Chiral Primary Amine-Squaramide Catalyzed Highly Enantioselective Michael Addition of Isobutyraldehyde to Nitroolefins

Article abstract of DOI:10.1055/s-0036-1588090

Chiral primary amine-squaramides have not been extensively studied to date in the field of organocatalysis. In this paper, novel chiral squaramides derived from natural product stevioside were developed. Both enantiomers of a series of γ-nitroaldehydes we

Full text of DOI:10.1055/s-0036-1588090

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
Z.-W. Ma et al.
Paper
Synthesis
Chiral Primary Amine–Squaramide Catalyzed Highly Enantio-
selective Michael Addition of Isobutyraldehyde to Nitroolefins
Zhi-Wei Ma*a
Xiao-Feng Liub
Bin Sunb
Xian-Hui Huangb
Jing-Chao Tao*b
O
O
N
H
HN
H2N
O
O
R
COOEt
(S,S) or (R,R)
O
NO2
NO2
H
H
a Department of Fundamental Courses, Henan University of
Animal Husbandry and Economy, No. 2 Yingcai Street, Huiji
District, Zhengzhou 450044, Henan, P. R. of China
mazhiwei1986@126.com
b College of Chemistry and Molecular Engineering, Zheng-
zhou University, No. 100 Science Avenue, High-Tech Zone,
Zhengzhou 450001, Henan, P. R. of China
primary amine–squaramide
(15 mol%)
H
or
CHCl3, r.t.
NO2
R
R
14 examples
yield: 79–98%
ee: 90–99%
jctao@zzu.edu.cn
Received: 31.08.2016
Accepted after revision: 14.10.2016
Published online: 22.11.2016
In 2008, the first report on employing a chiral squar-
amide in the conjugate addition reactions of 1,3-dicarbonyl
compounds to β-nitrostyrenes by Rawal’s group emerged.6
After the Rawal’s seminal work, chiral amine-squaramides
have emerged as powerful hydrogen-bonding bifunctional
organocatalysts not only for promoting simple carbon–
carbon and carbon–heteroatom bond formation, but also
for assisting various domino reactions, thus providing a
rapid access to highly valuable enantioenriched molecules.7
As part of our ongoing interest in asymmetric organoca-
talysis,4g,8 we have developed a highly enantioselective
Michael addition of isobutyraldehyde to nitroolefins using
isosteviol-derived chiral primary amine–thiourea 1 as cata-
lyst (Figure 1).4g Considering that squaramides has become
another complementary or even superior H-bond donor
catalyst in asymmetric organocatalysis and encouraged by
the rapid development in the field of asymmetric reactions
using squaramides as catalysts, we envisioned that the
newly designed isosteviol-derived squaramide catalysts,
which were obtained by means of the replacement of the
thiourea moiety with a squaramide moiety, could facilitate
the Michael addition of isobutyraldehyde to nitroolefins, af-
fording the expected optically active products.
DOI: 10.1055/s-0036-1588090; Art ID: ss-2016-h0596_op
Abstract Chiral primary amine–squaramides have not been extensive-
ly studied to date in the field of organocatalysis. In this paper, novel chi-
ral squaramides derived from natural product stevioside were devel-
oped. Both enantiomers of a series of γ-nitroaldehydes were generated
by using these squaramide catalysts for the Michael addition reaction of
isobutyraldehyde to nitroolefins. This asymmetric reaction proceeded
well to afford the desired products in high yields (up to 98%) with high
to excellent enantioselectivities (up to 99% ee).
Key words primary amine–squaramide, isobutyraldehyde, nitroole-
fin, Michael addition, enantiomers
The Michael reaction promoted by organocatalysts is
one of the most efficient and broadly applicable C–C bond
forming reactions due to the value of the Michael adducts
used as synthetic building blocks.1 Since the pioneering
work of List and Barbas in 2001,2 there has been dramatic
advance in developing more selective and efficient organo-
catalysts for this cornerstone transformation, and much sig-
nificant progress has been made in recent years.3
Organocatalytic asymmetric Michael addition of un-
modified aldehydes/ketones with nitroolefins to produce
enantiomerically enriched Michael products has been
explored extensively,4 but only a few examples have been
reported that use α,α-disubstituted aldehydes as Michael
donors. It is therefore of great interest to develop new cata-
lytic methods for this relatively underexplored transforma-
tion. On the other hand, many organocatalysts have been
successfully used in the asymmetric Michael reaction of
isobutyraldehyde to nitroalkenes,4g,5 such as thioureas,4g,5a–c
sulfamides,5d guanidines,5e and proline derivatives,5f–i but
no similar enantioselective Michael reactions employing
squaramide catalysts have been reported.
O
O
S
N
NH
N
H
HN
H
H2N
H2N
COOEt
COOEt
2
1
Figure 1 Isosteviol-derived thiourea 1 and squaramide 2
Starting from commercially available natural product
stevioside, amine 3 was readily prepared via hydrolyzation,
esterification, oximation, and reduction reactions.4g Treat-
ment of amine 3 with dimethyl squarate (4) in CH2Cl2 af-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
Z.-W. Ma et al.
Paper
Synthesis
forded mono-squaramide 5 in 85% yield. Consequently, chi-
ral 1,2-cyclohexyldiamines (6) were then used in the sec-
ond displacement reaction with mono-squaramide 5 to
generate desired bifunctional squaramide catalysts 2a or 2b
in good yields (82% for 2a and 83% for 2b) (Scheme 1).
Table 1 Screening of Catalysts and Solventsa
O
O
Ph
2a (20 mol%)
NO2
NO2
H
Ph
H
solvent, r.t., 20 h
8
7
9
O
O
O
O
Entry
Catalyst
Solvent
Yield (%)b
ee (%)c
NH2
1
2
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
CH2Cl2
CH2Cl2
CHCl3
Et2O
90
90
94
32
57
nrd
nrd
nrd
80
34
92 (S)
93 (R)
94 (S)
43 (S)
67 (S)
nde
N
H
OMe
MeO
OMe
4
CH2Cl2, r.t., 48 h
85%
3
COOEt
COOEt
5
3
4
O
O
5
MeCN
DMF
6
N
H
HN
H2N
NH2
nde
6
7
DMSO
MeOH
H2O
CH2Cl2, r.t., 48 h
82% or 83%
H2N
8
nde
COOEt
2
9
39 (S)
42 (S)
10
brine
O
O
O
O
a Unless otherwise specified, all reactions were carried out using isobutyral-
dehyde (7; 0.40 mmol), trans-β-nitrostyrene (8; 0.20 mmol) and 20 mol%
catalyst in 1.0 mL solvent at r.t. for 20 h.
b Isolated yield.
