Highly efficient asymmetric Michael addition of aldehyde to nitroolefin using perhydroindolic acid as a chiral organocatalyst

Article abstract of DOI:10.1039/c2ob00003b

Perhydroindolic acids, the by-products obtained in the industrial production of a trandolapril intermediate, were used as chiral organocatalysts in asymmetric Michael addition reactions of aldehydes to nitroolefins. These proline-like catalysts are unique

Full text of DOI:10.1039/c2ob00003b

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PAPER
Highly efficient asymmetric Michael addition of aldehyde to nitroolefin using
perhydroindolic acid as a chiral organocatalyst†
Lina Zhao,a Jiefeng Shen,a Delong Liu,b Yangang Liub and Wanbin Zhang*a,b
Received 1st January 2012, Accepted 2nd February 2012
DOI: 10.1039/c2ob00003b
Perhydroindolic acids, the by-products obtained in the industrial production of a trandolapril intermediate,
were used as chiral organocatalysts in asymmetric Michael addition reactions of aldehydes to nitroolefins.
These proline-like catalysts are unique for their rigid bicyclic structure with two H atoms attached to the
bridgehead C atoms lying on the opposite side of the ring. They therefore showed high efficiency in
asymmetric Michael additions of aldehydes to nitroolefins. Under the optimal conditions, excellent
diastereo- and enantioselectivities (up to 99/1 dr and 98% ee) were obtained with high chemical yields for
a series of aldehydes and nitroolefins using only 5 mol% catalyst loading. The methodology features
easily available catalysts, high catalytic efficiency and environmentally green procedures.
acid 1a (Fig. 2), the key intermediate of ACE inhibitor trandola-
pril, could be obtained from large-scale industrial production.
Introduction
Asymmetric Michael additions as a practical and atom-economic
strategy to construct carbon–carbon bonds have drawn much
attention for decades.1 Specifically, the organocatalytic Michael
addition of an aldehyde to a nitroalkene is deemed to be one of
the most important reactions due to the crucial role of nitroalk-
anes in organic synthesis.1,2 In 2001, Barbas first reported the
asymmetric Michael addition, by using proline derivatives as cat-
alysts with up to 78% ee, however, when using L-proline and
trans-4-hydroxyl-L-proline only 25% ee was obtained (Fig. 1).3
After that, the amine-catalyzed Michael addition (named the
Barbas–Michael reaction),4 has been improved by Hayashi,5
Zhao,6 Chan,7 and Loh8 by using proline-like catalysts (mol-
ecules containing a proline moiety, Fig. 1). However, current
procedures retain several shortcomings, such as: the difficulty in
obtaining readily available catalysts, high catalytic loading
requirements and unsatisfactory results, and further modifications
of these proline-like catalysts had to be carried out for excellent
asymmetric catalytic results.2,3,5–7 The search for highly efficient
and easily available proline-like organocatalysts therefore
remains a worthwhile endeavor.
Furthermore, perhydroindolic acids 1b, 1c, 1d (Fig. 2), the by-
products of 1a, are discarded resulting in the waste of resources
and environmental pollution.10 However, these proline-like com-
pounds are unique for their rigid bicyclic structure with two H
atoms attached to the bridgehead C atoms lying on the opposite
side of the ring. We therefore envisage that they would be good
catalysts for asymmetric catalysis. Herein, we report a highly
efficient asymmetric Michael addition of aldehydes to nitroo-
lefins using perhydroindolic acid as a chiral organocatalyst.
Results and discussion
We first applied 1a–1d in Michael additions of aldehydes to
nitroalkenes to determine the effect of different configurations
of the catalyst used in the reaction. Thus, the reaction of
(E)-(2-nitrovinyl)benzene and n-butyraldehyde was carried out
in the presence of 20 mol% of catalyst loading at room
Recently, we have been committed to developing new and
easily available organocatalysts and applying them to various
asymmetric transformations.9 We found that perhydroindolic
aSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong
University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
E-mail: wanbin@sjtu.edu.cn; Fax: +86-21-5474-3265;
Tel: +86-21-5474-3265
bSchool of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan
Road, Shanghai 200240, P. R. China
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob00003b
Fig. 1 The proline-type catalysts.
2840 | Org. Biomol. Chem., 2012, 10, 2840–2846
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Table 2 Influence of additives for the Michael addition of aldehyde 4a
to nitroalkene 5a catalyzed by catalyst 1da
Fig. 2 Trandolapril intermediate 1a and its by-products 1b–1d.
