Self-assembled proline-amino thioureas as efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefins

Article abstract of DOI:10.1016/j.tetasy.2010.11.025

A small co-catalyst library of amino thioureas has been established from chiral 1,3-diamines. These bifunctional thioureas can form assemblies with proline to cooperatively catalyze the asymmetric Michael addition of aldehydes to nitroolefins. Both the re

Full text of DOI:10.1016/j.tetasy.2010.11.025

Tetrahedron: Asymmetry 21 (2010) 2925–2933
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Self-assembled proline-amino thioureas as efficient organocatalysts
for the asymmetric Michael addition of aldehydes to nitroolefins
Wan-Hui Wang a, Takeshi Abe a, Xiang-Bo Wang a, Koichi Kodama a, Takuji Hirose a, , Guang-You Zhang b
⇑
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:
A small co-catalyst library of amino thioureas has been established from chiral 1,3-diamines. These
bifunctional thioureas can form assemblies with proline to cooperatively catalyze the asymmetric
Michael addition of aldehydes to nitroolefins. Both the reaction rate (up to 98% yield for 18 h) and the
enantioselectivity (up to 94% ee) were significantly improved upon in less polar solvents.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 October 2010
Accepted 24 November 2010
Available online 11 January 2011
1. Introduction
tides,17,18 have been reported. Nevertheless, the development of
suitable co-catalysts which form assemblies with proline is still
The rediscovery of proline as an organocatalyst for the enantio-
selective aldol reaction1 has initiated the rapid growth of research
in the field of asymmetric organocatalysis over the last decade.2–6
Proline is still an attractive organocatalyst because of its versatility
and wide availability. However, it has some potential drawbacks:7
low solubility and consequently low reactivity in typical organic
solvents; the need for high catalyst loading (typically 20–
30 mol %) and excess reagents; and the use of solvents, such as
DMSO and DMF, which present difficulties in work-up and purifi-
cation. Therefore, considerable effort has been made to improve
the catalyst activity and selectivity by the synthesis of a variety
of proline derivatives8–12 or the construction of new catalysts that
mimic the structure of proline.13 However, these newly designed
compounds do not always produce satisfactory results. A practical
alternative strategy using co-catalysts or additives has emerged
and is attracting increasing interest.14 Suitable co-catalysts or
additives can form an assembly with the carboxylate moiety of
proline and enhance the reactivity and selectivity of the catalytic
system by promoting enamine formation.15 Moreover, the catalyst
system can easily be modified by replacement of the co-catalyst in-
stead of a multistep chemical synthesis. Consequently, the best
catalyst system may be more efficiently established by screening
desirable for certain catalytic reactions.7
The asymmetric Michael addition reaction of nitroolefins with
aldehydes or ketones is an important method for the synthesis of
versatile c-nitrocarbonyl compounds. These are synthetically use-
ful building blocks because the nitro group can be readily converted
into a variety of functional groups including amines and nitrile oxi-
des.27,28 Application of the co-catalyst strategy in the asymmetric
Michael addition is relatively unexplored. In 2007, Clarke and
Fuentes first reported the self-assembly of prolinamide-based
organocatalysts and pyridinone derivatives for the Michael addi-
tion of ketones to nitroolefins, where the addition of achiral pyrid-
inone derivatives can transform a non-selective chiral prolinamide
catalyst into a selective one.29 Following the same strategy, Zhao
and Mandal demonstrated that self-assembled simple amino acids
and alkaloid thiourea derivatives could act as efficient catalysts for
the Michael addition of ketones to nitroolefins.16 Most recently,
Demir and Eymur investigated the asymmetric Michael addition
of aldehydes to nitroolefins catalyzed by an assembly of proline
and 1,3-bis[3,5-bis(trifluoromethyl)phenyl] thiourea (Schreiner’s
thiourea) via intermolecular hydrogen bonding.25 A moderate
reaction rate, an excellent diastereoselectivity of up to syn/anti
65/1 dr (diastereomeric ratio), and a moderate enantioselectivity
of up to 76% ee (enantiomeric excess) were achieved.
a
library of structurally diverse co-catalysts.16 Recently, this
strategy has been successfully applied in the asymmetric proline-
Our group has recently reported the catalytic Michael reaction
of nitroolefins and aldehydes with moderate to good diastereose-
lectivity and high enantioselectivity using ionic liquid supported-
prolinamides derived from a chiral cis-1,3-diamine.30 Diverse
bifunctional molecules can easily be prepared using chiral 1,3-dia-
mines as a starting material. Herein, we employ the co-catalyst
strategy for the asymmetric Michael addition. Chiral bifunctional
amino thioureas were chosen as co-catalysts since the synergistic
effect of the two functional groups may enhance the formation of
catalyzed Morita–Baylis–Hillman reactions,17–20 aldol reac-
tions,7,14,21–23 Mannich reactions,15
a
-aminoxylations,15,24 and
Michael reactions.16,25 Diverse co-catalysts, such as amines,24
water,26 diols,21 amino alcohols,19,20 ureas,15 thioureas,25 and pep-
⇑
Corresponding author. Tel./fax: +81 48 858 3522.
E-mail address: hirose@apc.saitama-u.ac.jp (T. Hirose).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.025

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W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
the enamine. In addition, the large chiral building block assembled
with proline may provide higher chiral induction. Herein, we re-
port efficient organocatalysts self-assembled from proline and
bifunctional amino thioureas derived from chiral 1,3-diamines
for the enantioselective Michael addition of aldehydes to
nitroolefins.
lective (90% ee, entry 6). When only
L-proline or 1 was used, the
reaction proceeded very slowly. -Proline on its own showed no
L
reaction at 0 °C (entry 7), and only provided 19% yield and a 44%
ee at room temperature (entry 8). This suggests that the thiourea
not only improves the reaction rate but also enhances the enanti-
oselectivity (see entry 6 vs 8). Interestingly, the use of 1 alone
afforded the same (2R,3S)-configured syn adduct as the major
product but with a higher ee (83%, entry 9). We also found that
the reaction rate decreased significantly with a reduced amount
of thiourea, although the diastereoselectivity and enantioselectivi-
ty remained almost the same (entries 10 and 11). It is reasonable to
conclude that proline and thiourea form an assembly and promote
the reaction cooperatively.