N
H
HN
S
N
H
HN
R
R
c Determined by chiral HPLC analysis.
d No reaction.
S
H2N
H2N
e Not determined.
2a
COOEt
COOEt
2b
Scheme 1 Preparation of squaramides 2a and 2b
Decreasing the catalyst loading from 20 mol% to 15
mol% afforded higher yield and enantioselectivity (Table 2,
entries 1 vs. 2). However, a further decrease in the catalyst
loading to 10 mol% resulted in an obvious decrease in the
yield of the reaction (entry 3). It should be noted that de-
creasing isobutyraldehyde dosage resulted in decreased
yield (entry 4). Moreover, when the reaction was conducted
With these novel catalysts in hand, the effects of the
squaramide catalysts were investigated. A model reaction of
isobutyraldehyde to trans-β-nitrostyrene was performed in
CH2Cl2 at room temperature in the presence of 20 mol% of
squaramide catalysts (Table 1).
Gratifyingly, and as expected, the catalysts 2a and 2b
were efficient and exhibited reversed senses of asymmetric
induction, providing S-enriched and R-enriched adduct re-
spectively (Table 1, entry 1 vs 2). These results indicate that
both of the S,S-configuration of 1,2-diaminocyclohexane
moiety and the R,R-configuration can well match the
isosteviol scaffold of 2, resulting in high yields (S-adduct,
90%; R-adduct, 90%) with high enantioselectivities (S-ad-
duct, 92% ee; R-adduct, 93% ee). We then simply examined
the effects of other conditions on the reaction using squara-
mide 2a.
A substantial change of the solvent has an impact effect
on the catalytic activity and the stereoselection. We were
delighted to observe that both the chemical yield and ste-
reoselectivity increased with CHCl3 as the solvent (94%
yield, 94% ee) (Table 1, entry 3). The Michael product was
obtained with poor results when the reaction was carried
out in Et2O and MeCN (entries 4 and 5). The reaction did
not occur in DMF, DMSO and MeOH (entries 6, 7, and 8). Al-
though 80% yield of the product was obtained when water
was used as reaction medium, the enantioselectivity was
low (entry 9). The reaction in brine also gave low conver-
sion and enantioselectivity (34% yield, 42% ee) (entry 10).
Table 2 Optimization of the Reaction Conditionsa
O
O
Ph
2a (X mol%)
NO2
NO2
H
Ph
H
CHCl3, r.t., 20 h
7
8
9
Entry
X (mol%)
Yield (%)b
ee (%)c
1
20
15
10
15
15
15
94
96
59
87
61
95
94 (S)
95 (S)
93 (S)
93 (S)
95 (S)
98 (R)
2
3
4d
5e
6f
a Unless otherwise specified, all reactions were carried out using isobutyral-
dehyde (7; 0.40 mmol), trans-β-nitrostyrene (8; 0.20 mmol) and X mol% 2a
in 1.0 mL CHCl3 at r.t. for 20 h.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Isobutyraldehyde used: 0.30 mmol.
e The reaction was conducted at 0 °C.
f Catalyst 2b was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
Z.-W. Ma et al.
Paper
Synthesis
at 0 °C, though the enantioselectivity was still 95% ee, only
moderate yield could be obtained (entry 5). With optimal
reaction conditions established, the conjugate reaction
with squaramide 2b was carried out. The use of squaramide
catalyst 2b provided product with still high yield (95%) and
better enantioselectivity (98% ee), as well as a reversal of
the absolute configuration of 9a (entry 6).
Table 3 Substrate Scope of the Catalytic Asymmetric Michael Addition
of Isobutyraldehyde to Nitroolefinsa
O
R
2a (15 mol%)
NO2
NO2
H
H
CHCl3, r.t.
O
NO2
(S)-9
R
H
O
R
2b (15 mol%)
Under the optimized conditions, we further studied the
generality of the asymmetric Michael addition of isobutyr-
aldehyde 7 to a variety of nitroolefins 8a–i in the presence
of squaramide catalyst 2a and 2b, and the results are sum-
marized in Table 3. Both catalysts afforded the products in
high yields with high to excellent enantioselectivity in the
asymmetric conjugate addition reaction. Generally, both
enantiomers of the corresponding products could be
achieved in almost the same yield and enantiomeric excess
with catalyst 2a and 2b, respectively. The use of catalyst 2a
gave the conjugate adducts 9a–i with S-configuration,
whereas catalyst 2b afforded the R-configuration. It appears
that higher enantioselectivities were obtained using cata-
lyst 2b. This is probably due to the more appropriate match
of the R,R-configuration of 1,2-diaminocyclohexane moiety
and the isosteviol scaffold, although both configurations
can well match the isosteviol scaffold. These results indicat-
ed that the position and the electronic property of the sub-
stituent on the aromatic ring had a limited effect on both
yield and enantioselectivity (entries 1–10). Heteroaromatic
nitroolefins were also suitable substrates, and the desired
products were obtained with excellent yields and enanti-
oselectivities (entries 11–13). Conjugated nitroalkene 8n as
an acceptor worked well with isobutyraldehyde to give
good to high yields and enantioselectivities (entry 14).
However, these catalysts could not catalyze the asymmetric
addition of isobutyraldehyde to aliphatic nitroolefins. It is
worth mentioning that the results promoted by squaramide
2a and 2b are better than those by thiourea catalyst 1.4g
To further explore the scope of the reaction, the Michael
addition of isobutyraldehyde to N-phenylmaleimide was
tested and the results are displayed in Scheme 2. N-Phenyl-
maleimide also proved a good substrate and furnished the
corresponding adducts in excellent yields and enantioselec-
tivities.
