Novel chiral ammonium ionic liquids as efficient organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins

Article abstract of DOI:10.1016/j.tet.2010.05.030

Two chiral ammonium ionic liquids 1a and 1b have been newly synthesized from commercially available (+)-cis-2-benzamidocyclohexanecarboxylic acid. These CILs have been demonstrated to be efficient organocatalysts for asymmetric Michael addition of aldehyd

Full text of DOI:10.1016/j.tet.2010.05.030

Tetrahedron 66 (2010) 4970e4976
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Novel chiral ammonium ionic liquids as efficient organocatalysts for asymmetric
Michael addition of aldehydes to nitroolefins
,
b
Wan-Hui Wang a, Xiang-Bo Wang a, Koichi Kodama a, Takuji Hirose a , Guang-You Zhang
*
a School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama 338-8570, Japan
b School of Chemistry and Chemical Engineering, University of Jinan, 106 Jiwei Road, Jinan 250022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two chiral ammonium ionic liquids 1a and 1b have been newly synthesized from commercially available
(þ)-cis-2-benzamidocyclohexanecarboxylic acid. These CILs have been demonstrated to be efficient
organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins with excellent yields (up
to 99%), high enantioselectivities (up to 90%) and modest to high diastereoselectivities (syn/anti ratio
up to 99/1).
Received 1 March 2010
Received in revised form 8 May 2010
Accepted 10 May 2010
Available online 13 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chiral ammonium ionic liquid
Asymmetric Michael addition
1,3-Diamine
1. Introduction
materials such as amine,15e17 natural amino acids,18e21 and
carbohydrates22e24 have been developed (Fig.1). Chiral ammonium
Ionic liquids (ILs) have attracted increasing interest due to their
unique properties, such as non-volatility, high thermal stability,
low toxicity, and reusability. Ionic liquids, also called as room
temperature molten salt, entirely composed of cations and anions;
cations are typically imidazolium, pyridinium or ammonium
species, and anions usually include halogen anions, BFꢀ4 , PF6ꢀ, NTf2ꢀ.
By modifying the structures of the cations or anions of ILs, their
properties can be altered for desired applications. Based on the
tunable feature of ILs, diverse functionalized ionic liquids (FILs)
have been designed and synthesized by attachment of functional
groups onto the side chains of ILs.1 Recently, chiral ionic liquids
(CILs), as one kind of FILs, have been the focus of attention due to
their promising applications in chiral discrimination, asymmetric
synthesis and the optical resolution of racemates.2e8 However, only
a limited number of CILs have been synthesized and used as highly
efficient catalysts for asymmetric reactions up to now.
Imidazolium ionic liquids as the biggest class of ILs have been
widely researched.9 Unfortunately, the labile C2 proton limits its
use in organic reactions.10e13 In contrast, the saturated quaternary
ammonium ionic liquids are more resistant against oxidation and
reduction.14 Compared to the extensive work on the chiral imida-
zolium ILs, chiral ammonium ILs have been explored far less. Only
few chiral ammonium ILs derived from chiral pool starting
ILs have been successfully used as stationary phases in gas
OH
COOH
R
H
R
N
Ph
H3N
A
A
I: R = CH3, A = NTf2
IV: A = BF4, PF6, NTf2
II
: R = C8H17, A = OTf
III: R = Pyridin-3-ylmethyl, A = Cl
Bn
H
O
O
N
N
Bu
CO2H
O
N
N
H
O
H
Bn
NTf2
2A
V:
VI
A = BF4, PF6, OTf, NTf2
Figure 1. Known chiral ammonium ILs.
chromatography and high-performance liquid chromatography for
the resolution of racemic compounds.25,26 However, successful
application of chiral ammonium ILs for asymmetric synthesis has
been rarely reported. Ephedrine-based chiral ammonium IL I has
been used as ‘chiral induction solvent’ for the enantioselective
photoisomerization with poor enantioselective induction (up to
12% ee).27 Vo-Thanh group has reported a series of application of
ephedrine-based ammonium ILs as chiral solvents for asymmetric
* Corresponding author. Tel./fax: þ81 48 858 3522; e-mail address: hirose@apc.
saitama-u.ac.jp (T. Hirose).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.030

W.-H. Wang et al. / Tetrahedron 66 (2010) 4970e4976
4971
synthesis.28e30 The Morita/Baylis/Hillman reaction of benzalde-
2. Results and discussion
hyde and methyl acrylate promoted by CIL II afforded the coupling
product with up to 44% ee28 The asymmetric aza-Diels/Alder re-
action of chiral imines with Danishefsky’s diene in CIL II provided
the corresponding cycloadducts with moderate diastereoselectivity
(up to 72% de).29 Most recently, they reported the Michael reaction
of diethyl-2-acetamidomalonate and enones using CIL III as chiral
reaction media, giving moderate enantioselectivity (up to 70%
ee).30 Lombardo et al. have applied proline-derived chiral ammo-
nium IL VI as a catalyst in asymmetric aldol reaction successfully,
providing moderate diastereoselectivities (anti/syn ratio up to 80/
20) and high enantioselectivities (up to 94% ee).31 It is worth noting
that Ni et al. have recently developed an efficient catalytic system
with ammonium-based pyrrolidine organocatalyst for the asym-
metric Michael addition on water.32 Although the catalyst itself is
not isolated as an ammonium ionic liquid, the aqueous solution of
the ammonium-based organocatalyst can be easily recovered and
reused for at least six times. The development of eco-friendly, re-
cyclable and highly efficient chiral ammonium IL for asymmetric
synthesis is still a challenging research field.
2.1. Synthesis of chiral ionic liquids
Scheme 1 shows the synthesis of pyrrolidine-based chiral am-
monium ILs 1a and 1b. (þ)-cis-2-Benzamidocyclohexane-carbox-
ylic acid 2 was activated with ethyl chloroformate and then reacted
with dimethylamine to afford the corresponding cis-diamide 3 in
97% overall yield. Subsequent reduction and debenzylation led to
cis-1,3-diamine 5. The coupling reaction between N-Cbz-L-proline
and 5 in the presence of DCC/DMAP yielded amide 6. After qua-
ternization with ethyl iodide or n-butyl iodide and anion exchange
with NTfꢀ2 , Cbz-protected IL 7 was obtained with up to 85% overall
yield. Deprotection of IL 7 with H2 and Pd/C gave the desired CILs 1a
and 1b. Both of the CILs are viscous liquids at room temperature
and soluble in polar solvent, such as alcohols, dichloromethane and
THF, but immiscible in non-polar solvents, such as diethyl ether and
n-hexane.
