lithium salt†
Masanori Yoshida,* Atsushi Sato and Shoji Hara
Received 9th March 2010, Accepted 16th April 2010
First published as an Advance Article on the web 12th May 2010
DOI: 10.1039/c003940c
Enantioselective Michael addition of aldehydes to nitroalkenes was successfully carried out by
asymmetric catalysis with L-phenylalanine lithium salt, giving g-nitroaldehydes in good yields with
high enantioselectivity.
Introduction
Results and discussion
Asymmetric carbon–carbon bond formation is an extremely
important technology in modern organic synthesis. An exhaustive
investigation of transition metal catalysts and asymmetric ligands
by chemists has made various organic syntheses with high enan-
tioselectivity possible. Compared with the history of transition
metal catalysis, asymmetric organocatalysis is still in a developing
period; however, organocatalysis has achieved explosive growth
in the past decade.1 In organocatalysis based on the formation
of an imine–enamine intermediate from carbonyl compounds,
secondary amines, especially L-proline and its derivatives, have
generally been employed as catalysts. Within common natural
amino acids, however, only a few secondary amino acids are
available, while more than 20 types of primary amino acids are
readily obtainable from commercial sources. Although the use of
primary amines as asymmetric catalysts is behind compared with
that of secondary amines, results of successful works have been
published in recent years.2
The Michael addition of aldehydes to nitroalkenes is a use-
ful method to obtain g-nitroaldehydes, and various enantios-
elective organocatalyses have been published.3–5 Most of them
are enamine-based catalyses using a secondary amine catalyst,4
since secondary amines can generate enamines from carbonyl
compounds more readily than can primary amines. However,
in the case of using sterically hindered carbonyl compounds,
such as a-branched aldehydes, as substrates, primary amines
can generate enamines more readily than can secondary amines.
Indeed, primary amine catalysts are generally effective for the
Michael addition of a-branched aldehydes with nitroalkenes.5
Recently, we found that the Michael addition of isobutyralde-
hyde with nitrostyrene was effectively promoted by a primary
amino acid lithium salt, and we reported the results in a short
communication.6,7 In this paper, we disclose the details of primary
amino acid lithium salt-catalyzed Michael addition reactions of
various aldehydes with nitroalkenes.
First, we examined the Michael addition of isobutyraldehyde (1a)
to (E)-b-nitrostyrene (2a) by using a primary amino acid, L-
phenylalanine, as a catalyst; however, the catalyst did not dissolve
in the reaction media and no reaction was observed (Table 1,
entry 1). We assumed that the addition of L-phenylalanine to 1a
did not occur well, since the amino acid firmly forms a zwitterion,
R(NH3 )COO-, in the reaction conditions. Therefore, in order
+
to increase the basicity, L-phenylalanine was treated with a base
to prepare an amino acid salt, Phe–OM.7 To our delight, we
found that L-phenylalanine lithium salt, which can be readily
prepared from L-phenylalanine and lithium hydroxide, promoted
the reaction of 1a with 2a effectively to give the Michael adduct 3a
in 92% yield with 94% ee (Table 1, entry 2). Other alkaline metal
salts and a magnesium salt of L-phenylalanine also promoted
the Michael addition to afford 3a with high enantioselectivity;
however, the reaction rate was reduced compared to that of the
lithium salt (Table 1, entries 3–7). Methyl L-phenylalaninate was
also used as a catalyst; however, the starting material 2a was
recovered (Table 1, entry 8). From these results, it was found that
an amino acid lithium salt is necessary to progress the Michael
addition of 1a to 2a effectively. The lithium cation probably
behaves as a Lewis acid to aid the formation of enamine between
the catalyst and 1a, as shown in eqn (1).8 Although an attack of
an enolate of 1a can produce 3a, the enamine mechanism seems
to be preferable, since the use of a stronger base than the lithium
salt resulted in a slow reaction rate.2,5,9
(1)
Then, other readily obtainable amino acid lithium salts were
evaluated for the Michael addition reaction. Relatively bulky
amino acids, L-phenylalanine, L-valine, D-phenylglycine and L-
tert-leucine, gave 3a with over 90% ee (Table 1, entries 9–11).