7
8
CHCl3, r.t.
(R)-9
Entry
1
R
Catalyst
Product 9 Yield (%)b ee (%)c
2a
2b
Ph (8a)
(S)-9a
(R)-9a
96
95
95
96
2
3
4-FC6H4 (8b)
2a
2b
(S)-9b
(R)-9b
92
92
95
92
4-ClC6H4 (8c)
4-BrC6H4 (8d)
3-O2NC6H4 (8e)
4-O2NC6H4 (8f)
2-MeOC6H4 (8g)
4-MeOC6H4 (8h)
1-naphthyl (8i)
2-naphthyl (8j)
2-furyl (8k)
2a
2b
(S)-9c
(R)-9c
91
92
96
99
4
2a
2b
(S)-9d
(R)-9d
89
90
96
99
5
2a
2b
(S)-9e
(R)-9e
97
97
96
99
6
2a
2b
(S)-9f
(R)-9f
90
91
96
99
7
2a
2b
(S)-9g
(R)-9g
88
90
95
96
8
2a
2b
(S)-9h
(R)-9h
85
89
94
97
9
2a
2b
(S)-9i
(R)-9i
79
82
95
97
10
11
12
13
14
2a
2b
(S)-9j
(R)-9j
81
80
97
96
2a
2b
(S)-9k
(R)-9k
97
98
93
94
2-thienyl (8l)
2a
2b
(S)-9l
(R)-9l
98
96
92
95
5-Cl-2-thienyl (8m) 2a
(S)-9m
(R)-9m
95
98
90
97
2b
PhCH=CH (8n)
2a
2b
(S)-9n
(R)-9n
86
84
95
97
a Unless otherwise specified, all reactions were carried out using isobutyral-
dehyde (7; 0.40 mmol), trans-β-nitroalkene (8; 0.20 mmol) and 15 mol% 2a
or 2b in 1.0 mL CHCl3 at r.t. for 20–36 h.
b Isolated yield.
c Determined by chiral HPLC analysis.
On the basis of the experimental results described
above, taking squaramide 2a as an example, we propose the
plausible transition state model, which reasonably explains
the absolute configuration of the Michael adducts. As de-
picted in Figure 2, similar to the action of primary amine–
thiourea catalyst, the isobutyraldehyde is activated by the
primary amine through the enamine intermediate, and the
nitrostyrene is directed and activated by the squaramide
moiety of the catalyst 2a through H-bond interactions si-
multaneously. The nitrostyrene is attacked from the Re-face
leading to the formation of addition product 9 S-configura-
tion.
O
O
N
H
N
H
NH
O
O
N
COOEt
Re-face attack
Figure 2 Proposed transition state
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D
Z.-W. Ma et al.
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Synthesis
IR (KBr): 713, 832, 927, 1025, 1091, 1148, 1178, 1218, 1366, 1440,
O
1495, 1587, 1616, 1701, 1719, 1797, 2847, 2932, 3174 cm–1
.
O
1H NMR (400 MHz, CDCl3/TMS): δ = 0.72 (s, 3 H), 0.85–0.88 (m, 1 H),
0.91 (s, 3 H), 0.94–1.13 (m, 4 H), 1.17 (s, 3 H), 1.25 (t, J = 7.2 Hz, 4 H),
1.32–1.42 (m, 4 H), 1.55–1.59 (m, 2 H), 1.63–1.73 (m, 3 H), 1.76–1.93
(m, 4 H), 2.16 (d, J = 13.2 Hz, 1 H), 3.73 (dd, J = 7.2, 17.2 Hz, 1 H), 4.03–
4.15 (m, 2 H), 4.40 (d, J = 10.4 Hz, 3 H), 5.93 (s, 1 H).
2a (10 mol%)
N
H
CHCl3, r.t., 5 h
O
O
O
H
(S)-11: 87% yield, 93% ee
N
O
7
O
O
10
13C NMR (100 MHz, CDCl3/TMS): δ = 13.4, 14.1, 18.9, 24.5, 29.0, 33.3,
37.9, 39.8, 41.2, 42.4, 55.4, 55.5, 56.9, 60.0, 60.5, 62.8, 63.5, 177.3,
183.2, 189.2.
2b (10 mol%)
N
CHCl3, r.t., 5 h
H
O
HRMS: m/z [M + H]+ calcd for C27H40NO5: 458.2906; found: 458.2908.
(R)-11: 71% yield, 98% ee
Scheme 2 Michael reaction of isobutyraldehyde to N-phenylmaleimide
Amine-Squaramide Catalysts 2a,b
The mono-squaramide 5 (0.46 g, 1 mmol) was added to a stirred solu-
tion of (S,S)- or (R,R)-cyclohexane-1,2-diamine 6 (0.11 g, 1 mmol) in
anhyd CH2Cl2 (25 mL). The reaction mixture was stirred at r.t. over-
night. TLC indicated that the reaction was complete. The solvent was
removed under reduced pressure and the crude product was purified
by column chromatography (silica gel, MeOH/CH2Cl2 = 1:10).
In summary, we have demonstrated for the first time
that novel chiral primary amine–squaramide organocata-
lysts derived from commercially available natural product
stevioside can promote the asymmetric conjugate addition
of isobutyraldehyde to various nitroolefins at room tem-
perature in high yields (up to 98%) with high to excellent
enantioselectivities (up to 99% ee). Furthermore, both en-
antiomers of the corresponding products can be achieved
with almost the same enantiomeric excess using the chiral
squaramide organocatalysts 2a and 2b simply by changing
the configuration of 1,2-diaminocyclohexane moiety. This
finding provides a novel approach to obtain both enantio-
mers of γ-nitroaldehydes. Further investigation of the effi-
cacy of these organocatalysts in other catalytic asymmetric
reactions is under way in our laboratory.
Catalyst 2a
White solid; yield: 0.44 g (82%); mp 174.3–175.1 °C; [α]D20 –255.6 (c
1.0, CHCl3).