Catalyst
loading
Entry [mol%]
Yield/
[%]b
syn/
eed
[%]
t [h]
Additive
antic
Table 1 Screening of catalysts 1a–1d for Michael additions of
aldehyde 4a to nitroalkene 5aa
1
2
3
10
10
10
7 d
5 d
7 d
—
TFA
59
43
45
93/7
91/9
93/7
85
92
86
Methane
sulfonamide
CH3CO2H
Benzoic acid
Et3N
DIPEA
DBU
TMEDA
DABCO
DMAP
Pyridine
Et3N
DIPEA
Et3N
4
5
6
7
8
9
10
11
12
13
14
15
16
10
10
10
10
10
10
10
10
10
5
7 d
5 d
3.5
3.5
3.5
3.5
12
16
7 d
7
59
68
97
95
95
98
95
93
72
93
97
94
90
93/7
92/8
95/5
94/6
92/8
96/4
95/5
94/6
93/7
87/13 95
93/7 95
89/11 95
83/17 92
89
91
94
95
94
93
91
92
86
Entry
Catalyst
t [h]
Yield [%]b
syn/antic
ee [%]d
1
2
3
4
1a
1b
1c
1d
72
72
72
72
trace
trace
93
—
—
91/9
92/8
—
—
−86
86
95
a Reactions were conducted with 0.2 mmol (E)-(2-nitrovinyl)benzene
and 2 mmol butaldehyde at room temperature in the presence of catalyst
with CH2Cl2 as a solvent. b Isolated yield. c Determined by 1H NMR
spectra of crude products. The relative and absolute configurations of
6aa were determined by comparison with the literature data.7
d Determined by chiral HPLC.
5
2
2
7
16
72
DIPEA
a Reactions were conducted with 0.2 mmol (E)-(2-nitrovinyl)benzene
and 2 mmol butaldehyde in the presence of catalyst with different
additives in CH2Cl2 at room temperature. b Isolated yield. c Determined
by 1H NMR spectra of crude products. The relative and absolute
configurations of 6aa were determined by comparison with the literature
data.7 d Determined by chiral HPLC.
moiety then tends to attack the double C–C bond of (E)-(2-nitro-
vinyl)benzene to afford the terminal molecule. Accordingly,
different catalysts result in different reaction results. With 1b as a
chiral catalyst, much larger steric repulsion will exist between
the a-H atom of the cyclohexyl moiety and phenyl group of the
activated (E)-(2-nitrovinyl)benzene (eqn (1)). The large steric
repulsion leads to a relatively long distance between the enamine
moiety and double bond of (E)-(2-nitrovinyl)benzene and thus
no reaction occurs. Alternatively, if 1d was used as a catalyst, the
e-H atom plus upward pointing C atom results in a short distance
between the enamine moiety and the double bond of (E)-
(2-nitrovinyl)benzene (eqn (2)). The reaction can therefore occur
readily.
Fig. 3 A proposed stereochemical pathway for 1b and 1d.
The catalyst loading was then decreased with 1d as a chiral
organocatalyst. No obvious influence was found on the diastereo-
and enantioselectivity, but only 59% yield was obtained even
after 7 days (Table 2, entry 1). Several bases and acids were
chosen as additives with the aim to improve the reaction activity.
As shown in Table 2, acidic additives had a slight effect on the
reaction (entries 2–5). Compared to acidic additives, many basic
additives (entries 5–12) dramatically shortened the reaction time
providing excellent yield (up to 97% yield within 3.5 h). It
appears that the basic conditions are in favour of the leaving of
(E)-(2-nitrovinyl)benzene, promoting reaction activity. Et3N and
DIPEA are somewhat better than others according to a combi-
nation of diastereo- and enantioselectivity, and they were used in
the following reactions.
temperature in CH2Cl2 (Table 1). However, the intermediate 1a
and its enantiomer 1b showed no reaction activity even after
72 h (entries 1 and 2). To our delight, their diastereoisomers, 1c
and 1d, resulted in a highly efficient reaction with excellent dia-
stereo- and enantioselectivity, affording syn-selective Barbas–
Michael reaction products (entries 3 and 4).11
The difference in reactivity between the utilized catalysts can
be explained by the proposed stereochemical pathway shown in
Fig. 3 with catalysts 1b and 1d. Originally, the n-butyraldehyde
reacts with 1b and 1d to afford a nucleophilic enamine inter-
mediate whilst the (E)-(2-nitrovinyl)benzene is directed toward
the carboxylic group by a hydrogen bond, which enhances the
electrophilic property of the nitroolefin.12 The formed enamine
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Table 3 Influence of solvents and temperature for the Michael addition
of aldehyde 4a to nitroalkene 5a catalyzed by catalyst 1da
Table 4 Exploration of aldehydes for Michael addition catalyzed by
catalyst 1ba
T [°C] t [h] Yield [%]b syn/antic ee [%]d
Entry
Product
R1
t [h]
Yield [%]b
syn/antic
ee [%]d
Entry Solvent
1
2
3
4
6aa
6ba
6ca
6da
Et
15
24
12
72
95
97
98
96
96/4
92/8
95/5
97/3
97
98
95
95
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
Toluene
DMF
THF
i-PrOH
DCM
20
20
20
20
20
20
0
−20
7
7
97
91
90
50
36
14
95
88
93/7
89/11
92/8
95
95
90
92
85
84
96
97
Me
n-Bu
i-Pr
30
16
7 d
7 d
15
72
93/7
87/13
82/18
96/4
a Reactions were conducted with 0.2 mmol (E)-(2-nitrovinyl)benzene
and 2 mmol propaldehyde in the presence of catalyst with DIPEA as an
additive in CH2Cl2 at 0 °C. b Isolated yield. c Determined by 1H NMR
spectra of crude products. The relative and absolute configurations of 6
were determined by comparison with the literature data.7 d Determined
by chiral HPLC.