A secondary amino acid, L-proline, and its lithium salt did not
show catalytic activity under the reaction conditions (Table 1,
entries 18 and 19). O-tert-Butyldimethylsilyl tyrosine lithium salt,
Tyr(O-TBS)-OLi, was very soluble in dichloromethane; however,
Division of Chemical Process Engineering, Graduate School of Engineering,
Hokkaido University, 8, Kita 13-jo Nishi, Kita-ku, 060-8628, Sapporo,
Japan. E-mail: myoshida@eng.hokudai.ac.jp; Fax: +81 11 706 6557;
Tel: +81 11 706 6557
† Electronic supplementary information (ESI) available: Compound char-
acterization data of the Michael adducts 3. See DOI: 10.1039/c003940c
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Table 1 Catalyst screen for the Michael addition of 1a to 2aa
or DMF, gave the Michael adduct 3a in low yields with low enan-
tioselectivity with many minor products, although nitroalkene 2a
was consumed very rapidly (Table 2, entries 1 and 2). In CH3CN,
acetone, AcOEt, THF and Et2O, the Michael adduct 3a was
afforded in high yields with moderate enantioselectivity (Table 2,
entries 3–7). When low-polarity solvents, CHCl3, CH2Cl2, 1,2-
dichloroethane and toluene, were used, better enantioselectivity
was observed than that with high-polarity solvents (over 90%
ee) (Table 2, entries 8–11). Hexane gave relatively poor results
due to the low solubility of 2a and the catalyst in the solvent
(Table 2, entry 12). Thus, CH2Cl2 was chosen as a solvent for
further investigations.
Entry
Catalystb
Yield c(%)
eed (%)
1
2
Phe-OH
Phe-OLi
n.r.
92
—
94
83
88
84
92
92
—
94
94e
93
80
88
87
84
78
67
—
—
94
3
4
Phe-ONa
Phe-OK
84
73
5
6
Phe-ORb
Phe-OCs
60
22
Next, we examined further optimization of the reaction condi-
tions for Michael addition of 1a to 2a with Phe–OLi in CH2Cl2
and found that the reaction was completed within 5 h at 25 ◦C
(Table 3, entry 1). Although a longer reaction time was required,
the amount of 1a could be reduced to 1.2 equivalents to 2a
without considerable loss of yield and enantioselectivity of the
product 3a (Table 3, entry 2). By carrying out the reaction at
7
8
9
Phe-OMgBr
Phe-OCH3
Val-OLi
11
n.r.
89
10
11
12
13
14
15
16
17
18
19
20
D-PhenylGly-OLi
tert-Leu-OLi
Leu-OLi
Ile-OLi
Ala-OLi
Trp-OLi
Met-OLi
Ser-OLi
Pro-OLi
92
80
93
95
70
90
91
32
0
◦C, the enantioselectivity was improved to 98% ee (Table 3,
entry 3). We then investigated the substrate scope of the reaction
Trace
n.r.
80
Pro-OH
Tyr(O-TBS)-OLi
Table 3 Michael addition of 1a with nitroalkenes 2a–p using
L-phenylalanine lithium salt as a catalysta
a The reaction was carried out with 1a (1 mmol), 2a (0.5 mmol) and
a catalyst (0.1 mmol) in dichloromethane (1 mL) at 25 ◦C for 14 h.
b Phe: L-phenylalanine; Val: L-valine; D-PhenylGly: D-2-phenylglycine;
Leu: L-leucine; Ile: L-isoleucine; Ala: L-alanine; Trp: L-tryptophane; Met:
L-methionine; Ser: L-serine; Pro: L-proline; Tyr: L-tyrosine. c Isolated
yield based on 2a. d Determined by chiral HPLC analysis. The absolute
configuration of the major enantiomer was determined as S by comparison
of the optical rotation with that of the literature.11 e (R)-3a was obtained
as a major enantiomer.