IR (KBr): 974, 1029, 1096, 1128, 1150, 1181, 1223, 1375, 1467, 1529,
1585, 1669, 1722, 1794, 2849, 2937, 3255 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 0.71 (s, 3 H), 0.84–0.90 (m, 1 H),
0.94 (s, 3 H), 0.97–1.05 (m, 3 H), 1.09 (d, J = 11.2 Hz, 1 H), 1.16 (s, 3 H),
1.24 (t, J = 6.8 Hz, 4 H), 1.28–1.44 (m, 8 H), 1.54–2.01 (m, 13 H), 2.05
(d, J = 11.2 Hz, 1 H), 2.63 (s, 1 H), 2.81 (s, 3 H), 3.62 (s, 1 H), 4.00–4.13
(m, 2 H), 4.28 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): δ = 13.4, 14.2, 18.9, 20.4, 21.7, 24.6,
28.9, 34.0, 38.0, 39.9, 41.3, 42.3, 43.7, 55.6, 56.9, 60.0, 62.8, 177.5,
182.1.
HRMS: m/z [M+ H]+ calcd for C32H50N3O4: 540.3801; found: 540.3801.
All chemicals were used as received unless otherwise noted. Reagent
grade solvents were redistilled prior to use. 1H NMR and 13C NMR
spectra were recorded on a Bruker DPX 400 NMR spectrometer with
TMS as internal reference. IR spectra were recorded on a Thermo Ni-
colet IR200 unit. ESI mass spectra were recorded on an HPLC Q-Exac-
tive HRMS spectrometer (Thermo, USA) by using MeOH as mobile
phase. Chromatography was performed on silica gel (200–300 mesh).
Melting points were determined with an aXT5 A apparatus and are
uncorrected. Optical rotations were determined with a PerkinElmer
341 polarimeter. Enantiomeric excesses were determined by chiral
HPLC at r.t. with use of a Labtech 2006 pump, a Labtech UV600 ultra
detector, and Chiralcel OD-H (4.6 mm × 250 mm) columns. The abso-
lute configurations of the known adducts 9a–l, n, and 11 were as-
signed by HPLC and specific rotation comparisons with the reported
data, those of the unknown adduct 9m was assigned by analogy.
Catalyst 2b
20
White solid; yield: 0.45 g (83%); mp 175.8–176.4 °C; [α]D +52.6 (c
1.0, CHCl3).
IR (KBr): 853, 974, 1029, 1095, 1150, 1181, 1223, 1375, 1467, 1527,
1584, 1670, 1721, 1793, 2849, 2937, 3267 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 0.79 (s, 3 H), 0.85–0.88 (m, 1 H),
0.92 (s, 3 H), 0.95–1.06 (m, 3 H), 1.11 (d, J = 11.6 Hz, 1 H), 1.17 (s, 3 H),
1.23 (t, J = 6.8 Hz, 4 H), 1.31–1.45 (m, 7 H), 1.56–1.63 (m, 4 H), 1.70–
2.06 (m, 10 H), 2.15 (d, J = 13.2 Hz, 1 H), 2.71 (m, 1 H), 3.71–3.73 (m, 1
H), 4.00–4.12 (m, 3 H), 4.29–4.30 (m, 2 H), 7.72 (s, 1 H), 8.00 (s, 1 H).
13C NMR (100 MHz, CDCl3/TMS): δ = 13.4, 14.1, 18.9, 20.4, 21.7, 24.4,
24.6, 29.0, 33.6, 38.0, 38.1, 39.8, 41.3, 42.2, 43.7, 54.8, 55.6, 59.9, 63.0,
177.5, 182.0.
HRMS: m/z [M + H]+ calcd for C32H50N3O4: 540.3801; found: 540.3803.
Mono-Squaramide 5
Amine compound 3 (0.35 g, 1 mmol) in CH2Cl2 (10 mL) was added
dropwise to a solution of dimethyl squarate (4; 0.14 g, 1 mmol) in
CH2Cl2 (10 mmol). The reaction mixture was stirred for 48 h at r.t. TLC
indicated that the reaction was complete. The solvent was removed
and the residue was purified by column chromatography (silica gel,
EtOAc/PE = 1:5) to afford the pure product (0.39 g, 85%) as a white
solid; mp 196.7–197.8 °C; [α]D20 –57.7 (c 1.0, CHCl3).
Asymmetric Michael Reactions; General Procedure
Isobutyraldehyde (7; 29 mg, 0.40 mmol) was added to a mixture of a
catalyst 2a or 2b (15 mol%) and a nitroalkene 8 (0.20 mmol) in CHCl3
(1.0 mL). The reaction mixture was stirred at r.t. for the time required.
After the nitroalkene had been consumed (TLC), the mixture was sub-
jected to TLC on silica gel (EtOAc/PE = 1:2) to afford the pure desired
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Synthesis
Michael product 9. The enantiomeric excesses of the products 9 were
determined by chiral HPLC analysis with Chiralcel OD-H columns (Ta-
ble 3).
(S)-3-(4-Bromophenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9d]5f
20
White solid; yield: 53.2 mg (89%); mp 89–90 °C; [α]D –3.7 (c 1.0,
CHCl3); 96% ee.
Only the Michael addition products obtained using the catalyst 2a are
listed below. For the yields and ee values of the Michael addition
products prepared using the catalyst 2b, see Table 3.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 20.1 min (minor), 29.5 min (major).
IR (KBr): 530, 650, 719, 757, 782, 836, 884, 1009, 1077, 1091, 1221,
1361, 1415, 1435, 1490, 1556, 1636, 1413, 2850, 2925, 2970, 3000,
(S)-2,2-Dimethyl-4-nitro-3-phenylbutanal [(S)-9a]5f
3412 cm–1
.
20
Light yellow oil; yield: 42.4 mg (96%); [α]D –7.8 (c 1.0, CHCl3); 95%
1H NMR (400 MHz, CDCl3/TMS): δ = 1.00 (s, 3 H, CH3), 1.12 (s, 3 H,
CH3), 3.74–3.78 (dd, J = 4.0, 11.2 Hz, 1 H, CH), 4.67–4.71 (dd, J = 4.0,
13.2 Hz, 1 H, CH2), 4.79–4.85 (dd, J = 11.2, 13.2 Hz, 1 H, CH2), 7.08–
7.11 (d, J = 8.4 Hz, 2 H, ArH), 7.46–7.48 (d, J = 8.4 Hz, 2 H, ArH), 9.49 (s,
1 H, CHO).
ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 18.7 min (minor), 27.3 min (major).