DCM
93/7
a Reactions were conducted with 0.2 mmol (E)-(2-nitrovinyl)benzene
and 2 mmol butaldehyde in the presence of catalyst with DIPEA as an
additive in CH2Cl2 at suitable temperature. b Isolated yield. c Determined
by 1H NMR spectra of crude products. The relative and absolute
configurations of 6aa were determined by comparison with the literature
data.7 d Determined by chiral HPLC.
Table 5 Nitroolefins generality for Michael addition catalyzed by
catalyst 1ba
We wanted to further decrease catalyst loading since the high
reaction activity was obtained by using basic additives such as
Et3N and DIPEA in the presence of 10 mol% catalytic loading.
To our delight, when the above reaction was carried out in the
presence of 5 mol% 1d, almost no change was found in diaster-
eoselectivity and enantioselectivity with DIPEA as an additive,
albeit with a slight drop in reactivity (entries 13–14). However,
further decreasing the catalyst loading to 2 mol% resulted in
decreased diastereoselectivity and long reaction times (entries
15–16). Therefore 5 mol% catalytic loading was adopted in
further reactions.
We then investigated the influence of solvents on the reaction
and almost all reactions presented excellent catalytic results
(Table 3). High yield and excellent enantioselectivity were
obtained by using CH2Cl2, CH3CN and toluene (entries 1–3).
CH2Cl2 was the best solvent according to the reactions’ activity
and stereoselectivity. DMF also afforded high diastereoselectivity
and enantioselectivity, but only a moderate yield was obtained
(entry 4). i-PrOH and THF proved unsuitable for the reaction.
As shown in Table 3, reduced diastereo- and enantioselectivity
and yield were obtained even with long reaction times (entries
5–6).
Yield syn/
ee
Entry Product R1
R2
T [h] [%]b
antic [%]d
1
6ba
6bb
6bc
6bd
6be
6bf
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
Ph
4-ClPh
3-ClPh
4-FPh
4-CF3Ph
4-CH3OPh
3-CH3OPh
2-CH3OPh
2-CH3Ph
24
10
48
16
12
96
5d
96
7d
97
99
95
98
99
96
85
99
57
45
84
93
99
83
99
n.r.
98
94
92/8 98
91/9 97
94/6 95
92/8 97
87/13 96
94/6 96
93/7 96
97/3 96
93/7 97
91/9 96
92/8 95
89/11 96
86/14 96
87/13 94
65/35 95
2
3
4
5
6
7
8
9
6bg
6bh
6bi
10
11
12
13
14
15
16
17
18
6bj
6bk
6bl
6bm
6bn
6bo
6bp
6cb
6cc
3,4-(CH3O)2Ph 7d
1-Naphthyl
2-Naphthyl
2-Furyl
2-Thienyl
3-Pyridyl
Cyclohexyl
4-ClPh
96
72
72
5d
36
7d
90
7d
—
—
98/2 97
99/1 96
2-CH3OPh
Temperature had a little effect on the reaction, and excellent
enantioselectivity and diastereoselectivity were observed from
20 °C to −20 °C (entries 1, 7–8). 0 °C was somewhat better than
others and was adopted in following reactions.
a Reactions were conducted with 0.2 mmol (E)-(2-nitrovinyl)benzene
and 2 mmol propaldehyde in the presence of catalyst with DIPEA as an
additive in CH2Cl2 at 0 °C. b Isolated yield. c Determined by 1H NMR
spectra of crude products. The relative and absolute configurations of 6
were determined by comparison with the literature data.7,8,13
d Determined by chiral HPLC.
With the optimal reaction conditions in hand, we surveyed a
series of aldehydes (Table 4). Excellent catalytic behavior was
obtained when using linear aldehydes, such as n-butyraldehyde,
propaldehyde and hexaldehyde (entries 1–3). Propaldehyde with
decreased steric hindrance gave the best result. As for nonlinear
aldehydes, large steric hindrance resulted in lower reaction
activity and a 72 h reaction time was required for isovaleralde-
hyde though excellent stereo- and enantioselectivity was
obtained (entry 4). Unfortunately, no reaction occurred when
using α-branching aldehydes, such as cyclohexyl formaldehyde
and isobutyraldehyde, mainly due to their much larger steric
hindrance.