2.2. Optimization of the reaction conditions
The asymmetric Michael addition reaction of nitroolefins with
aldehydes is an important method for the synthesis of versatile
Michael addition of propanal to trans-b-nitrostyrene was chosen
g-nitrocarbonyl compounds, which are useful building blocks since
as a model reaction to determine the optimal conditions for CILs 1a
and 1b. Initially, the solvent effect has been investigated and the
representative results are presented in Table 1. It was found that the
nature of the solvent has an important influence on the outcomes
of this reaction. When highly polar solvents such as MeOH and IPA
were used, high yields were obtained (90e92%), while IPA led to
higher enantioselectivity (entries 1 and 2). Lower enantiomeric
excess (46% ee) was observed in acetonitrile (entry 3). Although the
reaction in dichloromethane (DCM) and 1,4-dioxane has shown
higher selectivity, the reaction was retarded and resulted in com-
paratively lower yields (entries 5 and 7). A mixed solvent of DCM/
THF (1:1, v/v) improved the diastereoisomeric ratio slightly to 72/
28 (entry 8). Finally, THF was identified as the best solvent for CIL 1a
as it gave high yield (96%) and comparatively high ee (84% ee, entry
6). After the screening of solvent for CIL 1a, three kinds of solvents
(IPA, THF, and DCM) were selected for examination of CIL 1b.
Among these solvents, DCM was proved to be the most efficient
solvent since the excellent yield (95%), good diastereoselectivity
(78/22 dr), and high ee (89%) were obtained (entry 11). The acidic
additive could promote the formation of the enamine intermediate,
and thereby, improve both the reactivity and stereoselectivity.32 It
has been proved to be important to Michael addition catalyzed by
the nitro group can be readily converted into a variety of functional
groups including amines, nitrile oxides.33e35 More recently, the
development of chiral IL organocatalysts for asymmetric Michael
reaction with high stereoselectivity has received widespread
attention.36 The pyrrolidine structure is regarded as one of the
‘privileged’ backbones for asymmetric conjugate addition.37 The
pyrrolidine-based chiral imidazolium ILs37e40 and pyridinium ILs41
have been proved to be efficient catalysts for asymmetric Michael
addition.
Our group has focused on the investigation of asymmetric
catalysis using the derivatives of commercially available (þ)-cis-
2-benzamidocyclohexanecarboxylic acid 2, such as chiral 1,3-
aminoalcohols.42,43 As an extension of our work, we designed
and synthesized a class of novel chiral ammonium ILs, which
consist of a 1,3-diamine derived from acid 2 and a chiral pyrrolidine
unit. The pyrrolidine group can serve as a catalytic site, and the
1,3-diamine-derived ammonium IL can act as both a phase tag
and a chirality inducing group. Herein, we report the synthesis of
novel chiral ammonium ILs and their application for asymmetric
Michael additions of aldehydes to nitroolefins as efficient
organocatalysts.
CON(CH3)2
NHCOPh
CH2N(CH3)2
NHCH2Ph
COOH
a
b
NHCOPh
90%
97%
2
3
4
O
O
c
d
e
N
N
HN
N
HN
N
Cbz
Cbz
NH2
81%
85%
98%
N
R
NTf2
5
6
7
O
f
N
HN
N
1a R = Et
1b
H
R = n-Bu
91%
R
NTf2
Scheme 1. Synthesis of chiral ionic liquids. Reaction conditions: (a) (1) ClCO2Et, Et3N, 0 ꢁC-rt; (2) 50% Me2NH Solution, rt. (b) LiAlH4, dry THF, 0 ꢁC-reflux. (c) Pd/C, H2, EtOH, 70 ꢁC.
(d) N-Cbz-L-proline, DCC, DMAP, dry THF. (e) (1) RI, toluene, 90 ꢁC. (2) LiNTf2, CH3CN/H2O. (f) Pd/C, H2, EtOH, 40 ꢁC.

4972
W.-H. Wang et al. / Tetrahedron 66 (2010) 4970e4976
pyrrolidine-based organocatalyst.39,44 The effect of other additives
was also examined using CIL 1b in DCM. The reaction without an
additive or with a weak acid proceeded slowly and gave lower
stereoselectivity (entries 12 and 13). Although TsOH could provide
comparable diastereomeric ratio and ee, the reactivity dropped
significantly, probably due to protonation of pyrrolidine nitrogen
(entry 14).45
and trans-b-nitrostyrene are summarized in Table 3. The reaction
of linear aldehydes proceeded smoothly with reaction time
ranged from 12 to 36 h, and gave excellent yields (95e99%),
moderate to high diastereoselectivities (67/33e90/10 dr) and
enantioselectivities (72e88% ee, entries 1e6, 9, and 10). Although
the reaction of branched i-valeraldehyde required longer reaction
time, high diastereoselectivities (97/3e99/1 dr) and good enan-
tioselectivities (77e82% ee) were obtained (entries 7 and 8). Also,
it was observed that the enantioselectivity decreased slightly
with the increase of carbon chain length of aldehydes, for either
CIL 1a or 1b was used.
Table 1
Screening of solvent and additive in the Michael addition catalyzed by CILs 1a
and 1ba
O
Ph
O
20 mol% CIL
Ph
+
NO2
NO2
Table 3
H
H
Michael addition of aldehydes to trans-
b
-nitrostyrenea
O
Ph
O
CIL
Entry CIL Additive
Solvent
Yieldb (%) drc (syn/anti) eed (%) syn (anti)
Ph
+
NO2
NO2
H
H
1
2
3
4
5
6
1a TFA
1a TFA
1a TFA
1a TFA
1a TFA
1a TFA
1a TFA
1a TFA
1b TFA
1b TFA
1b TFA
MeOH
IPA
CH3CN
AcOEt
Dioxane 81
THF
DCM
DCM/THF 93
IPA
THF
92
90
90
94
65/35
66/34
63/37
68/32
64/36
68/32
64/36
72/28
74/26
81/19
78/22
66/34
77/23
82/18
63 (64)
79 (83)
46 (52)
77 (81)
84 (89)
84 (81)
90 (91)
81 (81)
78 (82)
84 (84)
89 (89)
52 (62)
73 (75)
89 (88)
5 mol% TFA
R
R
Entry
R
CIL T (h) Yieldb (%) drc (syn/anti) eed (%) syn (anti) Pr.