2. Results and discussion
The chiral amino thioureas 1–7 were readily synthesized from
chiral 1,3-diamines and the corresponding isothiocyanates in high
yields (Scheme 1). However, the reaction of the chiral 1,3-amino
alcohol was very slow and gave 8 in low yield after 12 h.
In Zhao’s report,16
D-proline showed strong mismatching effects
with an alkaloid thiourea and delivered poor activity and selectiv-
ity in the catalytic asymmetric Michael addition of acetone to
2.1. Optimization of the reaction conditions
trans-b-nitrostyrene. However, we observed that when D-proline
With a small co-catalyst library in hand, we chose the asym-
metric Michael addition of propanal to trans-b-nitrostyrene as a
model reaction for optimizing reaction conditions. As seen in
was used, the enantiomeric (2S,3R)-configured syn product was ob-
tained with a similar diastereoselectivity and a slightly lower
enantioselectivity (entry 12 vs 4). The lower enantioselectivity
may be rationalized by considering the catalytic effect of 1 alone
as mentioned above. The well-matched assembly with D-proline
can be attributed to the fact that the 1,3-amino thiourea provides
more space and flexibility for the combination than the 1,2-amino
Table 1, using 10 mol % of L-proline and thiourea 1, the reaction
in moderately polar dichloromethane (DCM) gave good yield and
moderate enantioselectivity (79% ee) at 0 °C (entry 1). The reaction
proceeded more smoothly in benzene, a less polar solvent, with
high enantioselectivity (92% ee) and moderate diastereoselectivity
(entry 2). Although benzene provided the highest reaction yield,
toluene gave slightly better diastereoselectivity and enantioselec-
tivity (entry 3). With a longer reaction time, an excellent yield
(96%), moderate diastereoselectivity (70/30 dr), and a high enanti-
oselectivity (94% ee) were obtained in toluene (entry 4). When a
catalyst loading of 5 mol % was used, no change in enantioselectiv-
ity or diastereoselectivity was observed, although a longer reaction
time was necessary to maintain the yield (entry 5). The reaction
proceeded faster at room temperature, but was not as enantiose-
thiourea. When achiral a-amino acids such as glycine and 2-meth-
ylalanine were used, low yields (49% and 35%), moderate diastere-
oselectivity (71/29 and 72/28 dr), and low enantioselectivity (15%
and 8% ee) were obtained after 7 days (entries 13 and 14). The low
reaction rate indicates that the primary amino group is slow to
form the enamine intermediate, probably because of its low basi-
city; N-methylglycine with a secondary amino group gave a higher
yield with similar stereoselectivity (entry 15 vs 13, 14). However, it
is interesting to note that the configuration of the syn product
S
S
R
N
H
N
H
1-4
N
N
N
NH2
y. 87-98%
RNCS
dry DCM
r.t. 12 h
N
CF3
CF3
R
5
NH2
N
H
N
H
1, 5-8: R =
2: R =
y. 86%
CF3
CF3
S
N
R
N
N
6
NH2
H
H
RNCS
N
N
y. 87%
dry DCM
r.t. 12 h
F
N
S
N
3: R =
4: R =
NH2
R
S
7
N
H
N
H
F
y. 92%
N
RNCS
OH
NH2
8
R
N
H
N
H
dry DCM
r.t. 12 h
y. 17%
HO
Scheme 1. Synthesis of chiral bifunctional thioureas.

W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
2927
Table 1
Optimization of the catalytic reaction conditionsa
Amino acid
Thiourea 1
O
Ph
O
NO2
9a
NO2
H
H
Ph
Entry
Amino acid (mol %)
Thiourea (mol %)
Temp. (°C)
Time
Solvent
Yieldb (%)
drc (syn/anti)
eed (%) syn (anti)
1
2
3
4
5
6
7
8
1 (10)
1 (10)
1 (10)
1 (10)
1 (5)
1 (10)
—
0
0
0
0
0
rt
0
rt
4 h
DCM
78
88
73
96
80
79
—
65/35
66/34
69/31
70/30
69/31
74/26
—
79 (77)
92 (89)
94 (94)
94 (95)
93 (90)
90 (90)
—
L
L
L
L
L
L
L
L
-Pro (10)
-Pro (10)
-Pro (10)
-Pro (10)
-Pro (5)
4 h
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
4 h
17 h
36 h
8 h
-Pro (10)
-Pro (10)
-Pro (10)
36 h
72 h
—
19
73/27
44 (49)
9
10
—
1 (10)
1 (5)
rt
0
72 h
17 h
Toluene
Toluene
14
85
67/33
69/31
83 (87)
94 (90)
L
-Pro (10)
-Pro (10)
-Pro (10)
11
12e
1 (2.5)
1 (10)
0
0
17 h
17 h
Toluene
Toluene
58
79
68/32
68/32
93 (93)
89 (89)
L
D
13e,f
Gly (10)
2-Me-Ala (10)
N-Me-Gly
1 (10)
1 (10)
1 (10)
rt
rt
rt
7 days
7 days
7 days
Toluene
Toluene
Toluene
49
35
92
71/29
72/28
64/36
15 (6)
8 (12)
12 (10)
14f
15f
a
b
c
d
e
f
The reaction was conducted with nitrostyrene (0.1 mmol), aldehyde (0.3 mmol), amino acid, and 1 in 0.5 mL of solvent.
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis.
The absolute configuration of the major product is (2S,3R).
Gly: glycine; 2-Me-Ala: 2-methylalanine; N-Me-Gly: N-methylglycine.
catalyzed by glycine is different from that obtained by using other
achiral amino acids such as 2-methylalanine and N-methylglycine.
The substituents at the a-position or on the N atom appear to con-
tribute to the assembly with 1.
turn weaken the assembly with proline, resulting in a lower yield.
Amino thioureas 2 and 3 gave similar results (entry 2 vs 3).