Finally, we examined several kinds of nitroolefins (Table 5).
In the case of aryl-substituted nitroolefins, high yields and excel-
lent diastereo- and enantioselectivity were observed for both
2842 | Org. Biomol. Chem., 2012, 10, 2840–2846
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electron-withdrawing and electron-donating substituted nitroalk-
enes (entries 1–9). However, the reaction activity decreased for
some electron-donating substituted nitroalkenes (entries 6–9).
The most obvious being the nitroalkene with di-methoxyl
groups, which gave only 45% yield of product even after 7 days.
However excellent diastereo- and enantioselectivity were also
obtained (entry 10). Replacement of the phenyl ring by a
naphthalene ring resulted in excellent dr and ee values being
obtained with high yields of products (entries 11–12). In
addition, this method also allowed the use of heteroaromatic
nitroolefins in excellent asymmetric catalytic behavior (entries
13–15). Unfortunately, no reaction occurred when using aliphatic
nitroalkenes with a cyclohexyl group (entry 16). It is obvious
that the present catalytic system is suitable for asymmetric
Michael additions of a series of aromatic nitroolefins.
mixture was stirred at 0 °C until the complete consumption of
nitroolefin (monitored by TLC). The solvent was then evaporated
and the residue was purified by flash column silica-gel chromato-
graphy (PE/EA = 8/1) to provide the corresponding Michael
adducts. Diastereoselectivities were measured by 1H NMR
analysis of the crude product directly. The enantiomeric excess
(ee) was determined by HPLC analysis of samples with different
fractions.15 The absolute configurations of the products were
determined by comparing with reported literature data.
(2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal (6aa).7 From alde-
hyde 4a and nitroolefin 5a at 0 °C according to the general pro-
1
cedure to give pale yellow oil. H NMR (400 MHz, CDCl3): δ
9.71 (d, J = 2.5 Hz, 1H), 7.38–7.14 (m, 5H), 4.75–4.58 (m, 2H),
3.83–3.74 (m, 1H), 2.72–2.63 (m, 1H), 1.55–1.45 (m, 2H), 0.83
(t, J = 7.5 Hz, 3H). HPLC conditions: The enantiomeric excess
was determined by HPLC (Chiralcel OD-H), Hex–i-PrOH 91 : 9,
UV 230 nm, 0.9 mL min−1, syn: tR = 32.96 min (major) and tR
= 24.73 min (minor).
Isobutyraldehyde with large steric hindrance was also adopted
to pursue higher diastereoselectivity. As we expected, up to 99/1
diastereoselectivity were also obtained with excellent enantios-
electivity (entries 17, 18). However, long reaction times were
needed for the reaction to go to completion.
(2R,3S)-2-Methyl-4-nitro-3-phenylbutanal (6ba).7 From alde-
hyde 4b and nitroolefin 5a at 0 °C according to the general pro-
1
cedure to give pale yellow oil. H NMR (400 MHz, CDCl3): δ
Conclusions
9.70 (d, J = 1.8 Hz, 1H), 7.37–7.12 (m, 5H), 4.83–4.75 (m, 1H),
4.72–4.64 (m, 1H), 3.86–3.74 (m, 1H), 2.85–2.70 (m,1H), 0.99
(d, J = 7.2 Hz, 3H). HPLC conditions: The enantiomeric excess
was determined by HPLC (Chiralcel OD-H), Hex–i-PrOH
90 : 10, UV 210 nm, 0.8 mL min−1, syn: tR = 48.66 min (major)
and tR = 31.92 min (minor).
In summary, we have successfully applied the by-products of a
trandolapril key intermediate in asymmetric Michael additions of
aldehydes to nitroolefins. These proline-like catalysts enjoy the
merits of easy availability and especially high catalytic efficiency
in asymmetric catalysis. As a result, they showed excellent dia-
stereo- and enantioselectivity (up to 99/1 dr and 98% ee)
together with high yields in the catalytic reactions. The method-
ology could also be expanded to a series of aldehydes and
nitroolefins with excellent asymmetric catalytic results using 1d
as a chiral organocatalyst. Encouraged by its excellent perform-
ance, a broader application is under investigation in our
laboratory.