1
2
3
4
5
6
7
8
9
10
Me
1a
1b 12
1a 12
1b 12
n-Pr 1a 24
1b 24
1a 60
1b 60
n-Bu 1a 36
1b 36
12
95
95
96
99
96
98
37
84
97
99
68/32
77/23
82/18
89/11
80/20
87/13
97/3
99/1
73/27
90/10
84 (81)
88 (89)
76 (75)
87 (82)
75 (71)
81 (78)
77
82
72 (73)
80 (77)
8a
8b
8c
8d
8e
96
85
7
Et
8e
9
97
95
95
52
66
70
10
11
12
13
14
DCM
DCM
DCM
i-Pr
1b
d
1b AcOH
1b TsOH$H2O DCM
a
The reaction was conducted with
b-nitrostyrene (0.1 mmol), aldehyde
a
The reaction was conducted with
b-nitrostyrene (0.1 mmol), aldehyde
(0.6 mmol), and CIL 1a (20 mol %) in 1 mL of THF or CIL 1b (15 mol %) in 1 mL of DCM
(0.6 mmol), and CIL (20 mol %) in 1 mL of solvent at rt for 12 h.
b
Isolated yield.
at rt.
c
Determined by 1H NMR.
b
Isolated yield.
d
Determined by chiral HPLC.
The ratio of DCM to THF was 1/1.
Determined by 1H NMR.
c
e
d
Determined by chiral HPLC.
Furthermore, the catalyst loading of CILs 1a and 1b was tested
and the results are presented in Table 2. With increasing the cata-
lyst loading, the yield (84e96%), diastereoselectivity (66/34e71/29
dr) and enantioselectivity (82e86% ee) were enhanced slightly
(entries 1e5 and 7e9). It is worth noting that no improvement of
enantioselectivity (81% ee) and diastereoselectivity (67/33 dr) was
observed when the reaction was conducted at 0 ꢁC (entry 6).
Finally, the preferred catalyst loading of 15 mol % and 20 mol % was
chosen for CIL 1b and 1a, respectively.
The reactions of substituted trans-b-nitroolefins and propanal
have been studied and the results are listed in Table 4 (entries
1e10). The reaction of propanal with various substituted trans-
-nitroolefins gave the desired Michael products in excellent yields
b
(up to 99%), modest diastereoselectivities (up to 77/23 dr) and high
enantioselectivities (up to 90% ee, entries 1e8). The substituents on
the aromatic ring of nitroolefins have almost no influence on the
enantioselectivity of the corresponding adducts and show an effect
on the reaction rate and diastereoselectivity. The reaction of
nitroolefins bearing an electron donating group Me or MeO took
long reaction time and gave higher diastereomeric ratio. On the
other hand, nitroolefin with an electron withdrawing group reacted
faster but gave lower diastereoselectivity (entries 1e6 vs entries 7
and 8). The reaction of (E)-2-(2-nitrovinyl)thiophene proceeded
smoothly (entries 9 and 10) in high yields (93e97%), modest dia-
tereoselectivities (61/39e68/32 dr) and high enantioselectivities
(up to 88% ee).
Table 2
Catalyst loading of the Michael addition catalyzed by CILs 1a and 1ba
Entry CIL (mol %) Solvent Yieldb (%) drc (syn/anti) eed (%) syn (anti)
1
2
3
4
5
6e
7
8
9
1a (10)
1a (15)
1a (20)
1a (25)
1a (30)
1a (20)
1b (15)
1b (20)
1b (25)
THF
THF
THF
THF
THF
THF
DCM
DCM
DCM
84
91
96
96
96
73
95
95
98
66/34
65/35
68/32
68/32
71/29
67/33
77/23
78/22
80/20
82 (84)
83 (84)
84 (81)
83 (83)
86 (90)
81 (82)
88 (89)
89 (89)
90 (89)
As seen in Table 4 (entries 1e10), CIL 1b exhibited higher
catalytic activity and stereoselectivity than CIL 1a for the Michael
addition of aldehydes to trans-b-nitroolefins. Thus, using CIL 1b,
the reactions of n-valeraldehyde and substituted nitroolefins have
been further studied (entries 11e14). The substrate of n-valer-
aldehyde gave higher diastereoselectivities (up to 90/10 dr) and
a little lower enantioselectivities (up to 82% ee), compared to
propanal (entries 2, 4, 6, and 8 vs entries 11e14). Moreover, it was
found that high ees for both syn- (73e90% ee) and anti-di-
astereomers (75e89% ee) were obtained, albeit with only mod-
erate diastereomeric ratios. In addition, the enantiomeric excess of
the major syn-isomer is noticeably higher than that under in-
fluence of pyrrolidine-derived imidazolium ionic liquids reported
by Headley et al.39
a
The reaction was conducted with
b-nitrostyrene (0.1 mmol), aldehyde
(0.6 mmol), CIL, and TFA (5 mol %) in 1 mL of solvent at rt for 12 h.
b
Isolated yield.
c
Determined by 1H NMR.
d
Determined by chiral HPLC.
The reaction was conducted at 0 ꢁC for 36 h.
e
2.3. Scope of substrate
The scope of substrate was explored under the optimized
conditions. The results of Michael addition between aldehydes

W.-H. Wang et al. / Tetrahedron 66 (2010) 4970e4976
4973
Table 4
a coupling constant of 9.1 Hz. On the other hand, it was difficult to
determine the orientation of H2 due to the severely overlapped
signal. To form the common chair conformation, we supposed that
H2 should be equatorial and the ammonium methylene group tend
to be axial. Therefore, we suspected that the CILs take the confor-
mation as shown in Figure 2. Furthermore, this conformation was
proved to be more stable than the ring-flipped conformer by
theoretical calculation using the PM3 method.
Michael addition of aldehydes to substituted trans-
b
-nitroolefinsa
Ar
O
O
CIL
5 mol% TFA
Ar
+
NO2
NO2
H
H
R
R
Entry
R
Ar
CIL Time Yieldb drc
eed (%)
Product
(h)
(%)
(syn/anti) syn (anti)
1
2
3
4
5
6
7
8
Me 4-MeOC6H4 1a 36
1b 36
87
96
91
99
86
87
93
95
93
97
94
97
85
96
74/26
73/27
73/27
73/27
75/25
77/23
62/38
65/35
61/39
68/32
86/14
82/18
90/10
78/22
82 (85)
86 (86)
83
8f
8g
8h
8i
Me 4-MeC6H4
Me 2-MeC6H4
Me 4-BrC6H4
Me 2-Thienyl
1a 36
1b 36
1a 36
1b 36
1a 17
1b 17
1a 17
1b 17
J
aa = 9.1 Hz
89
J
ae = 5.2 Hz
82 (81)
90 (88)
85
H1
H6e
H2
88
H6a NH
NTf2
N
9
84 (86)
88 (89)
80 (75)
82 (84)
79 (80)
73 (76)
8j
O
R2
10
11
12
13
14
R1
n-Pr 4-MeOC6H4 1b 36
8k
8l
8m
8n
n-Pr 4-MeC6H4
n-Pr 2-MeC6H4
n-Pr 4-BrC6H4
1b 36
1b 36
1b 24
Figure 2. The stable conformation of the CILs.
a
The reaction was conducted with
b-nitroolefin (0.1 mmol), aldehyde
Based on the experimental results, conformational analysis of
CIL 1b and the previously reported speculations on the stereo-
chemical outcome,35,46 we proposed that CIL-catalyzed Michael
additions predominantly occur via the enamine pathway as shown
in Figure 3. The bulky IL group and the hydrogen bonding between
the amide NH and the nitro group of nitroolefin are considered to
be important to the high catalytic activity and the stereoselectivity.