Replacement of the 3,5-bis(trifluoromethyl)phenyl group with a
phenyl group led to a similar results: a much lower reaction rate
and enantioselectivity (entry 4). Comparing the results obtained
by using 1 and 5, we can see that the configuration of the amino
thiourea has almost no effect on the absolute configuration of
the product in the present system (entry 5 vs 1). Considering fur-
ther the aforementioned results (Table 1, entries 6, 7, and 11),
we can conclude that the stereochemistry of the reaction is mainly
controlled by the configuration of proline. In addition, the enantio-
meric excesses of the major syn products are much higher (up to
2.2. Screening of chiral bifunctional thioureas
Under the optimized reaction conditions, we examined the cat-
alytic reactivity of different amino thioureas in combination with
L-proline. The results are summarized in Table 2. Using thiourea
2, with one methylene inserted between the thiourea and the
3,5-bis(trifluoromethyl)phenyl groups, the activity of the catalyst
decreased considerably (entry 1 vs 2). This can be explained by
the reduced electron-withdrawing effect of the thiourea’s substitu-
ent, lowering its hydrogen bond donating ability, which could in
76%) than that promoted by Schreiner’s thiourea and L
-proline.25
The amino thiourea bearing a rigid norbornyl skeleton also
worked well, and gave a yield and stereoselectivity comparable
Table 2
Screening of the co-catalystsa
10 mol % L-Proline
O
Ph
O
X mol % Co-catalyst
Toluene, 0 ºC
Yieldb (%)
NO2
NO2
H
H
Ph
9a
Entry
Co-catalyst (mol %)
Time (h)
drc (syn/anti)
eed (%) syn (anti)
1
2
3
4
5
6
7
8
9
1 (10)
2 (10)
3 (10)
4 (10)
5 (10)
6 (10)
7 (10)
7 (5)
17
17
17
17
17
17
17
17
17
17
96
76
76
40
83
93
96
94
17
64
70/30
63/37
68/32
63/37
65/35
66/34
67/33
69/31
64/36
68/32
94 (95)
90 (92)
90 (88)
82 (82)
92 (92)
91 (93)
90 (91)
90 (91)
77 (79)
39 (40)
8 (10)
Et3N (10)
10
a
b
c
The reaction was conducted with nitrostyrene (0.1 mmol), aldehyde (0.3 mmol), L-proline (10 mol %), and co-catalyst in 0.5 mL of toluene at 0 °C.
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis.
d

2928
W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
to the amino thiourea bearing a cyclohexyl group (entry 6 vs 1).
When the 4-methylpiperazinyl group was introduced, the reaction
rate was slightly enhanced, but the bulkiness gave no improve-
ment in enantioselectivity (entry 7 vs 6). In this system, thiourea
could be reduced to 5 mol %, with almost no effect on the reaction
outcome (entry 8). When the dimethylamino group was replaced
with a hydroxyl group, the yield and enantioselectivity dropped
significantly (entry 9). This result indicates that the Lewis base also
plays an important role in the catalytic process. In contrast to ami-
no thioureas, however, triethylamine only enhanced the reaction
rate, but could not improve upon the enantioselectivity (entry 10
and Table 1, entries 7 and 8).
5). When iso-butanal was used, the reaction proceeded very slowly,
with only a modest yield (44%) after 7 days, and the enantioselec-
tivity (71% ee) dropped significantly (entry 6).
Subsequently, the reaction of substituted trans-b-nitroolefins
with pentanal was investigated; the results are summarized in
Table 4. The reaction of substituted trans-b-nitrostyrenes gave
the desired Michael products in high yields (up to 98%), moderate
diastereoselectivities (up to 87/13 dr), and high enantioselectivi-
ties (up to 91% ee, entries 1–5). The substituents on the aromatic
ring of the nitrostyrenes have a modest effect on the reaction rate,
enantioselectivity, and diastereoselectivity. The reaction of
nitrostyrenes bearing an electron-donating group such as Me or
MeO took longer times and showed higher diastereoselectivity
and enantioselectivity (entries 2 and 3). On the other hand,
nitrostyrenes with an electron-withdrawing group reacted faster
but showed lower diastereoselectivity and enantioselectivity
(entries 4 and 5). The present catalytic system was not effective
for b-alkyl nitroolefins and gave no products after 48 h (entries 6
and 7).
The results were disappointing when this catalytic system was
tested for ketones. The reaction of cyclohexanone and trans
-b-nitrostyrene in toluene at room temperature gave the adduct
9k with a fair yield (56%), modest enantioselectivity (42% ee),
and high diastereoselectivity (90/10 dr) after 4 days (Scheme 2).
The acetone substrate showed no reaction under the same reaction
conditions (Scheme 2).
2.3. Scope of substrate
The scope of the substrates was studied using 1 and L-proline.
To begin with, aldehydes were investigated and the results are
listed in Table 3. The reaction of linear aldehydes proceeded
smoothly with reaction times ranging from 17 to 20 h, and gave
high yields (80–96%), moderate to high diastereoselectivities
(70/30–86/14 dr), and high enantioselectivities (90–94% ee, entries
1–4). The diastereomeric ratio increased considerably with an
increase in chain length of the aldehydes, while the reaction rate
decreased gradually. Although the reaction of branched iso-valeral-
dehyde required a longer reaction time, high diastereoselectivity
(95/5 dr) and high enantioselectivity (91% ee) were achieved (entry
Table 3
Michael addition of various aldehydes to trans-b-nitrostyrenea
10 mol % L-Proline
10 mol % Thiourea 1
O
Ph
O
R2
NO2
NO2
H
H
Ph
R1 R2
Toluene, 0 ºC
R1
9
Entry
R1
R2
Time
Yieldb (%)
drc (syn/anti)
eed (%) syn (anti)
Pr
1
2
3
4
5
6
Me
Et
n-Pr
n-Bu
i-Pr
Me
H
H
H
H
H
Me
17 h
20 h
20 h
20 h
45 h
96
91
86
80
64
44
70/30
81/19
84/16
86/14
95/5
—
94 (95)
91 (89)
91 (90)
90 (90)
91
9a
9b
9c
9d
9e
9f
7 days
71
a
b
c
The reaction was conducted with nitrostyrene (0.1 mmol), aldehyde (0.3 mmol), L-proline (10 mol %) and 1 (10 mol %) in 0.5 mL of toluene at 0 °C.