IR (KBr): 530, 669, 721, 786, 839, 902, 1014, 1093, 1222, 1362, 1420,
1557, 1636, 1714, 2850, 2925, 2965, 3003, 3413 cm–1
.
13C NMR (100 MHz, CDCl3/TMS): δ = 18.9, 21.8, 47.9, 48.1, 76.1, 122.3,
1H NMR (400 MHz, CDCl3/TMS): δ = 1.02 (s, 3 H, CH3), 1.15 (s, 3 H,
CH3), 3.78–3.82 (dd, J = 4.2, 11.3 Hz, 1 H, CH), 4.69–4.73 (dd, J = 4.2,
13.1 Hz, 1 H, CH2), 4.84–4.91 (dd, J = 11.4, 12.9 Hz, 1 H, CH2), 7.21–
7.37 (m, 5 H, ArH), 9.54 (s, 1 H, CHO).
130.8, 131.9, 134.5, 203.9.
HRMS: m/z [M – H]– calcd for C12H13BrNO3: 298.0084; found:
298.0085.
13C NMR (100 MHz, CDCl3/TMS): δ = 18.9, 21.7, 48.2, 48.5, 76.3, 128.2,
128.7, 129.1, 135.4, 204.3.
HRMS: m/z [M – H]– calcd for C12H14NO3: 220.0979; found: 220.0977.
(S)-3-(3-Nitrophenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9e]5b
Light yellow oil; yiel: 51.6 mg (97%); [α]D20 +3.3 (c 1.0, CHCl3); 96% ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 30.0 min (minor), 49.6 min (major).
(S)-3-(4-Fluorophenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9b]5b
IR (KBr): 530, 675, 698, 737, 758, 792, 813, 903, 1092, 1221, 1360,
20
1421, 1534, 1557, 1636, 1713, 2853, 2924, 2965, 3003, 3412 cm–1
.
Light yellow oil; yield: 44.0 mg (92%); [α]D –1.6 (c 1.0, CHCl3); 95%
ee.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.06 (s, 3 H, CH3), 1.18 (s, 3 H,
CH3), 3.94–3.98 (dd, J = 4.0, 11.6 Hz, 1 H, CH), 4.77–4.81 (dd, J = 4.0,
13.6 Hz, 1 H, CH2), 4.92–4.98 (dd, J = 11.6, 13.6 Hz, 1 H, CH2), 7.54–
7.58 (t, J = 8.0 Hz, 1 H, ArH), 7.59–7.62 (m, 1 H, ArH), 8.14 (t, J = 1.6 Hz,
1 H, ArH), 8.18–8.20 (m, 1 H, ArH), 9.51 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3/TMS): δ = 19.0, 21.8, 48.0, 48.3, 75.9, 123.9,
129.8, 135.4, 138.1, 148.3, 203.2.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 16.0 min (minor), 29.4 min (major).
IR (KBr): 530, 755, 845, 902, 1092, 1165, 1222, 1361, 1422, 1512,
1557, 1604, 1713, 2850, 2925, 2968, 3003, 3412 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.01 (s, 3 H, CH3), 1.13 (s, 3 H,
CH3), 3.77–3.81 (dd, J = 4.0, 11.6 Hz, 1 H, CH), 4.67–4.72 (dd, J = 4.0,
12.8 Hz, 1 H, CH2), 4.80–4.86 (dd, J = 11.6, 12.8 Hz, 1 H, CH2), 7.01–
7.05 (m, 2 H, ArH), 7.17–7.21 (m, 2 H, ArH), 9.51 (s, 1 H, CHO).
HRMS: m/z [M – H]– calcd for C12H13N2O5: 265.0830; found: 265.0831.
13C NMR (100 MHz, CDCl3/TMS): δ = 18.9, 21.7, 47.8, 48.2, 76.4, 115.7
(d, J = 21.8 Hz), 130.7 (d, J = 8.0 Hz), 131.2 (d, J = 3.5 Hz), 162.4 (d,
J = 246.0 Hz), 204.1.
(S)-3-(4-Nitrophenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9f]5c
Light yellow solid; yield: 47.9 mg (90%); mp 58–59 °C; [α]D20 –10.1 (c
1.0, CHCl3); 96% ee.
HRMS: m/z [M
–
H]– calcd for C12H13FNO3: 238.0885; found:
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 37.9 min (minor), 61.0 min (major).
238.0883.
IR (KBr): 530, 665, 721, 786, 839, 883, 902, 1014, 1092, 1221, 1361,
(S)-3-(4-Chlorophenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9c]5f
1420, 1493, 1639, 1714, 2850, 2925, 2965, 3003, 3413 cm–1
.
20
Light yellow solid; yield: 46.4 mg (91%); mp 62–63 °C; [α]D –2.1 (c
1H NMR (400 MHz, CDCl3/TMS): δ = 1.05 (s, 3 H, CH3), 1.17 (s, 3 H,
CH3), 3.92–3.96 (dd, J = 4.0, 11.6 Hz, 1 H, CH), 4.76–4.81 (dd, J = 4.0,
13.2 Hz, 1 H, CH2), 4.90–4.96 (dd, J = 11.6, 13.6 Hz, 1 H, CH2), 7.43–
7.45 (d, J = 8.8 Hz, 2 H, ArH), 8.20–8.22 (d, J = 8.8 Hz, 2 H, ArH), 9.49 (s,
1 H, CHO).
1.0, CHCl3); 96% ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 17.7 min (minor), 28.2 min (major).
IR (KBr): 530, 665, 721, 786, 839, 883, 902, 1014, 1092, 1221, 1361,
1420, 1493, 1557, 1639, 1714, 2850, 2925, 2965, 3003, 3413 cm–1
.