Entry
R
T/◦C
t/h
Yieldb (%)
eec (%)
1
Ph, 2a
25
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
0
25
25
25
25
5
92, 3a
85, 3a
82, 3a
88, 3b
92, 3b
86, 3c
81, 3c
89, 3d
86, 3d
82, 3e
83, 3e
87, 3f
72, 3f
94, 3g
94, 3g
91, 3h
87, 3h
91, 3i
71, 3i
95, 3j
96, 3j
76, 3k
78, 3k
89, 3l
57,e 3l
91, 3m
94
93
98
93
96
94
99
86
92
86
92
95
99
89
96
90
97
87
96
86
95
89
93
91
96
94
88
88
91
2d
3
Ph, 2a
10
72
6
72
4
72
5
72
5
72
5
72
5
72
5
72
5
72
5
72
7
72
8
72
16
Ph, 2a
4
5
6
7
8
9
4-CH3OC6H4, 2b
4-CH3OC6H4, 2b
4-BrC6H4, 2c
4-BrC6H4, 2c
3-BrC6H4, 2d
3-BrC6H4, 2d
2-BrC6H4, 2e
2-BrC6H4, 2e
4-FC6H4, 2f
no enhancement of the reaction rate and enantioselectivity was
observed (Table 1, entry 20).10
Next, we examined a solvent screen with Phe–OLi (Table 2). The
Michael addition of 1a with 2a in a high-polarity solvent, DMSO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Table 2 Solvent screen for the Michael addition of 1a to 2aa
4-FC6H4, 2f
4-(CO2CH3)C6H4, 2g
4-(CO2CH3)C6H4, 2g
4-NO2C6H4, 2h
4-NO2C6H4, 2h
Furan-2-yl, 2i
Furan-2-yl, 2i
Thiophen-2-yl, 2j
Thiophen-2-yl, 2j
3-Pyridyl, 2k
3-Pyridyl, 2k
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
DMSO
DMF
CH3CN
Acetone
AcOEt
THF
14
18
90
82
96
95
86
93
92
88
82
76
43
58
90
85
86
83
86
92
94
94
93
86
=
(E)-PhCH CH, 2l
=
(E)-PhCH CH, 2l
Et2O
=
(E)-C3H7CH CH, 2m
Cyclohexyl, 2n
PhCH2CH2, 2o
CH3, 2p
120 8,f 3n
CHCl3
CH2Cl2
(CH2Cl)2
Toluene
Hexane
120 41,g 3o
9
10
11
12
24
60, 3p
a Unless otherwise mentioned, the reaction was carried out with 1a
(1 mmol), 2 (0.5 mmol) and Phe-OLi (0.1 mmol) in CH2Cl2 (1 mL).
b Isolated yield based on 2. c Determined by chiral HPLC analysis. d The
amount of 1a was reduced to 1.2 equiv. e Conversion: 64%. f Conversion:
41%. g Conversion: 82%.
a The reaction was carried out with 1a (1 mmol), 2a (0.5 mmol) and Phe-
OLi (0.1 mmol) in a solvent (1 mL) at 25 ◦C for 14 h. b Isolated yield based
on 2a. c Determined by chiral HPLC analysis.
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Table 4 Michael addition of aldehydes 1b–f with 2a using
Mechanism
L-phenylalanine lithium salt as a catalysta
Plausible transition states for the Michael addition of 1a to 2a
are shown in Fig. 1. As shown in eqn (1), it is likely that Michael
addition proceeds via formation of an enamine from 1a and Phe–
OLi.2,5,9 The benzyl group of the enamine occupies the opposite
side of the isobutenyl group to avoid a steric hindrance; therefore,
the carboxylate group is fixed on one side of the enamine. Since
the absolute configuration of the C-3 stereocenter in the Michael
adduct 3a was determined as S, it is thought that the enamine
attacks the Re face of nitrostyrene 2a.4,5 According to the Seebach
and Golin´ski’s model for Michael addition of an enamine to
a nitroalkene,15 there is an electrostatic interaction between the
nitrogen atom of enamine and the nitro group; therefore, the
transition state of the reaction can be presented as TS-1 or TS-2.
If direction of the approach of the enamine to nitrostyrene 2a is
controlled by chelation of the nitro group with the lithium cation,
the Michael addition will proceed via TS-2. On the other hand, if
the enamine approaches nitrostyrene 2a to avoid a steric hindrance
and/or an electrostatic repulsion between the carboxylate group
and the nitro group, the Michael addition will proceed via TS-1.
In this model, the steric hindrance between the two methyl groups
of the enamine and the phenyl group of nitrostyrene 2a is smaller
than that of TS-2. Therefore, it is likely that the Michael addition
of 1a to 2a proceeds via TS-1.