Isolated yield.
Determined by 1H NMR.
Determined by chiral HPLC analysis.
d
Table 4
Michael addition of pentanal to trans-b-nitroolefinsa
10 mol %
L
-Proline
O
R
O
H
10 mol % Thiourea 1
NO2
NO2
H
R
Toluene, 0 ºC
9
Entry
R
Time (h)
Yieldb (%)
drc (syn/anti)
eed (%) syn (anti)
Pr
1
2
3
4
5
6
7
Ph
20
28
28
18
18
48
48
86
84
91
98
95
—
84/16
84/16
87/13
77/23
78/22
—
91 (90)
86 (85)
89 (86)
81 (86)
82 (83)
—
9c
9g
9h
9i
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-ClC6H4
Cyclohexyl
i-Pr
9j
—
—
—
a
b
c
Reaction was conducted with nitroolefin (0.1 mmol), pentanal (0.3 mmol),
Isolated yield.
L-proline (10 mol %), and 1 (10 mol %) in 0.5 mL of toluene at 0 °C.
Determined by 1H NMR.
d
Determined by chiral HPLC analysis.

W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
2929
ammonium salt between
of 1. This was further confirmed by NMR experiments using a
mixture of hydroxy thiourea 8 and -proline (0.02 mmol each)
wherein the thiourea NH protons also showed
downfield shift (Fig. 1b).
Therefore, we suppose that the downfield shift of thiourea
protons is due to hydrogen bonding between thiourea group and
L
-proline and the dimethylamino group
O
Ph
O
10 mol % L-Proline
10 mol % Thiourea 1
NO2
NO2
L
Ph
Toluene, 96 h, r.t.
9k
a markedly
yield: 56%; syn/anti = 90/10; ee: 42% (syn), 48% (anti)
Scheme 2.
trans-b-nitrostyrene.
L
-Proline-thiourea catalyzed Michael addition of cyclohexanone to
the carboxylate of
ammonium salt formation between
amino group of thiourea. Furthermore, considering that the
L-proline, but not because of the influence of
L
-proline and the dimethyl-
pyrrolidine moiety (pKa = 10.6035) of
L-proline is more basic than
2.4. Proposed mechanism
N,N-dimethylethylamine (pKa = 9.9936) which is similar to the
dimethylamino group of 1, we suppose that the secondary amino
It is well known that the carboxylate anion can form strong
hydrogen bonds with the thiourea moiety.31–33 Rios et al. have re-
ported the assembly of proline and Schreiner’s thiourea in chloro-
form by UV and fluorescence spectroscopy techniques.22 To
illustrate the interaction between proline and amino thiourea, we
group of L-proline generates an ammonium cation and the carboxyl-
ate anion forms hydrogen bonds with thiourea 1 (Fig. 2A). In Zhao’s
study, the formation of an ammonium salt between amino thiourea
and
of a quinuclidinemoiety (pKa = 11.3037) compared to the pyrrolidine
moiety of -proline. The effect of triethylamine with a similar
basicity (pKa = 10.6538) can be interpreted in that the salt would be
formed and increase the solubility of -proline resulting in an
enhanced reaction rate (Table 2, entry 10).
L-prolinecanbe rationalizedbyconsidering thestrongerbasicity
carried out 1H NMR experiments with a mixture of
1 (0.01 mmol each) in 500
L
-proline and
l
l of CDCl3 and DMSO-d6. It was ob-
L
served that the solubility of L-proline in CDCl3 was increased to
0.009 M by the addition of 1 from the reported solubility34 of
L
0.0045 M for proline alone. This result is in agreement with Demir
et al.7 In addition, it was shown that
L
-proline forms an assembly
Based on the experimental results and the previously reported
speculations,14,39–41 we expect that the catalytic reaction proceeds
through an enamine mechanism (Fig. 2). The amino thiourea inter-
acts first with proline through two hydrogen bonds to form com-
plex A. After a dehydration reaction with the aldehyde, iminium
intermediate B14 or oxazolidinone intermediate C15 is generated,
which are possibly in equilibrium. Deprotonation of B or C gives
the enamine intermediate, which is more nucleophilic than the
aldehyde because of its higher HOMO energy level. A new C–C
with 1, since the signal of the carboxyl proton of -proline disap-
L
pears in the spectrum and more importantly the signals of thiourea
protons H1 and H2 show a significant downfield shift of 0.26 and
0.10 ppm respectively, relative to pure 1 in DMSO-d6 (Fig. 1a).
Zhao et al. have reported the salt formation between L-proline
and amino thiourea according to their NMR studies in CDCl3.16 In
our systems, however, the signals of the dimethylamino group
showed no substantial shift. Thus, it seems unlikely to form an
Figure 1. Partial 1H NMR spectra in DMSO-d6. (a) Thiourea 1 and a mixture of 1 and
L-proline (1/1). (b) Thiourea 8 and a mixture of 8 and L-proline (1/1).

2930
W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
CO2
N
H2
Thiourea
Ar
N
H
O
O
S
N
H
NH2
Product
R
N
A
CHO
H2O
H2O
Ar
O
O
H
N
Ar
Ar
N
S
N
N
H
H
O
O
O
O
H
S
S
Ar
N
N
N
H
N
H
O2N
N
N
R
E
H
H
H
H
N
N
R
R
C
B
Ar
N
Ar
N
N
H
O
O
S
H
nitroolefin
O
O
S
H
N
N
H
N
R
Ar
N
O
N
O
N
H
Ar
H
N
O
R
O
D
D*
Figure 2. Proposed catalytic reaction mechanism.
bond is formed with the nitroolefin via transition state D. Finally,
hydration of iminium E releases the product, and complex A is
regenerated.
4. Experimental
4.1. General
The bifunctional amino thiourea plays an important role in sev-
eral aspects of the catalytic cycle: hydrogen bond formation in B or
C to facilitate enamine generation, resulting in increased reaction
rate; assembly with the enamine intermediate and activation of
the nitroolefin by hydrogen bonding with the ammonium
group;42,43 and subsequent induction of the stereoselective nucle-
All 1H NMR and 13C NMR spectra were recorded on Bruker DRX
400 (400 MHz) or Bruker AVANCE 500 (500 MHz) spectrometers
(Comprehensive Analysis Center for Science [CACS], Saitama
University). Chemical shifts of 1H and 13C are given in parts per
million relative to tetramethylsilane (TMS) as an internal standard.
