Highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by designer chiral BINOL-quinine-squaramide: Efficient access to optically active nitro-alkanes and their isoxazole derivatives

Article abstract of DOI:10.1016/j.tetasy.2013.08.010

A chiral BINOL-quinine-squaramide has been identified as the best catalyst for the asymmetric Michael addition of nitroalkenes to 1,3-dicarbonyl compounds. A series of chiral nitroalkanes were prepared with approximately >99% ee. Furthermore, the methodol

Full text of DOI:10.1016/j.tetasy.2013.08.010

Tetrahedron: Asymmetry 24 (2013) 1276–1280
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective Michael addition of 1,3-dicarbonyl
compounds to nitroalkenes catalyzed by designer chiral
BINOL–quinine–squaramide: efficient access to optically active
nitro-alkanes and their isoxazole derivatives
⇑
Bin Liu, Xin Han, Ze Dong, Hao Lv, Hai-Bing Zhou, Chune Dong
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, State Key Laboratory of Virology,
Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2013
Accepted 9 August 2013
A chiral BINOL–quinine–squaramide has been identified as the best catalyst for the asymmetric Michael
addition of nitroalkenes to 1,3-dicarbonyl compounds. A series of chiral nitroalkanes were prepared with
approximately >99% ee. Furthermore, the methodology was applied successfully to the synthesis of enan-
tiomerically pure isoxazoles derivatives (>99% ee).
Ó 2013 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
S
Ph
Ph
N
N
H
N
H
The Michael addition reaction is one of the fundamental
bond-forming processes in organic chemistry and is an extremely
powerful tool for synthesis of functionalized organic molecules.1
Within this process, the addition of 1,3-dicarbonyl compounds to
nitroalkenes has attracted particular interest due to the reactivity
of the resulting enantiopure nitro carbonyl adducts.2 Therefore,
extensive research has been carried out on the development of this
catalytic asymmetric Michael transformation.3 The asymmetric
control in this reaction has been achieved with organocatalysts
based on diamines,4 thioureas, cinchona derivatives, etc.5,6 In this
context, the design and development of novel chiral bifunctional
hydrogen-bonding donor–acceptor organocatalysts, which can
activate nucleophiles and electrophiles simultaneously through
hydrogen-bonding, have emerged as an area of research in the field
of asymmetric catalysis. Wang et al. have developed a series of
chiral bifunctional thiourea multiple H-bond donor catalysts
(Scheme 1), which have shown excellent catalytic performance in
various asymmetric transformations, ranging from Michael addi-
tion to Nitro-Mannich additions.5d Inspired by Rawal’s work, chiral
squaramides have recently emerged as a promising class of organ-
ocatalysts in asymmetric transformations.7 We are interested in
the design and synthesis of a variety of chiral squaramides and
their application in a series of asymmetric transformations.8
Recently, we have reported that the indanol and cinchona alkaloid
derived chiral squaramide can function as a multiple H-bond donor
N
H
NH
HN
N
SO2
OH
OH
N
OMe
F3C
Wang's catalyst5d
CF3
this work
O
N
CH3
NO2
H3C
*
R
>99% ee
Scheme 1. Design of multiple hydrogen-bonding squaramide organocatalyst.
organocatalyst and has shown high catalytic activity and excellent
enantioselectivity in the asymmetric Michael addition of
1,3-dicarbonyl compounds to nitroalkenes.8a Encouraged by these
preliminary results, we carried out further research on new multi-
ple hydrogen-bond donor chiral squaramide organcatalysts. We
envisioned that BINOL derived squaramides with a cinchona
alkaloid moiety could function as multiple hydrogen bond donors
to provide four hydrogen bonds to electrophiles, leading to a highly
efficient synthesis of enantiomerically pure isoxazole derivatives
⇑
Corresponding author. Tel.: +86 27 68759586; fax: +86 27 68759850.
E-mail address: cdong@whu.edu.cn (C. Dong).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.08.010