13C NMR (100 MHz, CDCl3/TMS): δ = 19.1, 21.9, 48.1, 48.2, 75.8, 123.9,
1H NMR (400 MHz, CDCl3/TMS): δ = 1.00 (s, 3 H, CH3), 1.12 (s, 3 H,
CH3), 3.76–3.80 (dd, J = 4.0, 11.2 Hz, 1 H, CH), 4.67–4.72 (dd, J = 4.0,
12.8 Hz, 1 H, CH2), 4.80–4.86 (dd, J = 11.6, 13.2 Hz, 1 H, CH2), 7.14–
7.17 (d, J = 8.4 Hz, 2 H, ArH), 7.30–7.32 (d, J = 8.4 Hz, 2 H, ArH), 9.49 (s,
1 H, CHO).
13C NMR (100 MHz, CDCl3/TMS): δ = 18.9, 21.7, 47.8, 48.2, 76.2, 129.0,
130.4, 134.0, 134.1, 203.9.
130.2, 143.4, 147.7, 203.2.
HRMS: m/z [M – H]– calcd for C12H13N2O5: 265.0830; found: 265.0833.
(S)-3-(2-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9g]5f
Light yellow oil; yield: 44.2 mg (88%); [α]D20 +16.4 (c 1.0, CHCl3); 95%
ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 12.0 min (minor), 19.1 min (major).
HRMS: m/z [M – H]– calcd for C12H13ClNO3: 254.0589; found:
254.0589.
IR (KBr): 530, 733, 760, 785, 903, 982, 1027, 1092, 1222, 1362, 1420,
1556, 1636, 1714, 2850, 2923, 2965, 3004, 3410 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
Z.-W. Ma et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3/TMS): δ = 1.05 (s, 3 H, CH3), 1.10 (s, 3 H,
CH3), 3.82 (s, 3 H, OCH3), 4.09–4.15 (dd, J = 7.2, 14.0 Hz, 1 H, CH),
4.71–4.75 (dd, J = 4.4, 12.8 Hz, 1 H, CH2), 4.87–4.93 (dd, J = 10.8, 12.8
Hz, 1 H, CH2), 6.88–6.95 (m, 2 H, ArH), 7.12–7.14 (dd, J = 1.2, 7.2 Hz, 1
H, ArH), 7.24–7.29 (m, 1 H, ArH), 9.51 (s, 1 H, CHO).
HRMS: m/z [M + Na]+ calcd for C16H17NO3Na: 294.1106; found:
294.1094.
(S)-3-(Furan-2-yl)-2,2-dimethyl-4-nitrobutanal [(S)-9k]5b
Light yellow oil; yield: 40.9 mg, 97% yield; [α]D20 +20.1 (c 1.0, CHCl3);
13C NMR (100 MHz, CDCl3/TMS): δ = 20.0, 21.0, 48.4, 55.3, 60.4, 75.8,
93% ee.
111.3, 120.8, 124.0, 129.3, 157.4, 204.1.
HRMS: m/z [M + Na]+ calcd for C13H17NO4Na: 274.1055; found:
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 12.5 min (minor), 20.2 min (major).
274.1045.
IR (KBr): 530, 665, 721, 786, 839, 883, 902, 1014, 1092, 1221, 1361,
1420, 1493, 1557, 1639, 1714, 2850, 2925, 2968, 3003, 3413 cm–1
.
(S)-3-(4-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal [(S)-9h]5f
1H NMR (400 MHz, CDCl3/TMS): δ = 1.05 (s, 3 H, CH3), 1.18 (s, 3 H,
CH3), 3.91–3.94 (dd, J = 3.8, 7.2 Hz, 1 H, CH), 4.57–4.61 (dd, J = 3.9, 9.0
Hz, 1 H, CH2), 4.73–4.79 (dd, J = 3.1, 12.9 Hz, 1 H, CH2), 6.22 (d, J = 3.2
Hz, 1 H, ArH), 6.31–6.32 (dd, J = 1.9, 3.2 Hz, 1 H, ArH), 7.37 (d, J = 1.2
Hz, 1 H, ArH), 9.52 (s, 1 H, CHO).
20
Light yellow solid; yield: 42.7 mg (85%); mp 59–60 °C; [α]D +2.0 (c
1.0, CHCl3); 94% ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 20.8 min (minor), 31.2 min (major).
IR (KBr): 528, 755, 845, 897, 1091, 1162, 1217, 1360, 1418, 1511,
13C NMR (100 MHz, CDCl3/TMS): δ = 19.1, 21.2, 42.3, 48.2, 74.9, 109.7,
110.4, 142.8, 149.8, 203.5.
1557, 1604, 1713, 2850, 2921, 2968, 3004, 3406 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.00 (s, 3 H, CH3), 1.12 (s, 3 H,
CH3), 3.71–3.75 (dd, J = 4.0, 11.2 Hz, 1 H, CH), 3.78 (s, 3 H, OCH3),
4.64–4.68 (dd, J = 4.0, 13.2 Hz, 1 H, CH2), 4.78–4.84 (dd, J = 11.6, 12.8
Hz, 1 H, CH2), 6.84–6.86 (d, J = 8.4 Hz, 2 H, ArH), 7.11–7.13 (d, J = 8.4
Hz, 2 H, ArH), 9.52 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3/TMS): δ = 18.9, 21.6, 47.8, 48.4, 76.5, 114.1,
127.1, 130.1, 159.3, 204.5.
HRMS: m/z [M – H]– calcd for C10H12NO4: 210.0772; found: 210.0766.
(S)-2,2-Dimethyl-4-nitro-3-(thiophen-2-yl)butanal [(S)-9l]5a
Light yellow oil; yield:44.5 mg (98%); [α]D20 –10.2 (c 1.0, CHCl3); 92%
ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 17.3 min (minor), 29.6 min (major).
HRMS: m/z [M + Na]+ calcd for C13H17NO4Na: 274.1055; found:
274.1043.