Entry R1
R2
Yieldb (%) conv. (%) drc
eed (%)
10
1
2
3
4
5
CH3 Ph, 1b
84, 3q
60, 3r
59, 3s
61, 3t
100
92
71
72
65
2 : 1
3.5 : 1 22
CH3 C3H7, 1c
H
H
H
C3H7, 1d
PhCH2, 1e
(CH3)2CH, 1f 41, 3u
2 : 1
2 : 1
78
89
6.1 : 1 89e
a Unless otherwise mentioned, the reaction was carried out with1 (1 mmol),
2a (0.5 mmol) and Phe-OLi (0.1 mmol) in CH2Cl2 (1 mL) at 25 ◦C
for 48 h. b Isolated yield based on 2a. c Syn product was obtained as
a major diastereomer. The relative configuration was determined by 1H
NMR spectra. d Ee of the major diastereomer. Determined by chiral
HPLC analysis. e The absolute configuration of the major enantiomer was
determined as 2S,3R by comparison of the optical rotation with that of
the literature.5c,14
with 1a. Michael addition reactions with various b-nitrostyrene
derivatives, having an electron-donating group or an electron-
withdrawing group on the phenyl group, were completed within
4–6 h at 25 ◦C to provide the corresponding Michael adducts
3b–h in 82–94% yields with 86–95% ee (Table 3, entries 4–17). A
lowering of the reaction temperature to 0 ◦C increased the enan-
tioselectivity up to 99% ee. Heteroaromatic nitroalkenes, (E)-2-
(furan-2-yl)nitroethene (2i), (E)-2-(thiophen-2-yl)nitroethene (2j)
and (E)-2-(3-pyridyl)nitroethene (2k), also gave Michael adducts
in good yields (71–96%) with high enantioselectivity (86–96% ee)
(Table 3, entries 18–23). The Michael addition with conjugated
nitroalkadienes such as (E,E)-4-phenyl-1-nitrobuta-1,3-diene (2l)
and (E,E)-1-nitrohepta-1,3-diene (2m) afforded 1,4-adducts se-
lectively without the generation of 1,6-adducts (Table 3, entries
24–26).4g,5a,13 Unfortunately, Michael addition reactions using
aliphatic nitroalkenes such as (E)-2-cyclohexyl-1-nitroethene (2n)
and (E)-4-phenyl-1-nitrobut-1-ene (2o) were very slow, even at
25 ◦C, and gave the corresponding Michael adducts with many
minor by-products, although the enantioselectivity was high
(Table 3, entries 27 and 28). Since the reaction of a sterically
small substrate, (E)-1-nitroprop-1-ene (2p), was completed within
24 h to give the Michael adduct 3p in a good yield with high
enantioselectivity, it was found that the bulkiness of nitroalkenes
greatly affects the reaction rate (Table 3, entry 29).
Fig. 1 Plausible transition state for the Michael addition of 1a to 2a.
Next, various a-branched and unbranched aldehydes 1b–f were
employed as Michael donors for the reaction with 2a (Table 4).
Since Michael addition reactions were very slow at 0 ◦C, the
reactions were carried out at 25 ◦C. The use of asymmetric
a-branched aldehydes such as 2-phenylpropionaldehyde (1b)
and 2-methylvaleraldehyde (1c) led to low enantioselectivity,
although the corresponding Michael adducts, 3q and 3r, were
obtained in good yields with moderate syn-diastereoselectivity
(Table 4, entries 1 and 2). The Michael addition of a-unbranched
aldehydes, n-valeraldehyde (1d), hydrocinnamaldehyde (1e) and
isovaleraldehyde (1f), proceeded slowly to give the Michael
adducts 3s–u syn-selectively with high enantioselectivity (Table 4,
entries 3–5).
As for a transition state for the Michael addition of a-
unbranched aldehydes to nitroalkenes, TS-3 and TS-4 can be
chosen as candidates, since the absolute configuration of a major
enantiomer of the Michael adduct 3u, which was synthesized by
the reaction of 1f with 2a, was determined as 2S,3R (Fig. 2).