(2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal (6ca).7 From alde-
hyde 4c and nitroolefin 5a at 0 °C according to the general pro-
1
cedure to give pale yellow oil. H NMR (400 MHz, CDCl3): δ
9.92 (d, J = 2.4 Hz, 1H), 7.38–7.25 (m, 3H), 7.21–7.15 (m, 2H),
4.70–4.63 (m, 1H), 4.61–4.53 (m, 1H), 3.94–3.85 (m, 1H),
2.80–2.74 (m, 1H), 1.77–1.66 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H),
0.88 (d, J = 7.0 Hz, 3H). HPLC conditions: The enantiomeric
excess was determined by HPLC (Chiralcel OD-H), Hex–i-
PrOH 95 : 5, UV 210 nm, 0.8 mL min−1, syn: tR = 27.20 min
(major) and tR = 25.67 min (minor).
Experimental section
General
(R)-2-((S)-2-Nitro-1-phenylethyl)hexanal (6da).7 From alde-
hyde 4e and nitroolefin 5a at 0 °C according to the general pro-
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Varian MERCURY plus-400 spectrometer with
TMS as an internal standard. HRMS was performed on Analysis
Center of Shanghai Jiao Tong University. The enantioselectivity
was measured by high performance liquid chromatography
(HPLC) using Daicel Chiralcel AD-H, OD-H, AS-H, OJ-H
and OZ-H columns with hexane/2-propyl alcohol as eluent.
Column chromatography was performed using 100–200 mesh
silica gel. All commercially available substrates were used
as received. Nitroolefins were prepared according to literature
procedures.2d,e,m,14
1
cedure to give pale yellow oil. H NMR (400 MHz, CDCl3): δ
9.70 (d, J = 2.7 Hz, 1H), 7.44–7.15 (m, 5H), 4.84–4.57 (m, 2H),
3.86–3.72 (m, 1H), 2.81–2.63 (m, 1H), 1.52–1.07 (m, 6H), 0.78
(t, J = 6.8 Hz, 3H). HPLC conditions: The enantiomeric excess
was determined by HPLC (Chiralcel OD-H), Hex–i-PrOH
90 : 10, UV 210 nm, 0.8 mL min−1, syn: tR = 28.48 min (major)
and tR = 21.13 min (minor).
(2R,3S)-3-(4-Chlorophenyl)-2-methyl-4-nitrobutanal (6bb).7 From
aldehyde 4b and nitroolefin 5b at 0 °C according to the general
1
procedure to give pale yellow oil. H NMR (400 MHz, CDCl3):
δ 9.69 (d, J = 1.5 Hz, 1H), 7.36–7.28 (m, 2H), 7.15–7.09 (m,
2H), 4.82–4.73 (m, 1H), 4.68–4.59 (m, 1H), 3.83–3.75 (m, 1H),
2.81–2.70 (m, 1H), 1.00 (d, J = 7.2 Hz, 3H). HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
AD-H), Hex–i-PrOH 97 : 3, UV 210 nm, 0.9 ml min−1, syn: tR =
24.16 min (major) and tR = 33.93 min (minor).
General procedure for the Michael addition
The catalyst 1d (1.69 mg, 0.01 mmol), DIPEA (1.75 μL,
0.01 mmol) and aldehyde (2 mmol) were dissolved in CH2Cl2
(1 mL) at 0 °C. The solution was stirred for 5 min, and then the
appropriate nitroolefin (0.2 mmol) was added. The reaction
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(2R,3S)-3-(3-Chlorophenyl)-2-methyl-4-nitrobutanal (6bc).13a
From aldehyde 4b and nitroolefin 5c at 0 °C according to the
1
general procedure to give pale yellow oil. H NMR (400 MHz,
CDCl3) δ 9.71 (d, J = 1.8 Hz, 1H), 7.31–7.23 (m, 1H), 7.07 (dd,
J = 7.5, 1.7 Hz, 1H), 6.96–6.83 (m, 2H), 4.90–4.81 (m, 1H),
4.77–4.70 (m, 1H), 4.10–3.96 (m, 1H), 3.83 (s, 3H), 3.09–2.91
(m, 1H), 0.93 (d, J = 7.3 Hz, 3H). HPLC conditions: The enan-
tiomeric excess was determined by HPLC (Chiralcel AS-H),
1
general procedure to give pale yellow oil. H NMR (400 MHz,
CDCl3) δ 9.69 (d, J = 1.5 Hz, 1H), 7.32–6.97 (m, 4H),
4.84–4.75 (m, 1H), 4.69–4.61 (m, 1H), 3.82–3.74 (m, 1H),
2.82–2.70 (m, 1H), 1.01 (d, J = 7.3 Hz, 3H). HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
OZ-H), Hex–i-PrOH 90 : 10, UV 210 nm, 0.8 mL min−1, syn: tR
= 35.05 min (major) and tR = 29.42 min (minor).
Hex–i-PrOH 98 : 2, UV 210 nm, 0.95 mL min−1, syn: tR
45.50 min (major) and tR = 43.61 min (minor).