IR (KBr): 530, 665, 758, 806, 902, 999, 1092, 1221, 1361, 1422, 1558,
1636, 1713, 2853, 2925, 2965, 3004, 3413 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.12 (s, 3 H, CH3), 1.20 (s, 3 H,
CH3), 3.96–4.00 (dd, J = 4.4, 9.2 Hz, 1 H, CH), 4.61–4.70 (m, 2 H, CH2),
6.71 (d, J = 4 Hz, 1 H, ArH), 6.77 (d, J = 4 Hz, 1 H, ArH), 9.49 (s, 1 H,
CHO).
(S)-2,2-Dimethyl-3-(naphthalene-1-yl)-4-nitrobutanal [(S)-9i]5c
Light yellow solid; yield: 42.8 mg (79%); mp 105–106 °C; [α]D20 –77.4
(c 1.0, CHCl3); 95% ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 30.2 min (minor), 57.6 min (major).
13C NMR (100 MHz, CDCl3/TMS): δ = 19.1, 21.6, 44.7, 48.4, 77.4, 125.9,
127.5, 130.0, 136.8, 203.3.
IR (KBr): 497, 781, 795, 876, 1108, 1377, 1432, 1468, 1550, 1599,
HRMS: m/z [M
226.0540.
–
H]– calcd for C10H12NO3S: 226.0543; found:
1716, 2715, 2814, 2969, 3438 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 0.94 (s, 3 H, CH3), 1.18 (s, 3 H,
CH3), 4.83–4.87 (dd, J = 1.6, 10.4 Hz, 1 H, CH), 4.90–5.02 (m, 2 H, CH2),
7.36–7.52 (m, 3 H, ArH), 7.55–7.59 (t, J = 8 Hz, 1 H, ArH), 7.79–7.86
(dd, J = 8, 21.2 Hz, 2 H, ArH), 8.21–8.24 (d, J = 8.8 Hz, 1 H, ArH), 9.57 (s,
1 H, CHO).
13C NMR (100 MHz, CDCl3/TMS): δ = 18.9, 21.7, 40.3, 49.1, 77.0, 123.1,
124.9, 125.0, 126.0, 126.8, 128.8, 129.1, 132.3, 132.9, 134.1, 204.5.
(S)-3-(5-Chlorothiphen-2-yl)-2,2-Dimethyl-4-nitrobutanal (S)-9m
Light yellow oil; yield: 49.6 mg (95%); [α]D20 +13.1 (c 1.0, CHCl3); 90%
ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 254 nm); tR = 16.8 min (minor), 29.6 min (major).
IR (KBr): 530, 665, 758, 806, 902, 999, 1092, 1221, 1361, 1422, 1558,
HRMS: m/z [M – H]– calcd for C16H16NO3: 270.1136; found: 270.1136.
1636, 1713, 2853, 2925, 2965, 3004, 3413 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.12 (s, 3 H, CH3), 1.20 (s, 3 H,
CH3), 3.96–4.00 (dd, J = 4.4, 9.2 Hz, 1 H, CH), 4.61–4.70 (m, 2 H, CH2),
6.71 (d, J = 4 Hz, 1 H, ArH), 6.77 (d, J = 4 Hz, 1 H, ArH), 9.49 (s, 1 H,
CHO).
(S)-2,2-Dimethyl-3-(naphthalene-2-yl)-4-nitrobutanal [(S)-9j]5a
20
Light yellow oil; yield: 43.9 mg (81%); [α]D +3.1 (c 1.0, CHCl3); 97%
ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.85
mL/min, λ = 254 nm); tR = 31.3 min (minor), 63.8 min (major).
13C NMR (100 MHz, CDCl3/TMS): δ = 19.1, 21.6, 44.7, 48.4, 77.4, 125.9,
127.5, 130.0, 136.8, 203.3.
IR (KBr): 530, 752, 787, 827, 902, 1092, 1221, 1361, 1421, 1556, 1636,
HRMS: m/z [M + Na]+ calcd for C10H12ClNO3SNa: 284.0124; found:
284.0113.
1714, 2853, 2923, 2962, 3003, 3413 cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.03 (s, 3 H, CH3), 1.17 (s, 3 H,
CH3), 3.93–3.97 (dd, J = 4.0, 11.2 Hz, 1 H, CH), 4.74–4.79 (dd, J = 4.0,
12.8 Hz, 1 H, CH2), 4.95–5.01 (dd, J = 11.2, 12.8 Hz, 1 H, CH2), 7.30–
7.33 (dd, J = 1.6 Hz, 1 H, ArH), 7.46–7.51 (m, 2 H, ArH), 7.66 (s, 1 H,
ArH), 7.79–7.82 (m, 3 H, ArH), 9.55 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3/TMS): δ = 19.1, 21.8, 48.5, 48.7, 76.4, 126.4,
126.6, 127.6, 127.9, 128.4, 128.5, 132.9, 133.1, 204.3.
(S,E)-2,2-Dimethyl-3-(nitromethyl)-5-phenylpent-4-enal [(S)-9n]5c
20
Light yellow oil; yield: 42.5 mg (86%); [α]D +8.7 (c 1.0, CHCl3); 95%
ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.6
mL/min, λ = 254 nm); tR = 19.3 min (minor), 22.7 min (major).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
Z.-W. Ma et al.
Paper
Synthesis
IR (KBr): 530, 696, 750, 784, 902, 975, 1092, 1221, 1361, 1421, 1556,
1636, 1714, 2850, 2925, 2965, 3003, 3413 cm–1
metry 2007, 18, 299. (e) Krause, N.; Hoffmann-Röder, A. Synthe-
sis 2001, 171. (f) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877.
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.16 (s, 6 H, 2 × CH3), 3.25–3.31
(dt, J = 4.0, 10.0 Hz, 1 H, CH), 4.42–4.48 (dd, J = 10.8, 12.0 Hz, 1 H,
CH2), 4.50–4.54 (dd, J = 4.0, 12.0 Hz, 1 H, CH2), 5.99–6.05 (dd, J = 10.0,
15.6 Hz, 1 H, CH=CH), 6.51–6.55 (d, J = 15.6 Hz, 1 H, CH=CH), 7.24–
7.35 (m, 5 H, ArH), 9.51 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3/TMS): δ = 19.1, 21.0, 47.2, 47.8, 76.7, 122.8,
126.6, 128.2, 128.6, 135.9, 136.3, 203.8.