Generally, enamine-based Michael addition with nitroalkenes
gives a syn-diastereomer via the reaction of the thermodynam-
ically stable (E)-enamine with an (E)-nitroalkene, which can be
explained by an acyclic synclinal transition model proposed by
Seebach and Golin´ski (Scheme 1, a).4,5,15 Recently, Barbas’s group
succeeded in anti-selective Michael addition of aldehydes with
nitroalkenes by forming a (Z)-enamine using a primary amine
catalyst.16 They used a silyloxyacetaldehyde as a Michael donor
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Experimental
General
IR spectra were recorded using a JASCO FT/IR-410 spectro-
1
meter. H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded on a JEOL JNM-A400II or ECX-400P FT NMR.
Chemical shifts, d are referred to TMS. ESI high-resolution mass
spectra were measured on a JEOL JMS-T100GC or JMS-T100LC
spectrometer. Optical rotation was measured by a JASCO P-2200.
Melting points are measured by Yanagimoto micro melting point
apparatus and are uncorrected. HPLC was carried out using a
JASCO PU-2089 Plus intelligent pump and a UV-2075 Plus UV
detector.
Materials
Aldehydes were used after distillation. Nitroalkenes 2g,17a 2h,17a
2i,17b 2l,17c 2n,17d 2o17d and 2p17a,e were prepared according to the lit-
eratures. (E,E)-1-Nitrohepta-1,3-diene (2m) was prepared accord-
ing to the following procedure.17a,f (E)-4-Methoxy-b-nitrostyrene
(2b) was used after recrystallization. (E)-2-(3-Pyridyl)nitroethene
(2k) was used after purification by column chromatography.
Amino acid salts were prepared according to the literatures.6,7
Other materials were purchased from commercial suppliers and
were used without purification.
Fig. 2 Plausible transition state for the Michael addition of 1f to 2a.
Synthesis of (E,E)-1-nitrohepta-1,3-diene (2m)17a,f
In a round-bottomed flask, a mixture of nitromethane (40 mL)
and triethylamine (4.2 mL, 30 mmol) was added dropwise to a
solution of 2-hexenal (2.9 g, 30 mmol) in nitromethane (20 mL) at
0 ◦C. The reaction mixture was stirred for 10 h at 0 ◦C, then 20 h at
room temperature. Volatile organics were removed by evaporation
to give a crude product. (E)-1-Nitrohept-3-en-2-ol was isolated
by column chromatography (silica gel, hexane–EtOAc) in 47%
yield (2.23 g, 14 mmol). To a solution of (E)-1-nitro-3-hept-
3-en-2-ol (2.23 g, 14 mmol) and N,N-dimethylaminopyridine
(51 mg, 0.42 mmol) in CH2Cl2 (50 mL), trifluoroacetic anhydride
(2.1 mL, 15 mmol) was added at 0 ◦C. After the reaction
mixture was stirred for 5 h at room temperature, saturated
aqueous NaHCO3 was added and extracted with CH2Cl2. The
combined organic phase was washed with water, dried over MgSO4
and concentrated under reduced pressure. The obtained crude
(E)-1-nitro-2-trifluoroacetoxyhept-3-ene was dissolved in CH2Cl2
(50 mL), and N,N-dimethylaminopyridine (51 mg, 0.42 mmol)
was added to the solution at room temperature. After the reaction
mixture was stirred for over night at room temperature, saturated
aqueous NaHCO3 was added and extracted with CH2Cl2. The
combined organic phase was washed with water, dried over MgSO4
and concentrated under reduced pressure. (E,E)-1-Nitrohepta-
1,3-diene (2m) was isolated by column chromatography (silica gel,
hexane–EtOAc) in 50% yield (1.12 g, 7.02 mmol). dH(CDCl3) 0.94
(3H, t, J 7.2 Hz), 1.46–1.55 (2H, m), 2.21–2.26 (2H, m), 6.20 (1H,
dd, J 11.8, 14.9 Hz), 6.44 (1H, dt, J 7.2, 14.9 Hz), 7.07 (1H, d,
J 13.1 Hz), 7.59 (1H, dd, J 11.8, 13.1 Hz); dC(CDCl3) 13.5, 21.5,
35.3, 123.2, 137.3, 139.4, 151.2; n(neat)/cm-1 3104, 3031, 2962,
2930, 2873, 1723, 1697, 1641, 1609, 1512, 1464, 1339, 1229, 1202,
1167, 1042, 994, 961, 840, 739; [HR ESI-MS: Calc. for C7H11NO2
(M): 141.0790. Found: M+, 141.0788].