=
(2R,3S)-2-Methyl-4-nitro-3-o-tolylbutanal (6bi).13c From alde-
hyde 4b and nitroolefin 5i at 0 °C according to the general pro-
(2R,3S)-3-(4-Fluorophenyl)-2-methyl-4-nitrobutanal (6bd).13b
From aldehyde 4b and nitroolefin 5d at 0 °C according to the
1
cedure to give pale yellow oil. H NMR (400 MHz, CDCl3): δ
1
general procedure to give pale yellow oil. H NMR (400 MHz,
9.72 (d, J = 2.0 Hz, 1H), 7.23–7.08 (m, 4H), 4.83–4.61 (m, 2H),
4.22–4.03 (m, 1H), 2.82–2.71 (m, 1H), 2.38 (s, 3H), 0.96 (d, J =
7.3 Hz, 3H). HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralcel AS-H), Hex–i-PrOH 95 : 5, UV
CDCl3): δ 9.70 (d, J = 1.5 Hz, 1H), 7.22–7.11 (m, 2H),
7.07–6.99 (m, 2H), 4.83–4.73 (m, 1H), 4.68–4.59 (dd, J = 12.7,
9.6 Hz, 1H), 3.85–3.75 (m, 1H), 2.84–2.66 (m, 1H), 1.00 (d, J =
7.4 Hz, 3H). HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralcel AD-H), Hex–i-PrOH 97 : 3, UV
210 nm, 0.9 mL min−1, syn: tR = 23.11 min (major) and tR
=
24.89 min (minor).
210 nm, 0.9 mL min−1, syn: tR = 22.99 min (major) and tR
=
(2R,3S)-3-(3,4-Dimethoxyphenyl)-2-methyl-4-nitrobutanal
(6bj). From aldehyde 4b and nitroolefin 5j at 0 °C according to
the general procedure to give pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ 9.70 (d, J = 1.9 Hz, 1H), 6.86–6.62 (m,
3H), 4.84–4.72 (m, 1H), 4.69–4.61 (m, 1H), 3.86 (s, 3H), 3.85
(s, 3H), 3.79–3.70 (m, 1H), 2.82–2.68 (m, 1H), 1.02 (d, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 202.6, 149.4, 148.9,
129.0, 120.3, 111.6, 111.3, 78.5, 56.1, 56.0, 48.8, 43.9, 12.3.
HPLC conditions: The enantiomeric excess was determined by
HPLC (Chiralcel OJ-H), Hex–i-PrOH 75 : 25, UV 210 nm,
0.6 mL min−1, syn: tR = 80.56 min (major) and tR = 122.64 min
(minor). HRMS (ESI-TOF) Calcd for C13H17NO5 [M − H]
266.1028, Found: 266.1040. IR (v/cm−1): 2968, 2937, 2888,
2839, 1722, 1592, 1552, 1518, 1463, 1381, 1263, 1145,
1026,980, 901, 810, 768.
30.86 min (minor).
(2R,3S)-2-Methyl-4-nitro-3-(4-(trifluoromethyl)phenyl)butanal
(6be).13d From aldehyde 4b and nitroolefin 5e at 0 °C according
to the general procedure to give pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ 9.70 (d, J = 1.4 Hz, 1H), 7.61 (d, J = 8.2
Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.87–4.79 (m, 1H), 4.75–4.65
(m, 1H), 3.96–3.84 (m, 1H), 2.90–2.75 (m, 1H), 1.00 (d, J = 7.4
Hz, 3H). HPLC conditions: The enantiomeric excess was deter-
mined by HPLC (Chiralcel AD-H), Hex–i-PrOH 90 : 10, UV
210 nm, 0.8 ml min−1, syn: tR = 11.83 min (major) and tR
15.00 min (minor).
=
(2R,3S)-3-(4-Methoxyphenyl)-2-methyl-4-nitrobutanal (6bf)7.
From aldehyde 4b and nitroolefin 5f at 0 °C according to the
1
general procedure to give pale yellow oil. H NMR (400 MHz,
CDCl3): δ 9.69 (d, J = 1.7 Hz, 1H), 7.17–6.97 (m, 2H),
6.95–6.77 (m, 2H), 4.82–4.70 (m, 1H), 4.67–4.58 (m, 1H), 3.77
(s, 3H), 3.76–3.71 (m, 1H), 2.81–2.63 (m, 1H), 0.98 (d, J = 7.3
Hz, 3H). HPLC conditions: The enantiomeric excess was deter-
mined by HPLC (Chiralcel AS-H), Hex–i-PrOH 85 : 15, UV
(2R,3S)-2-Methyl-3-(naphthalen-1-yl)-4-nitrobutanal (6bk)7.