In addition, the possible ionic attraction between ammonium
cation and nitro group of the substrate should also contribute to
stabilization of the intermediate. The enamine tends to attack from
the less hindered Si face of the nitroolefin. Consequently, (2R, 3S)
configuration of the corresponding adduct is generated preferen-
tially (Fig. 3A). The flexible butyl side chain of ammonium group
may cause moderate repulsive interaction with an aryl group of
nitroolefin (Fig. 3B). The moderate diastereoselectivity of the re-
action could be rationalized by considering this weak interaction.
(0.6 mmol), and CIL 1a (20 mol %) in 1 mL of THF or CIL 1b (15 mol %) in 1 mL of DCM
at rt.
b
Isolated yield.
c
Determined by 1H NMR.
d
Determined by chiral HPLC.
2.4. Recycling studies of the CILs
The reaction of trans-b-nitrostyrene and propanal under the
optimized reaction conditions was chosen to test the recyclability
of CIL catalysts 1a and 1b. After the reaction was completed, the
reaction mixture was concentrated and the residue was extracted
three times with a mixed solvent of n-hexane/ether (2:1, v/v).
Removal of the solvent and purification by TLC gave the Michael
adduct. The precipitated CIL from the mixed solvent was dried
under vacuum and reused for the next run directly. As shown in
Table 5, the CIL catalysts could be efficiently reused only once.
Although the catalytic activities decreased at the third run, the
enantioselectivities were almost kept constant. This result is similar
to the data reported by Lombardo et al.31
H
H
NTf2
O
N
N
O
Ar
N
O
H
O
NO2
Table 5
H
N
3S
2R
Recycling studies of CILs 1a and 1b catalyzed Michael addition of propanal to trans-
R
b
-nitrostyrene under the optimized reaction conditions
A
R
Run
CIL
T (h)
Yielda (%)
drb (syn/anti)
eec (%) syn (anti)
Ar
H
1
2
3
1a
1a
1a
12
18
48
95
91
74
68/32
67/33
69/31
84 (81)
80 (80)
79 (79)
H
N
NTf2
N
O
H
O
O
Ar
1
2
3
1b
1b
1b
12
18
48
95
93
86
77/23
73/27
68/32
88 (89)
85 (84)
86 (87)
O
NO2
N
H
3R
N
2R
R
R
B
a
Ar
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC.
b
c
Figure 3. Proposed transition state of CIL 1b catalyzed Michael addition.
2.5. Mechanism of the reaction
3. Conclusion
In order to speculate the stable conformation of the catalytic
intermediate, we first studied CIL 1b by NMR spectroscopy. In the
1H NMR spectrum, the signal of proton H1 (Fig. 2) was a double
doublet with coupling constants of 9.1 and 5.2 Hz. Its HeH COSY
spectrum indicated that H1 only has a weak coupling to proton H2,
but is strongly coupled to two vicinal protons, H6a and H6e. The
large coupling constant (9.1 Hz) suggested that H1 should be axial.
It was further confirmed by spin decoupling measurement. By ir-
radiating H6e, the proton signal of H1 turned to be a doublet with
Two novel chiral ammonium ionic liquids 1a and 1b have been
synthesized from ‘chiral pool’ starting materials. Chiral ammonium
IL 1b bearing a longer butyl group was found to be superior to CIL
1a in catalyzing Michael addition of a range of aldehydes and
nitroolefins. Despite the difficulty of recycling, these CILs were
proved to be efficient catalysts for the asymmetric Michael addition
of aldehydes to nitrostyrenes in excellent yield, high enantiose-
lectivity and modest to high diastereoselectivity. This study will be
helpful to design and synthesize new type of chiral ammonium

4974
W.-H. Wang et al. / Tetrahedron 66 (2010) 4970e4976
ionic liquids for asymmetric catalysis. Further application of CIL 1a
and 1b in other catalytic enantioselective reactions is currently in
progress.
(20 mL) was stirred under hydrogen atmosphere at 70 ꢁC for 12 h.
After completion of the reaction, the catalyst was removed by
filtration through a Celite pad, which was then washed with 10 mL
of EtOH. The combined filtrate was concentrated, and dried in
20
4. Experimental
4.1. General
vacuo to afford 5 (1.07 g, 98%). [
a
]
ꢀ8.1 (c 1.0, MeOH); IR (neat):
D
3368, 3292, 2928, 1574, 1383, 1042 cmꢀ1
CDCl3)
: 5.98 (br, 2H), 3.48e3.32 (m, 1H), 2.75 (t, J¼10.4 Hz, 1H),
2.26 (s, 6H), 2.12e2.07 (m, 2H), 1.91 (br, 1H), 1.70e1.67 (m, 2H),
;
1H NMR (400 MHz,
d
All 1H NMR and 13C NMR spectra were recorded on Bruker DRX
400 (400 MHz) or Bruker DPX 400 (400 MHz) spectrometers
(Comprehensive Analysis Center for Science [CACS], Saitama
University). Chemical shifts of 1H and 13C were given in parts per
million relative to tetramethylsilane (TMS) as an internal standard.
The coupling constant J was given in hertz. IR spectra were recorded
on JASCO FT/IR 400. Enantiomeric excess determination was carried
out using a JASCO LC 900 series HPLC consisting of a CD detector.
Optical rotations were measured with a JASCO DIP-370 polarimeter.
Electrospray ionization (ESI) mass measurements were performed
on a Mariner (Perseptive Biosystems) mass spectrometer and
a NanoFrontier eLD mass spectrometer (CACS). All commercially
available substrates were used as received. All reactions unless
otherwise noted were carried out directly under air. Nitroolefins
were prepared according to the literature procedures.47
1.46e1.36 (m, 5H); 13C NMR (100 MHz, CDCl3)
d: 61.14, 51.21, 45.88,
34.18, 29.23, 27.16, 23.06, 22.30; HRMS (ESIþ) m/z calcd for
[C9H21N2]þ: 157.1699, found: 157.1718.