The coupling constant J is given in Hertz. IR spectra were recorded
on JASCO FT/IR 400. Enantiomeric excess determination was car-
ried out using a JASCO LC 900 series HPLC system consisting of a
CD detector with chiral columns (Daicel Chiralpak AD-H, Chiralcel
OD-H). Optical rotation was measured with a JASCO DIP-370 polar-
imeter. Electrospray ionization (ESI) mass measurements were
performed on a NanoFrontier eLD mass spectrometer (CACS).
Melting points were determined with a Mitamura Riken Kogyo
MEL-TEMP instrument, and are reported as uncorrected values.
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.44
ophilic attack of the enamine (D or D⁄). When
L-proline is used, the
reaction occurs through Si,Si-face attack (D) and gives the (2R,3S)-
configured syn product, while the amino thiourea can accommo-
date
D
-proline to allow Re,Re-face attack (D⁄) and give the
(2S,3R)-configured syn adduct because of its flexible aminomethyl
group. In both transition states, D and D⁄, the trans-enamine
should be preferred and fixed by the thiourea. However, the nitro-
olefin is relatively unconfined and the orientation may change,
which results in the anti product. This may be the reason for the
moderate diastereoselectivity.
3. Conclusion
4.2. Synthesis of chiral thioureas 1–8
In conclusion, we have developed a small co-catalyst library of
amino thioureas which can self-assemble with
the asymmetric Michael addition of aldehydes to nitroolefins.
Bifunctional thioureas can increase the solubility of -proline in
less polar solvents and significantly improve the reaction rate
and selectivity. Both thiourea and amino groups have been shown
to be important for self-assembly. We have demonstrated that self-
L-proline to catalyze
cis-(1R,2R)-2-((Dimethylamino)methyl)cyclohexylamine
trans-(1S,2R)-2-((dimethylamino)methyl)cyclohexylamine
and
were
L
prepared according to our previously reported method24 from
commercially available cis-(1S,2R)-2-benzamidocyclohexanecarb-
oxylic acid and trans-(1S,2S)-2-benzamidocyclohexanecarboxylic
acid, respectively. (1R,2R,3R,4S)-2-Amino-3-((dimethylamino)-
methyl)bicyclo[2.2.1]heptane and (1R,2R,3R,4S)-2-amino-3-((4-
methylpiperazin-1-yl)methyl)bicyclo[2.2.1]heptane were synthesized
from (1S,2S,3R,4R)-3-benzamidobicyclo[2.2.1]heptane-2-carbox-
assembled L-proline-amino thioureas are efficient organocatalysts
for asymmetric Michael addition, requiring a catalyst loading of
only 10 mol % and a small excess of aldehyde (3 equiv). Application
of this catalytic system in related asymmetric catalysis is currently
under investigation.
ylic acid45,46 using
a
similar method. ((1S,2R)-2-Amin-

W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
2931
ocyclohexyl)methanol was prepared according to the reported
procedure.47
4.2.6. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2R)-2-((dimeth-
ylamino)methyl)cyclohexyl)thiourea 5
White solid; mp: 114–116 °C; 86% yield; ½a D25
¼ ꢁ12:6 (c 0.39,
ꢀ
4.2.1. General procedure for the synthesis of thiourea
Chiral 1,3-diamine or 1,3-amino alcohol (0.5 mmol) and the
corresponding isothiocyanate (0.5 mmol) were stirred in dry
DCM (5 mL) at room temperature for 12 h. After removing the sol-
vent, the residue was purified by preparative TLC (CHCl3/
MeOH = 10:1) to give the product.
CHCl3); IR (KBr, cmꢁ1): 3166, 3026, 2934, 1619, 1542, 1500,
1468, 1405, 1377, 1275, 1185, 1134, 890, 702, 681; 1H NMR
(400 MHz, CDCl3) d: 8.98 (br, 1H), 7.75 (m, 2H), 7.65 (m, 1H),
3.64 (td, J = 10.4, 3.2 Hz, 1H), 2.89 (s, 1H), 2.33 (dd, J = 12.4,
9.6 Hz, 1H), 1.84 (s, 6H), 1.76 (d, J = 10.4 Hz, 1H), 1.59 (d,
J = 12.4 Hz, 1H), 1.53–1.42 (m, 1H), 1.42–1.24 (m, 2H), 1.12–1.09
(m, 2H); 13C NMR (100 MHz, CDCl3) d: 180.13, 139.62, 132.99,
132.66, 132.33, 126.94, 124.23, 123.26, 121.52, 118.32, 65.21,
62.99, 44.95, 39.44, 32.19, 30.77, 25.96, 24.35; HRMS (ESI+) calcd
for [C18H24N3F6S]+: 428.1590, found: 428.1597.
4.2.2. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-((dimeth-
ylamino)methyl)cyclohexyl)thiourea 1
Viscous liquid; 87% yield; ½a D25
¼ þ83:8 (c 0.50, CHCl3); IR (neat,
ꢀ
cmꢁ1): 3415, 3219, 3094, 2933, 1605, 1504, 1471, 1383, 1276,
1176, 1133, 885, 681; 1H NMR (400 MHz, DMSO-d6) d 10.05 (s,
1H), 8.66 (s, 1H), 8.29 (m, 2H), 7.74 (s, 1H), 4.47 (s, 1H), 2.40 (s,
1H), 2.19 (s, 1H), 2.08 (s, 6H), 1.96 (s, 1H), 1.69–1.22 (m, 8H). 13C
NMR (100 MHz, DMSO-d6) d: 179.87, 142.31, 130.79, 130.46,
130.14, 127.77, 125.06, 122.47, 122.35, 119.64, 116.56, 61.27,
53.62, 45.95, 35.83, 28.66, 27.41, 23.04; HRMS (ESI+) calcd for
[C18H24N3F6S]+: 428.1590, found: 428.1593.