Scheme 1 (a) Seebach and Golin´ski model; (b) Barbas’s anti-selective
synthesis.
to promote generation of the thermodynamically unstable (Z)-
enamine by forming a hydrogen-bond between the oxygen atom
of the siloxy group and the hydrogen atom of the amino group
(Scheme 1, b). These studies suggest that the Michael addition of
1f to 2a proceeds via the transition state TS-4, since we obtained a
syn Michael product; however, we cannot rule out the possibility
that the reaction proceeds via the transition state TS-3 in the case
of considering a steric and/or an electrostatic repulsion of the
carboxylate group with the nitro group and a steric hindrance
between the isopropyl group of the enamine and the phenyl group
of nitrostyrene.
Conclusions
In conclusion, we revealed that an alkaline metal salt of a primary
amino acid, especially L-phenylalanine lithium salt, catalyzes the
Michael addition of aldehydes with nitroalkenes to produce g-
nitroaldehydes. The use of isobutyraldehyde as a Michael donor
led to good yields and high enantioselectivity of g-nitroaldehydes.
From asymmetric a-branched and unbranched aldehydes, the cor-
responding Michael adducts were obtained syn-selectively. Various
functionalized-aromatic and heteroaromatic nitroalkenes were
found to be good Michael acceptors for this reaction. Conjugated
nitroalkadienes also gave the corresponding Michael adducts in
good yields with high enantioselectivity without generation of 1,6-
adducts.
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General procedure for the Michael addition of aldehydes to
nitroalkenes
2,2,3-Trimethyl-4-nitrobutanal (3p)
The enantioselectivity was determined by HPLC analysis [91%
ee, DAICEL CHIRALCEL OD-H, 20% isopropanol–hexane,
1.0 mL min-1, 209 nm; tr(major enantiomer) = 10.5 min, tr(minor
enantiomer) = 8.4 min]. [a]2D6 = –20.0◦ (c = 1.0, CHCl3), colorless
oil, dH(CDCl3) 1.03 (3H, d, J 6.8 Hz), 1.09 (3H, s), 1.10 (3H, s),
2.65–2.71 (1H, m), 4.17 (1H, dd, J 10.2, 12.2 Hz), 4.44 (1H, dd, J
3.9, 12.2 Hz), 9.47 (1H, s); dC(CDCl3) 12.9, 18.7, 19.1, 36.5, 47.6,
78.3, 203.9; n(neat)/cm-1 2977, 2942, 2883, 2820, 2716, 1725, 1556,
1469, 1436, 1380, 1241, 1128, 1050, 885, 847, 778, 717.
In a 7 mL vial, isobutyraldehyde (1a) (72 mg, 1 mmol) was
added to a slurry of L-phenylalanine lithium salt (17.1 mg,
0.1 mmol), CH2Cl2 (1 mL) and methyl 4-[(E)-2-nitrovinyl]benzoate
(2g) (103.6 mg, 0.5 mmol) at 0 ◦C. After the reaction mixture
was stirred for 72 h at 0 ◦C, saturated aqueous NaCl (1.5 mL)
was added to the vial and extracted with Et2O (3 mL ¥ 3).
The combined organic phase was dried over MgSO4, filtered and
concentrated under reduced pressure. The Michael adduct, methyl
4-(3,3-dimethyl-1-nitro-4-oxobutan-2-yl)benzoate (3g), was iso-
lated by column chromatography (silica gel, hexane–Et2O) in
94% yield (131.3 mg) as white solid. The enantioselectivity was
determined by HPLC analysis [96% ee, DAICEL CHIRALPAK
AD-H, 20% isopropanol–hexanes, 1.0 mL min-1, 209 nm; tr(major
Acknowledgements
This work was partly supported by the Global COE Program
(Project No. B01: Catalysis as the Basis for Innovation in Materials
Science) from the Ministry of Education, Culture, Sports, Science
and technology, Japan.