4.2.4. Synthesis of amide (6). To a stirred solution of DCC (0.48 g,
2.32 mmol), DMAP (0.02 g, 0.19 mmol), and N-Cbz-L-proline
(0.48 g, 1.94 mmol) in dry THF (15 mL) was added THF (5 mL) so-
lution of 5 (0.33 g, 2.13 mmol) at 0 ꢁC under N2 atmosphere. After
stirring for 30 min, the reaction mixture was warmed up to room
temperature and stirred for 36 h. The precipitate was filtered off
and washed with THF. After concentrating the combined filtrate,
1 N HCl (10 mL) was added to the residue and washed with CHCl3
(5 mLꢂ3). To the aqueous layer, saturated aqueous Na2CO3 was
added until pH 9 was achieved and the mixture was extracted with
CHCl3 (10 mLꢂ3), washed with brine (5 mLꢂ3), dried over anhy-
drous Na2SO4, and then the solvent was removed under reduced
pressure. The residue was purified by silica gel column chroma-
4.2. General procedures for the preparation of chiral ionic
liquids 1a and 1b
tography (CHCl3/MeOH¼5/1) to afford 6 (0.61 g, 81%) as a colorless
20
oil. [
a]
ꢀ58.1 (c 5.04, CHCl3); 1H NMR (400 MHz, CDCl3)
d: 9.34
D
4.2.1. N-((1R,2S)-2-(Dimethylcarbamoyl)cyclo-hexyl)benzamide
(3). To a solution of (þ)-cis-2-benzamidocyclohexanecarboxylic
acid 2 (4.95 g, 20 mmol) and triethylamine (2.23 g, 22 mmol) in dry
THF (20 mL), ethyl chloroformate (2.39 g, 22 mmol) was added
dropwise at 0 ꢁC. After stirring for 1 h, 50% aqueous solution of
dimethylamine (5.41 g, 60 mmol) was added and the mixture was
stirred for 48 h at room temperature. After diluting by CHCl3
(20 mL), the mixture was washed with 1 M HCl (10 mLꢂ3), satu-
rated NaHCO3 solution (10 mLꢂ3), and then water (10 mLꢂ3). The
organic phase was dried over anhydrous Na2SO4 and evaporated
(br, 1H), 7.35e7.31 (m, 5H), 5.20 (d, J¼12.3 Hz, 1H), 5.06 (d,
J¼12.1 Hz, 1H), 4.34e4.29 (br, 1H), 3.97e3.84 (m, 1H), 3.49 (br, 2H),
2.90e2.84 (m, 1H), 2.13 (s, 6H), 2.01e1.71 (m, 7H), 1.58e1.36 (m,
6H), 1.15e1.12 (m, 1H); 13C NMR (100 MHz, CDCl3)
d: 171.63, 154.93,
136.43, 128.36, 128.07, 127.99, 127.93, 66.89, 61.25, 60.96, 58.44,
51.50, 47.37, 45.61, 32.52, 31.21, 30.13, 26.96, 24.81, 23.43, 20.69,
18.43; IR (neat): 3328, 3209, 3033, 1708, 1662, 1528, 1258, 1115,
1030 cmꢀ1; HRMS (ESIþ) m/z calcd for [C22H33N3O3Naþ]: 410.2414,
found: 410.2474.
under vacuum to give 3 (5.33 g, 97%). [
a
]
20 ꢀ44.3 (c 2.01, CHCl3); IR
4.2.5. Synthesis of 7a and 7b. Ethyl iodide (0.57 g, 3.60 mmol) was
added to a stirred solution of 6 (0.47 g, 1.20 mmol) in toluene, and
stirred at 90 ꢁC for 24 h. After reaction mixture was concentrated
under reduced pressure, the residue was washed with 1,1,1-tri-
chloroethane (5 mLꢂ2), and then dried under vacuum to afford
white solid, which was used for the next step directly. After adding
a mixed solvent of CH3CN/H2O (1:1, v/v, 2 mL) and LiNTf2 (0.36 g,
1.27 mmol), the mixture was stirred for 48 h and concentrated. To
the residue, DCM was added, and then washed with H2O
(10 mLꢂ3), dried over anhydrous Na2SO4, concentrated to give 7a
D
(neat): 3423, 3028, 2928, 1650, 1520, 1260 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
: 7.78 (d, J¼8.0 Hz, 2H), 7.49e7.40 (m, 3H), 7.10
(br, 1H), 4.27 (m, 1H), 3.11e3.08 (m, 1H), 3.05 (s, 3H), 2.91 (s, 3H),
2.45e2.43 (m, 1H), 1.65e1.59 (m, 4H), 1.48e1.45 (m, 2H); 13C NMR
(100 MHz, CDCl3) d: 173.84, 166.90, 134.82, 131.30,128.52, 127.03,
47.62, 40.90, 37.48, 35.61, 29.25, 26.04, 22.99, 22.56; HRMS (ESIþ)
m/z calcd for [C16H22N2O2Na]þ: 297.1574, found: 297.1557.
4.2.2. (1R,2R)-N-Benzyl-2-((dimethylamino)methyl)-cyclohexan-
amine (4). To a suspension of LiAlH4 (1.06 g, 27.93 mmol) in dry
THF (15 mL) was added a solution of 3 (1.53 g, 5.58 mmol) in THF
(5 mL) slowly at 0 ꢁC. After refluxing for 36 h, the reaction was
quenched by cautious addition of saturated aqueous solution of
Na2SO4 (10 mL) and 10% aqueous NaOH solution (5 mL) and the
mixture was filtered through Celite. The filtrate was dried over
anhydrous Na2SO4 and concentrated, and then purified by silica gel
(0.68 g, 81%). [
a]
20 ꢀ6.31 (c 1.60, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d
: 7.36e7.31 (m, 5H), 6.83 (d, J¼7.6 Hz, 1H), 5.14e5.05 (m, 1H), 4.23
(br, 1H), 3.60e3.1 (m, 2H), 3.42e3.29 (m, 3H), 2.93 (s, 6H),
2.81e2.74 (m, 2H), 2.23 (br, 1H), 2.15e1.93 (m, 4H), 1.66e1.49 (m,
8H), 1.29 (m, 4H); 13C NMR (100 MHz, CDCl3)
d: 172.84, 155.40,
136.78, 128.55, 128.01, 127.30, 121.37, 118.18, 66.79, 65.82, 60.85,
60.54, 50.01, 49.67, 48.41, 47.11, 34.23, 29.64, 29.11, 28.43, 24.64,
23.29, 21.29, 8.17; IR (neat): 3379, 1697, 1678, 1534, 1196, 1135,
1057 cmꢀ1; HRMS (ESIþ) m/z calcd for [C24H38N3O3]þ:416.2908,
found: 416.2914.