From aldehyde 4b and nitroolefin 5k at 0 °C according to the
1
general procedure to give pale yellow oil. H NMR (400 MHz,
CDCl3): δ 9.76 (d, J = 1.8 Hz, 1H), 8.24–8.05 (m, 1H), 7.89 (d,
J = 8.0 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.63–7.33 (m, 4H),
5.00–4.82 (m, 3H), 3.10–2.92 (m, 1H), 0.99 (d, J = 7.3 Hz, 3H).
HPLC conditions: The enantiomeric excess was determined by
HPLC (Chiralcel AS-H), Hex–i-PrOH 90 : 10, UV 210 nm,
0.8 mL min−1, syn: tR = 37.14 min (major) and tR = 39.39 min
(minor).
210 nm, 0.8 mL min−1, syn: tR = 45.56 min (major) and tR
=
35.23 min (minor).
(2R,3S)-3-(3-Methoxyphenyl)-2-methyl-4-nitrobutanal (6bg).
From aldehyde 4b and nitroolefin 5g at 0 °C according to the
general procedure to give pale yellow oil. H NMR (400 MHz,
1
CDCl3): δ 9.69 (d, J = 1.6 Hz, 1H), 7.27–7.21 (m, 1H),
6.83–6.67 (m, 3H), 4.80–4.73 (m, 1H), 4.69–4.62 (m, 1H), 3.78
(s, 3H), 3.84–3.72 (m, 1H), 2.83–2.69 (m, 1H), 1.00 (d, J = 7.3
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 202.4, 160.1, 138.4,
130.3, 120.3, 114.6, 113.1, 78.2, 55.4, 48.6, 44.2, 12.3. HPLC
conditions: The enantiomeric excess was determined by HPLC
(Chiralcel OZ-H), Hex–i-PrOH 90 : 10, UV 210 nm, 0.8 mL
min−1, syn: tR = 40.98 min (major) and tR = 35.47 min (minor).
HRMS (ESI-TOF) Calcd for C12H15NO4 [M − H] 236.0923,
Found: 236.0938. IR (v/cm−1): 2970, 2939, 2888, 2839, 2729,
1724, 1601, 1552, 1491, 1456, 1382, 1263, 1161, 1045, 785,
702.
(2R,3S)-2-Methyl-3-(naphthalen-2-yl)-4-nitrobutanal (6bl).13a
From aldehyde 4b and nitroolefin 5l at 0 °C according to the
1
general procedure to give pale yellow oil. H NMR (400 MHz,
CDCl3): δ 9.75 (d, J = 1.6 Hz, 1H), 7.86–7.78 (m, 3H),
7.68–7.61 (m, 1H), 7.53–7.45 (m, 2H), 7.35–7.24 (m, 1H),
4.91–4.84 (m, 1H), 4.82–4.73 (m, 1H), 4.04–3.92 (m, 1H),
2.93–2.82 (m, 1H), 1.02 (d, J = 7.3 Hz, 3H). HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
AS-H), Hex–i-PrOH 90 : 10, UV 210 nm, 0.8 mL min−1, syn: tR
= 34.53 min (major) and tR = 41.53 min (minor).
(2R,3R)-3-(Furan-2-yl)-2-methyl-4-nitrobutanal (6bm).7 From
aldehyde 4b and nitroolefin 5m at 0 °C according to the general
1
(2R,3S)-3-(2-Methoxyphenyl)-2-methyl-4-nitrobutanal (6bh)7.
From aldehyde 4b and nitroolefin 5h at 0 °C according to the
procedure to give pale yellow oil. H NMR (400 MHz, CDCl3):
δ 9.70 (d, J = 1.0 Hz, 1H), 7.44–7.30 (m, 1H), 6.32–6.28 (m,
2844 | Org. Biomol. Chem., 2012, 10, 2840–2846
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1H), 6.21–6.16 (m, 1H), 4.78–4.66 (m, 2H), 4.13–4.03 (m, 1H),
2.87–2.75 (m, 1H), 1.06 (d, J = 7.3 Hz, 3H). HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
AS-H), Hex–i-PrOH 90 : 10, UV 210 nm, 0.8 mL min−1, syn: tR
= 24.77 min (major) and tR = 22.84 min (minor).
C14H19NO4 [M − H] 264.1236, Found: 264.1221. IR (v/cm−1):
2964, 2942, 2875, 2840, 2741, 1716, 1601, 1587, 1552, 1494,
1464, 1381, 1246, 1124, 1026, 756.
(6bn)7.
Acknowledgements
(2R,3R)-2-Methyl-4-nitro-3-(thiophen-2-yl)butanal
From aldehyde 4b and nitroolefin 5n at 0 °C according to the
general procedure to give pale yellow oil. H NMR (400 MHz,
This work was partly supported by the National Nature Science
Foundation of China (No. 20972095 and 21172145), Science
and Technology Commission of Shanghai Municipality (No.