(2) (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
(b) Betancort, J. M.; Barbas, C. F. Org. Lett. 2001, 3, 3737.
(3) For selected examples, see: (a) Moorthy, N. V. G.; Dyapa, R.;
Pansare, S. V. Org. Lett. 2015, 17, 5312. (b) Gu, X.; Dai, Y.; Guo,
T.; Franchino, A.; Dixon, D. J.; Ye, J. Org. Lett. 2015, 17, 1505.
(c) Fu, N.; Zhang, L.; Luo, S. Org. Lett. 2015, 17, 382. (d) Rout, S.;
Ray, S. K.; Unhale, R. A.; Singh, V. K. Org. Lett. 2014, 16, 5568.
(e) Mukaiyama, T.; Ogata, K.; Sato, I.; Hayashi, Y. Chem. Eur. J.
2014, 20, 13410. (f) Mukaiyama, T.; Ogata, K.; Sato, I.; Hayashi,
Y. Chem. Eur. J. 2014, 20, 13583. (g) Kótai, B.; Kardos, G.; Hamza,
A.; Farkas, V.; Pápai, I.; Soós, T. Chem. Eur. J. 2014, 20, 5631.
(h) Androvič, L.; Drabina, P.; Svobodová, M.; Sedlák, M. Tetrahe-
dron: Asymmetry 2016, 27, 782. (i) Liu, S.; Wang, Q.; Ye, L.; Shi,
Z.; Zhao, Z.; Yang, X.; Ding, K.; Li, X. Tetrahedron 2016, 72, 5115.
(j) Kanberoğlu, E.; Tanyeli, C. Asian J. Org. Chem. 2016, 5, 114.
(k) Guo, Q.; Fraboni, A. J.; Brenner-Moyer, S. E. Org. Lett. 2016,
18, 2628. (l) Zhao, B.-L.; Zhang, D.; Liu, L.; Du, D.-M. Org. Biomol.
Chem. 2016, 14, 6337.
(4) For selected examples, see: (a) Servín, F. A.; Madrigal, D.;
Romero, J. A.; Chávez, D.; Aguirre, G.; Anaya de Parrodi, C.;
Somanathan, R. Tetrahedron Lett. 2015, 56, 2355. (b) Nakashima,
K.; Hirashima, S.-i.; Kawada, M.; Koseki, Y.; Tada, N.; Itoh, A.;
Miura, T. Tetrahedron Lett. 2014, 55, 2703. (c) Hu, X.; Wei, Y.-F.;
Wu, N.; Jiang, Z.; Liu, C.; Luo, R.-S. Tetrahedron: Asymmetry
2016, 27, 420. (d) Rogozińska-Szymczak, M.; Mlynarski, J. Eur. J.
Org. Chem. 2015, 6047. (e) Wang, Y.; Li, D.; Lin, J.; Wei, K. RSC
Adv. 2015, 5, 5863. (f) Cao, X.; Wang, G.; Zhang, R.; Wei, Y.;
Wang, W.; Sun, H.; Chen, L. Org. Biomol. Chem. 2011, 9, 6487.
(g) Ma, Z.-W.; Liu, Y.-X.; Zhang, W.-J.; Tao, Y.; Zhu, Y.; Tao, J.-C.;
Tang, M.-S. Eur. J. Org. Chem. 2011, 6747.
HRMS: m/z [M + Na]+ calcd for C14H17NO3Na: 270.1106; found:
270.1096.
(R)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropionalde-
hyde [(R)-11]8a
Isobutyraldehyde (7; 29 mg, 0.40 mmol) was added to a mixture of
the catalyst 2b (10 mol%) and N-phenylmaleimide (10; 35 mg, 0.20
mmol) in CHCl3 (1.0 mL). The reaction mixture was stirred at r.t. for 5
h. After the N-phenylmaleimide had been consumed (TLC), the mix-
ture was subjected to TLC on silica gel (EtOAc/hexane) to afford the
pure Michael product (R)-11 (34.8 mg, 71%) as a white solid; mp 106–
107 °C; [α]D20 +5.5 (c 1.0, CHCl3); 98% ee.
HPLC: Chiralcel OD-H (hexanes/i-PrOH = 80:20, flow rate = 0.7
mL/min, λ = 210 nm); tR = 37.0 min (major), 49.2 min (minor).
IR (KBr): 499, 563, 627, 666, 703, 755, 814, 885, 1164, 1189, 1395,
1454,1471, 1490, 1500, 1705, 1773, 2730, 2822, 2932, 2989, 3459
cm–1
.
1H NMR (400 MHz, CDCl3/TMS): δ = 1.27 (s, 3 H, CH3), 1.31(s, 3 H,
CH3), 2.58–2.64 (dd, J = 5.6, 18.2 Hz, 1 H, CH2), 2.92–2.99 (dd, J = 9.6,
18.4 Hz, 1 H, CH2), 3.12–3.16 (dd, J = 5.6, 9.6 Hz, 1 H, CH), 7.27 (d,
J = 7.6 Hz, 2 H, ArH), 7.37–7.41 (t, J = 7.2 Hz, 1 H, ArH), 7.45–7.49 (t,
J = 7.2 Hz, 2 H, ArH), 9.50 (s, 1 H, CHO).
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13C NMR (100 MHz, CDCl3/TMS): δ = 19.6, 20.3, 31.8, 45.0, 48.5, 126.5,
128.7, 129.2, 131.8, 174.8, 176.9, 202.8.
HRMS: m/z [M – H]– calcd for C14H14NO3: 244.0979: found: 244.0978.
Acknowledgment
The authors gratefully acknowledge the Key Project of Colleges and
Universities of Henan Province of China (15 A150049), Science and
Technology Development Program of Jinshui District of Zhengzhou
City ([2014]33-7), and Program for Second batch of Science and Tech-
nology Innovation Team of Henan University of Animal Husbandry
and Economy (HUAHE2015008) for generous financial support.
Supporting Information
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130, 14416.
Supporting information for this article is available online at
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Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal.
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