4.2.7. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,3R,4S)-3-
((dimethylamino)methyl)bicyclo[2.2.1]heptan-2-yl)thiourea 6
White solid; mp: 76–78 °C; 87% yield; ½a D25
¼ þ141:4 (c 0.51,
ꢀ
CHCl3); IR (KBr, cmꢁ1): 3405, 3305, 3052, 2965, 1604, 1537,
1473, 1388, 1341, 1279, 1186, 1170, 1130, 879, 705, 679; 1H
NMR (400 MHz, CDCl3) d: 7.89 (s, 2H), 7.55 (s, 1H), 6.39 (s, 1H),
3.97 (m, 1H), 2.72–2.69 (m, 1H), 2.55 (m, 1H), 2.35 (s, 6H), 2.28
(m, 1H), 2.13 (d, J = 12.4 Hz, 2H), 1.59–1.53 (m, 3H), 1.45–1.25
(m, 3H); 13C NMR (100 MHz, CDCl3) d: 186.25, 142.91, 131.83,
131.52, 124.54, 121.83, 121.37, 116.78, 58.29, 45.25, 42.75, 41.58,
38.07, 21.92, 21.66; HRMS (ESI+) calcd for [C19H24N3F6S]+:
440.1590, found: 440.1587.
4.2.3. 1-(3,5-Bis(trifluoromethyl)benzyl)-3-((1R,2R)-2-((dimeth-
ylamino)methyl)cyclohexyl)thiourea 2
Viscous liquid; 98% yield; ½a D25
¼ þ95:1 (c 0.21, CHCl3); IR (neat,
ꢀ
cmꢁ1): 3425, 3219, 2931, 2858, 1594, 1537, 1500, 1463, 1378,
1341, 1279, 1174, 1133, 902, 705, 682; 1H NMR (400 MHz, CDCl3)
d: 10.34 (s, 1H), 7.81 (s, 3H), 6.13 (d, J = 7.2 Hz, 1H), 5.22 (dd,
J = 15.8, 6.0 Hz, 1H), 4.66 (dd, J = 15.8, 3.6 Hz, 1H), 3.82 (d,
J = 5.2 Hz, 1H), 2.29 (t, J = 12.4 Hz, 1H), 1.96 (s, 6H), 1.79 (dd,
J = 12.4, 3.6 Hz, 2H), 1.72–1.69 (m, 1H), 1.61–1.56 (m, 3H), 1.51–
1.11 (m, 5H). 13C NMR (100 MHz, CDCl3) d: 184.63, 141.49,
132.28, 131.95, 131.62, 131.29, 127.77, 127.31, 124.60, 121.89,
121.25, 119.18, 60.86, 50.79, 49.41, 44.36, 38.78, 31.45, 25.44,
25.32, 20.37; HRMS (ESI+) calcd for [C19H26N3F6S]+: 442.1746,
found: 442.1750.
4.2.8. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R,3R,4S)-3-((4-
methylpiperazin-1-yl)methyl)bicyclo[2.2.1]heptan-2-yl)-
thiourea 7
White solid; mp: 67–69 °C; 92% yield; ½a D25
¼ þ19:9 (c 0.41,
ꢀ
CHCl3); IR (KBr, cmꢁ1): 3416, 3145, 3103, 2951, 2810, 1619,
1533, 1467, 1383, 1339, 1277, 1177, 1136, 1006, 886, 757, 681;
1H NMR (400 MHz, CDCl3) d: 9.79 (s, 1H), 8.20 (s, 1H), 7.73 (s,
2H), 7.60 (s, 1H), 4.11 (m, 1H), 3.38 (s, 1H), 2.60 (m, 3H), 2.27 (s,
3H), 2.18 (s, 1H), 2.09 (s, 4H), 1.96 (m, 2H), 1.54 (m, 4H), 1.45
(m, 3H), 1.25 (m, 1H); 13C NMR (100 MHz, CDCl3) d: 182.19,
140.38, 132.91, 124.27, 121.57, 117.54, 58.87, 58.40, 58.37, 57.04,
54.38, 50.72, 45.61, 40.59, 37.76, 34.79, 29.70, 23.28, 21.22,
18.43; HRMS (ESI+) calcd for [C22H29N4F6S]+: 495.2012, found:
495.2007.
4.2.4. 1-(3,5-Difluorobenzyl)-3-((1R,2R)-2-((dimethylamino)-
methyl)cyclohexyl)thiourea 3
Viscous liquid; 93% yield; ½a D25
¼ þ118:4 (c 0.42, CHCl3); IR
ꢀ
(neat, cmꢁ1): 3425, 3222, 2930, 2858, 1596, 1537, 1501, 1460,
1341, 1117, 999, 848, 759; 1H NMR (500 MHz, CDCl3) d: 10.25 (s,
1H), 6.88 (d, J = 6.0 Hz, 2H), 6.73–6.69 (m, 1H), 6.06 (d, J = 5.0 Hz,
1H), 5.07 (dd, J = 15.5, 6.0 Hz, 1H), 4.51 (dd, J = 15.5, 3.0 Hz, 1H),
3.83 (d, J = 4.0 Hz, 1H), 2.28 (t, J = 12.0 Hz, 1H), 1.96 (s, 7H), 1.79
(J = 12.0, 3.0 Hz, 2H), 1.73–1.68 (m, 2H), 1.61–1.55 (m, 1H), 1.49–
1.40 (m, 1H), 1.33–1.26 (m, 2H), 1.25–1.17 (m, 1H); 13C NMR
(100 MHz, CDCl3) d: 184.24, 164.35, 164.22, 161.87, 161.75,
142.87, 142.79, 142.70, 110.40, 110.34, 110.15, 102.89, 102.64,
102.39, 60.75, 50.74, 49.66, 44.32, 38.77, 33.93, 31.50, 29.69,
25.44, 25.33, 24.93, 20.38; HRMS (ESI+) calcd for [C17H26N3F2S]+:
342.1810, found: 342.1812.