column chromatography (CHCl3/MeOH¼5/1) to afford 4 (1.24 g,
20
90%) as a colorless liquid. [
a
]
ꢀ5.88 (c 0.18, CHCl3); IR (neat):
D
3334, 3026, 2926,1455,1261,1029 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 7.36e7.23 (m, 5H), 3.82 (d, J¼13.1 Hz, 1H), 3.72 (d, J¼13.1 Hz, 1H),
Compound 7b was prepared by a similar method as described
20
2.82e2.80 (br,1H), 2.34e2.22 (m, 2H), 2.20 (s, 6H),1.80 (br,1H),1.69
above in a yield of 85%. [
a
]
ꢀ8.57 (c 1.01, CHCl3); 1H NMR
D
(br, 1H), 1.57e1.48 (m, 2H), 1.39e1.30 (m, 5H); 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
: 7.38e7.31 (m, 5H), 6.86 (d, J¼8.4 Hz, 1H), 5.10
CDCl3)
d
: 141.58, 128.40, 128.24, 126.81, 60.94, 55.68, 51.71, 46.35,
(dd, J1¼16.8 Hz, J2¼12.0 Hz, 2H), 4.24 (br, 1H), 4.16 (br, 1H),
3.39e3.64 (m, 2H), 3.17e3.15 (m, 1H), 2.95 (d, J¼12.8 Hz, 6H),
2.89e2.76 (m, 1H), 2.23 (br, 1H), 2.15e2.11 (m, 2H), 1.97e1.89 (m,
2H), 1.60e1.49 (m, 8H), 1.39e1.25 (m, 4H), 0.97 (t, J¼7.2 Hz, 3H); 13C
37.80, 29.15, 26.83, 24.19, 22.39; HRMS (ESIþ) m/z calcd for
[C16H27N2]þ: 247.2169, found: 247.2145.
4.2.3. (1R,2R)-2-((Dimethylamino)methyl)cyclo-hexanamine (5). A
mixture of 4 (1.72 g, 6.98 mmol) and 10% Pd/C (0.09 g) in EtOH
NMR (100 MHz, CDCl3) d: 172.80, 155.48, 136.75, 128.58, 128.06,
127.42, 121.42, 118.23, 66.88, 66.23, 65.69, 60.55, 50.53, 50.33,

W.-H. Wang et al. / Tetrahedron 66 (2010) 4970e4976
4975
48.50, 47.15, 34.30, 29.58, 29.14, 28.48, 24.57, 21.33, 19.51, 13.52; IR
(neat): 3381, 1697, 1534, 1196, 1136, 1058 cmꢀ1; HRMS (ESIþ) m/z
calcd for [C26H42N3O3]þ:444.3221, found: 444.3231.
Chiralpak OD-H, i-PrOH/hexane¼20/80,
l
¼254 nm, flow rate
0.8 mL/min), syn-isomer: tminor 18.4 min and tmajor 22.4 min; anti-
isomer: tminor 19.8 min and tmajor 35.2 min.
4.2.6. Synthesis of CIL 1a and 1b. A mixture of 7a (0.57 g,
0.82 mmol) and 10% Pd/C (56.9 mg) in EtOH (8 mL) was stirred
under hydrogen atmosphere at 40 ꢁC for 12 h. The catalyst was
filtered off and washed with EtOH (3 mLꢂ3). The combined filtrate
was concentrated and purified by alumina column chromatography
4.3.3. (R)-2-((S)-2-Nitro-1-phenylethyl)pentanal
NMR (400 MHz, CDCl3)
(8c)34,49,50 1H
.
: 9.76 (d, J¼2.4 Hz, 1H), 7.36e7.29 (m, 3H),
d
7.18e7.16 (m, 2H), 4.72e4.62 (m, 2H), 3.80e3.75 (m, 1H), 2.72e2.68
(m, 1H), 1.50e1.47 (m, 1H), 1.37e1.34 (m, 2H), 1.20e1.17 (m, 1H),
0.80 (t, J¼6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 203.26, 136.71,
(CHCl3/MeOH¼30/1 to 10/1) to give CIL 1a (0.38 g, 83%). [
a
]
20 ꢀ20.3
129.12, 127.97, 78.42, 53.78, 43.11, 29.46, 19.75, 13.95. HPLC (Daicel
D
(c 0.34, CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
: 8.16 (d, J¼6.4 Hz, 1H),
Chiralpak OD-H, i-PrOH/hexane¼10/90,
l
¼254 nm, flow rate
4.15e4.12(m, 1H), 3.66 (dd, J1¼9.2 Hz, J2¼5.2 Hz, 1H), 3.34e3.24 (m,
2H), 3.17 (dd, J1¼13.6 Hz, J2¼4.4 Hz, 1H), 3.02e2.99 (m, 1H), 2.96 (s,
6H), 2.88e2.80 (m, 2H), 2.28 (br, 1H), 2.18e2.04 (m, 1H), 1.97e1.95
(m,1H),1.81e1.58 (m, 8H),1.48e1.39 (m, 2H),1.31e1.27 (m, 4H); 13C
1.0 mL/min), syn-isomer: tminor 21.0 min and tmajor 29.5 min; anti-
isomer: tminor 25.8 min and tmajor 46.2 min.
4.3.4. (2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal
NMR (400 MHz, CDCl3)
(8d)34,51 1H
.
NMR (100 MHz, CD3CN)
d
: 175.62, 121.51, 118.33, 66.28, 60.69,
d
: 9.93 (d, J¼2.0 Hz, 1H), 7.37e7.29 (m, 3H),
50.04, 49.42, 47.05, 46.95, 34.64, 30.62, 29.94, 27.98, 26.02, 24.33,
20.14, 7.60; IR (neat): 3371, 3307, 1659, 1514, 1227, 1197, 1138,
1057 cmꢀ1; HRMS (ESIþ) m/z calcd for [C16H32N3O]þ: 282.2540,
found: 282.2542; HRMS (ESIꢀ) m/z calcd for [N(SO2CF3)2]ꢀ:
279.9178, found: 279.9187.
7.20e7.18 (m, 2H), 4.69e4.54 (m, 2H), 3.93e3.87 (m, 1H), 2.78 (d,
J¼10.8 Hz, 1H), 1.75e1.69 (m, 1H), 1.10 (d, J¼7.2 Hz, 3H), 0.88 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 204.46, 137.03, 129.18,
128.12, 127.97, 79.03, 58.71, 41.91, 27.94, 21.70, 16.96. HPLC (Daicel
Chiralpak AD-H, i-PrOH/hexane¼2/98, ¼254 nm, flow rate 0.5 mL/
l
CIL 1b was prepared by a similar method as described above in
min), syn-isomer: tminor 34.1 min and tmajor 28.5 min.
a yield of 91%. [
a
]
20 ꢀ14.2 (c 1.13, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d
: 8.22 (d, J¼8.9 Hz, 1H), 4.19 (d, J¼4.9 Hz, 1H), 3.75 (dd, J1¼9.1 Hz,
4.3.5. (R)-2-((S)-2-Nitro-1-phenylethyl)hexanal (8e)33,49 1H NMR
.