enantiomer) = 13.5 min, tr(minor enantiomer) = 11.5 min]. [a]D26
=
+7.9◦ (c = 1.0, CHCl3), white solid, Mp. 88–89 ◦C, dH(CDCl3) 1.01
(3H, s), 1.14 (3H, s), 3.86 (1H, dd, J 4.1, 11.4 Hz), 3.92 (3H, s),
4.73 (1H, dd, J 4.1, 13.2 Hz), 4.89 (1H, dd, J 11.4, 13.2 Hz), 7.30
(2H, d, J 8.2 Hz), 8.01 (2H, d, J 8.2 Hz), 9.52 (1H, s); dC(CDCl3)
18.9, 21.8, 48.1, 48.2, 52.2, 75.9, 129.2, 129.9, 130.1, 140.7, 166.5,
203.6; n(neat)/cm-1 3101, 3060, 3031, 2975, 2952, 2816, 2723,
1723, 1611, 1553, 1436, 1378, 1284, 1192, 1112, 1020, 962, 900,
862, 797, 762, 710, 630; [HR ESI-MS: Calc. for C14H17NNaO5
(M+Na): 302.1004. Found: M++Na, 302.1007].
Notes and references
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2 For reviews on organocatalysis using a primary amines, see: (a) L.-W.
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1919.
Spectroscopic data of 3a–f,h–j,l,n,o,q–u are in agreement with
the published data and are presented in the Electronic Supple-
mentary Information.†
3 Review on asymmetric Michael additions to nitroalkenes: O. M. Berner,
L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 1877.
2,2-Dimethyl-4-nitro-3-(3-pyridyl)butanal (3k)
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The enantioselectivity was determined by HPLC analysis [93%
ee, DAICEL CHIRALPAK AD-H, 20% isopropanol–hexane,
1.0 mL min-1, 209 nm; tr(major enantiomer) = 11.1 min, tr(minor
enantiomer) = 13.0 min]. [a]2D3 = +9.9◦ (c = 1.0, CHCl3), orange
oil, dH(CDCl3) 1.05 (3H, s), 1.15 (3H, s), 3.82 (1H, dd, J 4.1,
11.4 Hz), 4.75 (1H, dd, J 4.1, 13.7 Hz), 4.88 (1H, dd, J 11.4,
13.7 Hz), 7.27–7.31 (1H, m), 7.57–7.60 (1H, m), 8.51–8.52 (1H,
m), 8.56–8.58 (1H, m), 9.51 (1H, s); dC(CDCl3) 18.9, 21.8, 46.0,
48.2, 75.7, 123.5, 131.4, 136.1, 149.6, 150.6, 203.4; n(neat)/cm-1
3420, 2975, 2934, 2872, 2822, 2722, 1725, 1555, 1469, 1430, 1379,
1186, 1027, 883, 822, 718; [HR ESI-MS: Calc. for C11H15N2O3
(M+H): 223.1083. Found: M++H, 223.1081].
(E)-2,2-Dimethyl-3-(nitromethyl)oct-4-enal (3m)
The enantioselectivity was determined by HPLC analysis [94%
ee, DAICEL CHIRALCEL OD-H, 20% isopropanol–hexane,
1.0 mL min-1, 209 nm; tr(major enantiomer) = 10.0 min, tr(minor
enantiomer) = 6.1 min]. [a]2D8 = –20.3◦ (c = 1.0, CHCl3), colorless
oil, dH(CDCl3) 0.86 (3H, t, J 7.3 Hz), 1.09 (6H, s), 1.31–1.41 (2H,
m), 1.98 (2H, dt, J 6.8, 7.3 Hz), 3.05 (1H, ddd, J 3.9, 9.8, 10.7 Hz),
4.30 (1H, dd, J 10.7, 11.7 Hz), 4.42 (1H, dd, J 3.9, 11.7 Hz),
5.26 (1H, dd, J 9.8, 15.1 Hz), 5.59 (1H, dt, J 6.8, 15.1 Hz), 9.47
(1H, s); dC(CDCl3) 13.4, 18.8, 20.5, 22.1, 34.5, 46.9, 47.3, 76.9,
123.2, 138.1, 204.0; n(neat)/cm-1 2963, 2931, 2873, 2714, 1728,
1556, 1466, 1436, 1380, 1339, 1202, 1056, 934, 887, 780, 718,
634.
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3036 | Org. Biomol. Chem., 2010, 8, 3031–3036
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