4.2.9. 1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S)-2-(hydr-
oxymethyl)cyclohexyl)thiourea 8
White solid, mp: 146–148 °C; 17% yield; ½a D25
¼ þ11:5 (c 0.44,
ꢀ
CHCl3); IR (KBr, cmꢁ1): 3300, 3075, 2945, 1541, 1467, 1383,
1340, 1279, 1175, 1132, 1015, 896, 705, 682; 1H NMR (400 MHz,
CD3OD) d: 8.25 (m, 2H), 7.65 (m, 1H), 4.82 (m, 1H), 3.63–3.58
(m, 1H), 3.45–3.43 (m, 1H), 1.95–1.93 (m, 2H), 1.74–1.63 (m,
5H), 1.55–1.30 (m, 3H); 13C NMR (100 MHz, CDCl3) d: 179.94,
138.66, 133.19, 132.93, 132.78, 124.21, 123.51, 119.15, 63.69,
53.04, 49.85, 41.80, 29.71, 25.21, 22.33; HRMS (ESI+) calcd for
[C16H19N2OF6S]+: 401.1117, found: 401.1119.
4.2.5. 1-((1R,2R)-2-((Dimethylamino)methyl)cyclohexyl)-3-
4.3. General procedure for the asymmetric Michael addition
reaction
phenylthiourea 4
White solid; mp: 157–159 °C; 90% yield; ½a D25
¼ þ68:0 (c 0.20,
ꢀ
CHCl3); IR (KBr, cmꢁ1): 3164, 2980, 2928, 1592, 1524, 1496,
1303, 1242, 1198, 1159, 1103, 748, 694; 1H NMR (400 MHz,
CD3OD) d: 7.46–7.42 (m, 2H), 7.30–7.24 (m, 3H), 4.46 (m, 1H),
2.90 (t, J = 11.6 Hz, 1H), 2.27 (s, 1H), 2.09–2.01 (m, 2H), 1.94–1.91
(m, 1H), 1.84 (s, 6H), 1.69–1.54 (m, 2H), 1.49–1.30 (m, 5H); 13C
NMR (100 MHz, CDCl3) d: 179.28, 136.94, 129.64, 128.57, 126.77,
126.13, 125.54, 60.28, 58.14, 45.03, 32.36, 30.00, 26.58, 25.13,
20.37; HRMS (ESI+) calcd for [C16H26N3S]+: 292.1842, found:
292.1846.
To a stirred solution of chiral thiourea (0.01 mmol) and L-pro-
line (0.01 mmol) in dry toluene (0.5 mL), nitroolefin (0.1 mmol)
and aldehyde (0.3 mmol) were added at 0 °C. The reaction mixture
was stirred for an appropriate time by monitoring on TLC. After
completion of the reaction, the solvent was removed and the resi-
due was purified by preparative TLC (n-hexane/ethyl acetate = 3:1)
to give the Michael adduct 9a–9j as colorless liquids. The relative
(syn) and absolute configurations of most products were deter-
mined by comparison with the known 1H NMR data and HPLC

2932
W.-H. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 2925–2933
data.27,48–58 The relative (syn) and absolute configurations of 9j
were tentatively assigned.
3.63 (m, 1H), 2.67–2.64 (m, 1H), 1.55–1.49 (m, 4H), 0.81 (t,
J = 7.2 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 Chiralcel OD-H, i-PrOH/hexane = 10:90,
k = 254 nm, flow rate 0.8 mL/min), syn-isomer: tminor 26.3 min
and tmajor 30.8 min; anti-isomer: tminor 28.5 min and tmajor
43.5 min.
4.3.1. (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal 9a27,48
1H NMR (400 MHz, CDCl3) d: 9.72 (d, J = 1.6 Hz, 1H), 7.36–7.15
(m, 5H), 4.82–4.66 (m, 2H), 3.84–3.80 (m, 1H), 2.81–2.76 (m,
1H), 1.01 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 202.42,
136.81, 129.12, 129.09, 128.16, 128.14, 128.06, 78.11, 48.42,
44.00, 12.15. HPLC (Daicel Chiralcel OD-H, i-PrOH/hexane = 20:80,
k = 254 nm, flow rate 1.0 mL/min), syn-isomer: tminor 15.9 min and
tmajor 21.2 min; anti-isomer: tminor 19.6 min and tmajor 24.5 min.
4.3.8. (R)-2-((S)-1-(4-Methylphenyl)-2-nitroethyl)pentanal
9h56,57
1HNMR(400 MHz, CDCl3) d: 9.69 (d, J = 2.8 Hz, 1H), 7.39–7.15(m,
4H), 4.69–4.58 (m, 2H), 4.13–4.07 (m, 1H), 3.76–3.70 (m, 1H), 2.69–
2.65 (m, 1H), 2.33 (s, 3H), 1.49–1.15 (m, 4H), 0.80 (t, J = 6.8 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 (Daicel
Chiralcel OD-H, i-PrOH/hexane = 10:90, k = 254 nm, flow rate
0.8 mL/min), syn-isomer: tminor 18.0 min and tmajor 23.4 min; anti-
isomer: tminor 20.1 min and tmajor 33.9 min.
4.3.2. (2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal 9b27,48
1H NMR (400 MHz, CDCl3) d: 9.72 (d, J = 2.4 Hz, 1H), 7.36–7.28
(m, 3H), 7.19–7.17 (m, 2H), 4.80–4.60 (m, 2H), 3.82–3.76 (m,
1H), 2.70–2.67 (m, 1H), 1.74–1.65 (m, 1H), 1.53–1.49 (m, 1H),
0.83 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 203.25,
136.75, 129.15, 129.13, 128.24, 128.17, 128.01, 78.58, 54.98,
42.66, 20.37, 11.53. HPLC (Daicel Chiralcel OD-H, i-PrOH/hex-
ane = 20:80, k = 254 nm, flow rate 0.8 mL/min), syn-isomer: tminor
17.0 min and tmajor 19.7 min; anti-isomer: tminor 18.8 min and tmajor
29.3 min.