J2¼5.2 Hz, 1H), 3.38e3.19 (m, 3H), 3.09 (d, J¼4.4 Hz, 6H), 3.06e3.04
(m, 1H), 2.96e2.88 (m, 2H), 2.27e2.09 (m, 2H), 1.91(br, 1H),
1.86e1.59 (m, 10H), 1.57e1.25 (m, 5H), 0.99 (t, J¼7.3 Hz, 3H); 13C
(400 MHz, CDCl3)
d
: 9.71 (d, J¼2.8 Hz, 1H), 7.35e7.29 (m, 3H),
7.18e7.16 (m, 2H), 4.79e4.64 (m, 2H), 3.80e3.77 (m, 1H), 1.55e1.14
(m, 6H), 0.78 (t, J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 203.37,
NMR (100 MHz, CDCl3)
d
: 176.56, 121.56, 118.36, 67.23, 66.08, 60.79,
136.81, 129.13, 128.24, 128.17, 128.01, 78.44, 53.91, 43.16, 28.55,
51.10, 50.01, 47.51, 35.74, 31.31, 28.29, 26.55, 24.74, 20.39, 19.59,
13.61; IR (neat): 3372, 3307, 1659, 1513, 1226, 1195, 1138,
1057 cmꢀ1; HRMS (ESIþ) m/z calcd for [C18H36N3O]þ: 310.2853,
found: 310.2857; HRMS (ESIꢀ) m/z calcd for [N(SO2CF3)2]ꢀ:
279.9178, found: 279.9182. Anal. Calcd for C20H36N4F6O5S2: C,
40.67; H, 6.14; N, 9.49; found: C, 40.87; H, 6.27; N, 9.30.
27.05, 22.49, 13.65. HPLC (Daicel Chiralpak OD-H, i-PrOH/
hexane¼10/90, ¼254 nm, flow rate 1.0 mL/min), syn-isomer: tminor
l
18.8 min and tmajor 24.4 min; anti-isomer: tminor 21.1 min and tmajor
37.4 min.
4.3.6. (2R,3S)-3-(4-Methoxyphenyl)-2-methyl-4-nitrobutanal
(8f)52,53 1H NMR (400 MHz, CDCl3)
. d: 9.71 (s, 1H), 7.13e7.07 (m,
4.3. General procedures for the asymmetric Michael addition
reaction
2H), 6.87e6.85 (m, 2H), 4.79e4.61 (m, 2H), 3.79 (s, 3H), 2.79e2.71
(m, 1H), 1.01 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 202.51,
159.25, 129.18, 129.12, 128.26, 114.47, 114.43, 78.35, 55.26, 48.74,
To a stirred solution of catalyst 1b (0.015 mmol) in DCM (1 mL),
44.30, 12.08. HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane¼10/90,
aldehyde (0.6 mmol), TFA solution of DCM (38
m
L, 0.015 mg/
mL,
l
¼254 nm, flow rate 1.0 mL/min), syn-isomer: tminor 34.4 min and
5 mol %), and nitroolefin (0.1 mmol) were added at room temper-
ature. The reaction mixture was stirred for an appropriate time by
monitoring on TLC. After completion of the reaction, the solvent
was removed and the residue was extracted with diethyl ether
(2 mLꢂ3) and purified by preparative TLC (n-hexane/ethyl
acetate¼4/1) to give the Michael adduct as a colorless oil. The rel-
ative (syn) and absolute configuration of most products have been
determined by comparison with the known 1H NMR data and HPLC
data. The relative (syn) and absolute configurations of 8h and 8m
have been accordingly tentatively assigned.
tmajor 38.6 min; anti-isomer: tminor 41.8 min and tmajor 46.9 min.
4.3.7. (2R,3S)-2-Methyl-3-(4-methylphenyl)-4-nitrobutanal
(8g)52
.
1H NMR (400 MHz, CDCl3)
d:
9.71 (d, 1H, J¼1.6 Hz),
7.15e7.03 (m, 4H), 4.79e4.63 (m, 2H), 3.80e3.74 (m, 1H), 2.78e2.73
(m, 1H), 2.32 (s, 3H), 1.00 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d: 202.69, 138.10, 133.81, 129.96, 129.90, 128.05, 78.37, 48.85,
43.85, 21.20, 12.22. HPLC (Daicel Chiralpak OD-H, i-PrOH/
hexane¼8/92, ¼254 nm, flow rate 0.5 mL/min), syn-isomer: tminor
l
54.7 min and tmajor 72.2 min; anti-isomer: tminor 91.1 min and tmajor
95.1 min.
4.3.1. (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal (8a)34,48
.
1H NMR
(400 MHz, CDCl3)
d
: 9.72 (d, J¼1.6 Hz, 1H), 7.36e7.15 (m, 5H),
4.3.8. (2R,3S)-2-Methyl-3-(2-methylphenyl)-4-nitrobutanal (8h). 1H
4.82e4.66 (m, 2H), 3.84e3.80 (m, 1H), 2.81e2.76 (m, 1H), 1.01 (d,
NMR (400 MHz, CDCl3)
d
: 9.73 (d, 1H, J¼1.2 Hz), 7.18e7.09 (m,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 202.42, 136.81, 129.12,
4H), 4.82e4.63 (m, 2H), 4.23e4.08 (m, 1H), 2.84e2.73 (m, 1H),
129.09, 128.16, 128.14, 128.06, 78.11, 48.42, 44.00, 12.15. HPLC
2.40 (s, 3H), 0.97 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d:
(Daicel Chiralpak OD-H, i-PrOH/hexane¼20/80,
l¼254 nm, flow
202.56, 137.11, 135.61, 131.38, 127.82, 126.84, 125.91, 78.12, 49.29,
rate 1.0 mL/min), syn-isomer: tminor 18.8 min and tmajor 27.1 min;
anti-isomer: tminor 23.7 min and tmajor 32.3 min.
39.00, 19.90, 12.27. HPLC (Daicel Chiralpak OD-H, i-PrOH/
hexane¼20/80,
l
¼254 nm, flow rate 0.8 mL/min), syn-isomer:
tminor 20.2 min and tmajor 23.7 min; anti-isomer: tminor 28.8 min
and tmajor 38.1 min.
4.3.2. (2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal (8b)34,48
.
1H NMR
(400 MHz, CDCl3)
d
: 9.72 (d, J¼2.4 Hz, 1H), 7.36e7.28 (m, 3H),
7.19e7.17 (m, 2H), 4.80e4.60 (m, 2H), 3.82e3.76 (m, 1H), 2.70e2.67
(m, 1H), 1.74e1.65 (m, 1H), 1.53e1.49 (m, 1H), 0.83 (t, J¼7.6 Hz, 3H);
4.3.9. (2R,3S)-3-(4-Bromophenyl)-2-methyl-4-nitrobutanal
(8i)34,53 1H NMR (400 MHz, CDCl3)
. d: 9.70 (s, 1H), 7.49e7.46 (m,
13C NMR (100 MHz, CDCl3)
d
: 203.25, 136.75, 129.15, 129.13, 128.24,
2H), 7.11e7.05 (m, 2H), 4.82e4.62 (m, 2H), 3.81e3.77 (m, 1H),
128.17, 128.01, 78.58, 54.98, 42.66, 20.37, 11.53. HPLC (Daicel
2.81e2.73 (m,1H),1.01 (d, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)

4976
W.-H. Wang et al. / Tetrahedron 66 (2010) 4970e4976
d: 201.92, 135.95, 132.27, 129.84, 122.20, 77.83, 48.61, 43.46, 12.23.