10dz1910105), Nippon Chemical Industrial Co., Ltd and Instru-
mental Analysis Center of Shanghai Jiao Tong University. We
thank Prof. Tsuneo Imamoto and Dr Masashi Sugiya of Nippon
Chemical Industrial Co., Ltd for helpful discussion.
1
CDCl3): δ 9.68 (d, J = 1.2 Hz, 1H), 7.25–7.21 (m, 1H),
6.97–6.87 (m, 2H), 4.83–4.64 (m, 2H), 4.27–4.12 (m, 1H),
2.90–2.68 (m, 1H), 1.12 (d, J = 7.3 Hz, 3H). HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
OZ-H), Hex–i-PrOH 98 : 2, UV 230 nm, 0.95 mL min−1, syn: tR
= 84.95 min (major) and tR = 57.26 min (minor).
(2R,3S)-2-Methyl-4-nitro-3-(pyridin-3-yl)butanal (6bo). From
aldehyde 4b and nitroolefin 5o at 0 °C according to the general
procedure to give pale yellow oil. H NMR (400 MHz, CDCl3):
Notes and references
1
1 For selected reviews on asymmetric Michael additions, see: (a) N. Krause
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δ 9.68 (d, J = 1.4 Hz. 1H), 8.56–8.45 (m, 2H), 7.54–7.50 (m,
1H), 7.33–7.22 (m, 1H), 4.84–4.79 (m, 1H), 4.73–4.65 (m, 1H),
3.90–3.80 (m, 1H), 2.91–2.77 (m, 1H), 1.01 (d, J = 7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 201.7, 149.9, 149.7, 135.7,
132.8, 124.0, 77.6, 48.1, 41.7, 12.4. HPLC conditions: The
enantiomeric excess was determined by HPLC (Chiralcel
OZ-H), Hex–i-PrOH 75 : 25, UV 210 nm, 0.6 mL min−1, syn: tR
= 49.58 min (major) and tR = 61.62 min (minor). HRMS
(ESI-TOF) Calcd for C10H12N2O3 [M + H] 209.0926, Found:
209.0925. IR (v/cm−1): 3035, 2974, 2935, 2881, 2854, 2730,
1724, 1576, 1556, 1381, 1025, 814, 717.
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(2R,3S)-3-(4-Chlorophenyl)-2-isopropyl-4-nitrobutanal (6cb).
From aldehyde 4c and nitroolefin 5b at 0 °C according to the
1
general procedure to give white solid (78.2–80.0 °C). H NMR
(400 MHz, CDCl3): δ 9.90 (d, J = 2.2 Hz, 1H), 7.36–7.27 (m,
2H), 7.16–7.08 (m, 2H), 4.71–4.62 (m, 1H), 4.58–4.47 (m, 1H),
3.92–3.83 (m, 1H), 2.78–2.70 (m, 1H), 1.76–1.64 (m, 1H), 1.10
(d, J = 7.2 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ 204.2, 135.8, 134.2, 129.6, 129.5, 78.9,
58.7, 41.5, 28.1, 21.8, 17.1. HPLC conditions: The enantiomeric
excess was determined by HPLC (Chiralcel OJ-H), Hex–i-PrOH
85 : 15, UV 210 nm, 0.7 mL min−1, syn: tR = 28.95 min (major)
and tR = 26.76 min (minor). HRMS (ESI-TOF) Calcd for
C13H16ClNO3 [M − H] 268.0740, Found: 268.0728. IR (v/
cm−1): 3029, 2964, 2934, 2875, 2845, 2742, 1716, 1554, 1492,
1468, 1379, 1087, 1013, 831, 721.
(2R,3S)-2-Isopropyl-3-(2-methoxyphenyl)-4-nitrobutanal
(6cc). From aldehyde 4c and nitroolefin 5c at 0 °C according to
the general procedure to give pale yellow oil. 1H NMR
(400 MHz, CDCl3): δ 9.91 (d, J = 2.4 Hz, 1H), 7.30–7.23 (m,
1H), 7.11 (dd, J = 7.4, 1.7 Hz, 1H), 6.94–6.83 (m, 2H),
4.83–4.75 (m, 1H), 4.61–4.54 (m, 1H), 4.17–4.07 (m, 1H), 3.85
(s, 3H), 3.08–3.02 (m, 1H), 1.74–1.63 (m, 1H), 1.10 (d, J = 7.2
Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 205.1, 157.7, 130.9, 129.4, 124.8, 121.2, 111.4, 77.5, 57.1,
55.5, 39.4, 28.4, 21.9, 17.3. HPLC conditions: The enantiomeric
excess was determined by HPLC (Chiralcel OJ-H), Hex–i-PrOH
96 : 4, UV 210 nm, 0.8 mL min−1, syn: tR = 37.63 min (major)
and tR = 31.79 min (minor). HRMS (ESI-TOF) Calcd for
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