4.3.9. (R)-2-((S)-1-(4-Bromophenyl)-2-nitroethyl)pentanal 9i56
1H NMR (400 MHz, CDCl3) d: 9.70 (d, J = 2.4 Hz, 1H), 7.49–7.45
(m, 2H), 7.07–7.05 (m, 2H), 4.72–4.61 (m, 2H), 3.78–3.73 (m,
1H), 2.71–2.66 (m, 1H), 1.48–1.15 (m, 4H), 0.82 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) d: 202.74, 135.88, 132.32, 129.67,
122.17, 78.12, 53.50, 42.55, 29.48, 19.67, 13.94. HPLC (Daicel Chi-
ralcel OD-H, i-PrOH/hexane = 10:90, k = 240 nm, flow rate 0.5 mL/
min, 15 °C), syn-isomer: tminor 62.1 min and tmajor 67.0 min; anti-
isomer: tminor 72.4 min and tmajor 95.7 min.
4.3.3. (R)-2-((S)-2-Nitro-1-phenylethyl)pentanal 9c27,49
1HNMR (400 MHz, CDCl3)d: 9.76 (d, J = 2.4 Hz, 1H), 7.36–7.29(m,
3H), 7.18–7.16 (m, 2H), 4.72–4.62 (m, 2H), 3.80–3.75 (m, 1H), 2.72–
2.68 (m, 1H), 1.50–1.47 (m, 1H), 1.37–1.34 (m, 2H), 1.20–1.17 (m,
1H), 0.80 (t, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 203.26,
136.71, 129.12, 127.97, 78.42, 53.78, 43.11, 29.46, 19.75, 13.95. HPLC
(Daicel Chiralcel OD-H, i-PrOH/hexane = 20:80, k = 254 nm, flow
rate 1.0 mL/min), syn-isomer: tminor 12.5 min and tmajor 15.3 min;
anti-isomer: tminor 13.9 min and tmajor 20.9 min.
4.3.10. (R)-2-((S)-1-(4-Chlorophenyl)-2-nitroethyl)pentanal 9j
1H NMR (400 MHz, CDCl3) d: 9.71 (d, J = 2.4 Hz, 1H), 7.36–7.31
(m, 2H), 7.15–7.13 (m, 2H), 4.75–4.60 (m, 2H), 3.83–3.75 (m,
1H), 2.73–2.65 (m, 1H), 1.50–1.19 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3) d: 202.92, 135.36, 134.17, 129.64,
129.36, 78.21, 53.58, 42.49, 29.56, 19.68, 13.95. HPLC (Daicel Chi-
ralcel OD-H, i-PrOH/hexane = 10:90, k = 240 nm, flow rate 0.5 mL/
min, 15 °C), syn-isomer: tminor 43.5 min and tmajor 46.3 min; anti-
isomer: tminor 55.1 min and tmajor 70.4 min.
4.3.4. (R)-2-((S)-2-Nitro-1-phenylethyl)hexanal 9d49,50
1H NMR (400 MHz, CDCl3) d: 9.71 (d, J = 2.8 Hz, 1H), 7.35–7.29
(m, 3H), 7.18–7.16 (m, 2H), 4.79–4.64 (m, 2H), 3.80–3.77 (m,
1H), 1.55–1.14 (m, 6H), 0.78 (t, J = 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d: 203.37, 136.81, 129.13, 128.24, 128.17,
128.01, 78.44, 53.91, 43.16, 28.55, 27.05, 22.49, 13.65. HPLC (Daicel
Chiralcel OD-H, i-PrOH/hexane = 10:90, k = 254 nm, flow rate
1.0 mL/min), syn-isomer: tminor 23.8 min and tmajor 28.4 min; anti-
isomer: tminor 25.6 min and tmajor 42.5 min.
4.3.11. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone 9k58
1H NMR (400 MHz, CDCl3) d: 7.36–7.24 (m, 3H), 7.19–7.17 (m,
2H), 4.95 (dd, J = 12.4, 4.8 Hz, 1H), 4.65 (dd, J = 12.4, 10.0 Hz, 1H),
3.78 (dt, J = 10.0, 4.4 Hz, 1H), 2.74–2.67 (m, 1H), 2.51–2.36 (m,
2H), 2.13–2.07 (m, 1H), 1.82–1.57 (m, 4H), 1.30–1.20 (m,1H). 13C
NMR (100 MHz, CDCl3) d: 211.98, 137.74, 128.95, 128.77, 128.36,
128.18, 127.79, 78.90, 52.53, 43.95, 42.77, 33.23, 28.55, 25.05.
HPLC (Daicel Chiralcel OD-H, i-PrOH/hexane = 10:90, k = 254 nm,
flow rate 0.6 mL/min), syn-isomer: tminor 21.4 min and tmajor
21.9 min; anti-isomer: tminor 24.3 min and tmajor 29.2 min.
4.3.5. (2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal 9e27,51
1H NMR (400 MHz, CDCl3) d: 9.93 (d, J = 2.0 Hz, 1H), 7.37–7.29
(m, 3H), 7.20–7.18 (m, 2H), 4.69–4.54 (m, 2H), 3.93–3.87 (m,
1H), 2.78 (d, J = 10.8 Hz, 1H), 1.75–1.69 (m, 1H), 1.10 (d,
J = 7.2 Hz, 3H), 0.88 (d, J = 6.8 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/hex-
ane = 2:98, k = 254 nm, flow rate 0.5 mL/min), syn-isomer: tminor
30.5 min and tmajor 25.6 min.
References
4.3.6. (R)-2,2-Dimethyl-4-nitro-3-phenylbutanal 9f52,53
1H NMR (400 MHz, CDCl3) d: 9.53 (s, 1H), 7.35–7.29 (m, 3H),
7.21–7.19 (m, 2H), 4.92–4.80 (m, 1H), 4.69 (dd, J = 13.0, 4.0, 1H),
3.79 (dd, J = 11.2, 4.0, 1H), 1.14 (s, 3H), 1.01 (s, 3H). 13C NMR
(100 MHz, CDCl3) d: 204.34, 135.29, 129.09, 128.74, 128.19,
48.42, 48.26, 21.72, 18.86. HPLC (Daicel Chiralcel OD-H, i-PrOH/
hexane = 10:90, k = 254 nm, flow rate 1.0 mL/min), tmajor 16.5 min
and tminor 25.1 min.
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