References and notes
HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane¼8/92,
l
¼230 nm,
1. Miao, W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897e908.
2. Bica, K.; Gaertner, P. Eur. J. Org. Chem. 2008, 3235e3250.
3. Patil, M. L.; Sasai, H. Chem. Rec. 2008, 8, 98e108.
flow rate 0.8 mL/min), syn-isomer: tminor 50.7 min and tmajor
57.3 min; anti-isomer: tminor 65.8 min and tmajor 68.6 min.
4. Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont, A.-C.; Plaquevent,
J.-C. Tetrahedron: Asymmetry 2003, 14, 3081e3093.
4.3.10. (2R,3S)-2-Methyl-4-nitro-3-(thien-2-yl)-butanal (8j)52,53
.
1H
5. Headley, A. D.; Ni, B. Aldrichimica Acta 2007, 40, 107e117.
NMR (400 MHz, CDCl3) : 9.70 (s, 1H), 7.26e7.24 (m, 2H), 6.97e6.90
d
ꢀ
ꢀ
ꢀ
6. Toma, S.; Meciarová, M.; Sebesta, R. Eur. J. Org. Chem. 2009, 321e327.
7. Luo, S.; Zhang, L.; Cheng, J.-P. Chem.dAsian J. 2009, 4, 1184e1195.
8. Ni, B.; Headley, A. D. Chem.dEur. J. 2010, 16, 4426e4436.
9. Jodry, J. J.; Mikami, K. Tetrahedron Lett. 2004, 45, 4429e4431.
10. Aggarwal, V. K.; Emme, I.; Mereu, A. Chem. Commun. 2002, 1612e1613.
11. Ebner, G.; Schiehser, S.; Potthast, A.; Rosenau, T. Tetrahedron Lett. 2008, 49,
7322e7324.
(m, 2H), 4.80e4.69 (m, 2H), 4.27e4.17 (m, 1H), 2.86e2.75 (m, 1H),
1.14 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 202.04, 139.16,
127.19, 126.82, 125.45, 78.41, 48.98, 40.09, 11.81. HPLC (Daicel
Chiralpak OD-H, i-PrOH/hexane¼10/90,
l
¼254 nm, flow rate
0.7 mL/min), syn-isomer: tminor 44.4 min and tmajor 51.2 min; anti-
isomer: tminor 47.9 min and tmajor 54.7 min.
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4.3.11. (R)-2-((S)-1-(4-Methoxyphenyl)-2-nitroethyl)pentanal
€
(8k)33,54,55
.
1H NMR (400 MHz, CDCl3)
d
: 9.70 (d, J¼2.8 Hz, 1H),
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7.09e7.07 (m, 2H), 6.88e6.83 (m, 2H), 4.69e4.56 (m, 2H), 3.79 (s,
3H), 3.75e3.63 (m, 1H), 2.67e2.64 (m, 1H), 1.49e1.55 (m, 4H), 0.81
(t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 203.43, 159.21,
129.01, 128.44, 114.45, 78.66, 55.23, 53.95, 42.43, 29.43, 19.76, 13.97.
HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane¼10/90,
l
¼254 nm,
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flow rate 0.8 mL/min), syn-isomer: tminor 32.0 min and tmajor
35.2 min; anti-isomer: tminor 39.0 min and tmajor 50.8 min.
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4.3.12. (R)-2-((S)-1-(4-Methylphenyl)-2-nitroethyl)pentanal
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.
1H NMR (400 MHz, CDCl3)
d
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7.15e7.39 (m, 4H), 4.69e4.58 (m, 2H), 4.13e4.07 (m, 1H), 3.76e3.70
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J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d: 203.43, 137.88, 133.53,
129.79, 127.80, 78.55, 53.86, 42.81, 29.43, 21.10, 19.78, 13.95. HPLC
27. Ding, J.; Desikan, V.; Han, X.; Xiao, T. L.; Ding, R.; Jenks, W. S.; Armstrong, D. W.
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(Daicel Chiralpak OD-H, i-PrOH/hexane¼10/90,
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¼254 nm, flow
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rate 0.8 mL/min), syn-isomer: tminor 23.4 min and tmajor 31.7 min;
anti-isomer: tminor 29.4 min and tmajor 49.3 min.
30. Truong, T.-K.-T.; Vo-Thanh, G. Tetrahedron 2010. doi:10.1016/j.tet.2010.03.101
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4.3.13. (R)-2-((S)-1-(2-Methylphenyl)-2-nitroethyl)pentanal
(8m). 1H NMR (400 MHz, CDCl3)
d
: 9.72 (d, J¼3.2 Hz, 1H), 7.22e7.18
(m, 3H), 7.12e7.10 (m, 1H), 4.66 (d, J¼3.2 Hz, 2H), 4.13e4.07 (m, 1H),
2.71e2.66 (m, 1H), 2.39 (s, 3H), 1.57e1.26 (m, 4H), 0.79 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d: 203.55, 136.97, 135.31, 131.22,
127.71, 126.85, 125.89, 78.20, 54.51, 37.90, 29.48, 20.12, 19.79, 13.91.
HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane¼20/80, ¼254 nm,
l
flow rate 0.8 mL/min), syn-isomer: tminor 22.2 min and tmajor
25.1 min; anti-isomer: tminor 36.0 min and tmajor 45.3 min.
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4.3.14. (R)-2-((S)-1-(4-Bromophenyl)-2-nitroethyl)pentanal
(8n)39
.
1H NMR (400 MHz, CDCl3)
d
:
9.70 (d, J¼2.4 Hz, 1H),
7.49e7.45 (m, 2H), 7.07e7.05 (m, 2H), 4.72e4.61 (m, 2H), 3.78e3.73
(m, 1H), 2.71e2.66 (m, 1H), 1.48e1.15 (m, 4H), 0.82 (t, J¼7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3)
d: 202.74, 135.88, 132.32, 129.67, 122.17,
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78.12, 53.50, 42.55, 29.48, 19.67, 13.94. HPLC (Daicel Chiralpak OD-
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l
isomer: tminor 60.2 min and tmajor 65.8 min; anti-isomer: tminor
76.9 min and tmajor 98.6 min.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.030. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.