B. Liu et al. / Tetrahedron: Asymmetry 24 (2013) 1276–1280
1277
Table 1
through a chiral squaramide organocatalyst catalyzed asymmetric
Optimized condition for the reaction of 2a with 3a catalyzed by 1a–1ea
Michael addition reaction (Scheme 1). Compared with our previous
indanol–cinchona–squaramides, the new catalyst performed well
at only 0.5 mol % loading in the asymmetric Michael addition reac-
tion of 1,3-dicarbonyl compounds to nitroalkenes leading to the
highest enantioselectivity (>99%) and diastereoselectivity (>99%).
Herein we report a new, readily prepared cinchona alkaloid-
squaramide containing the BINOL moiety as a highly efficient
organocatalyst in the asymmetric Michael addition reaction of
1,3-dicarbonyl compounds to nitroalkenes providing various opti-
cally active nitroalkanes 4 in up to 92% yield and with >99% ee. The
enantiopure nitro dicarbonyl products were successfully trans-
formed into isoxazoles without a loss of enantioselectivity, which
are important compounds for the inhibition of factor Xa and
human b-adrenergic receptors.9,10
O
O
NO2
O
O
NO2
Catalyst
*
+
4a
3a
2a
Entry
Loading (mol %)
Solvent
Yieldb (%)
eec (%)
1
2
3
1a, (3)
1a, (2)
1a, (1)
1a, (0.5)
1a, (0.5)
1b, (3)
1c, (3)
1d, (3)
1e, (3)
1a, (3)
1a, (3)
1a, (3)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
THF
86
85
83
81
89
81
84
80
77
37
71
69
98
95
97
97
>99
96
88
51
89
54
86
91
4
5d
6
7
8
9
10
11
12
2. Result and discussion
According to a previous method,8a the chiral organocatalyst 1a
was prepared in two steps from readily available BINOL and qui-
nine. Catalysts 1b–e (outlined in Scheme 2) were also synthesized
by using the same procedure.
With catalysts 1a–e in hand, their activity was tested in the Mi-
chael addition of trans-b-nitrostyrene 2a with 2,4-pentanedione
3a. The results are shown in Table 1. As can be seen in Table 1, cat-
alyst 1a performed well at 3 mol % loading in DCM at room tem-
perature with 98% ee (entry 1). For comparison, catalyst 1b,
derived from quinidine, exhibited a high enantioselectivity under
the same reaction conditions, giving the product with the opposite
configuration in 81% yield and with 96% ee (entry 6).
When the reaction was carried out with 3 mol% 1c–e, com-
pound 4a was obtained in 88%, 51%, and 89% ee respectively (en-
tries 7–9). From these results, it can be seen that the best
catalyst was 1a. With 3 mol % of 1a as the catalyst at room temper-
ature, various solvents were examined for this reaction (Table 1,
entries 10–12), the use of DCM was determined to be the most
appropriate solvent.
Catalyst loading of 2 and 1 mol % still maintained the enantiose-
lectivity. Reducing the loading of 1a to 0.5 mol % and prolonging
the reaction time to 36 h resulted in excellent enantioselectivity
(>99% ee) (entry 5). Therefore, 0.5 mol % of catalyst loading was
chosen for 1a.
Toluene
a
Reaction conditions: unless otherwise noted, acetoacetone 3a (0.4 mmol) was
added to an agitated solution of nitroolefin 2a (0.2 mmol) and catalyst 1a–e in
1.5 mL of solvent at room temperature for 24 h.
b
Isolated yield.
c
Determined by HPLC analysis using chiralpak AD-H columns.
The reaction was prolonged to 36 h.
d
With the optimized reaction conditions in hand, the use of cat-
alyst 1a was next investigated in the Michael addition of 1,3-dike-
tones with a series of b-nitrostyrenes 2 under the optimized
reaction conditions; the results are summarized in Table 2. In gen-
eral, nitrostyrenes bearing either electron-donating or electron-
withdrawing substituents (F, Me, MeO, CF3, Furyl etc.) at the meta-
or para-position on the phenyl ring afforded the corresponding Mi-
chael adducts 4 with excellent yields and enantioselectivities (up
to >99% ee) (entries 1–8, and 10–12). In the case of heteroaromatic
nitrostyrene 2i derived from furan, the desired products 4i and 4m
were also obtained with excellent yields and enantioselectivities
(entries 9 and 13).
As shown in Table 3, further extension of the substrate to a
ketoester was investigated. Under the above optimized reaction
conditions, the catalytic asymmetric Michael addition of ketoester
N
N
N
O
O
O
O
O
O
OMe
OMe
OMe
H
H
H
N
H
N
H
N
H
N
H
N
H
N
H
N
N
N
OH
OH
OH
OH
OH
OH
1a
1b
1c
N
N
O
O
O
O
OMe
H
H
N
H
N
H
N
H
N
H
N
N
OH
OH
OH
OH
1d
1e
Scheme 2. Synthesis of chiral squaramide organocatalysts 1.

1278
B. Liu et al. / Tetrahedron: Asymmetry 24 (2013) 1276–1280
Table 2
Table 4
a
Asymmetric Michael addition of nitroalkenes 2 with compound 3 catalyzed by 1a
Synthesis of chiral isoxazoles 7a
O
O
O
O
N
O
O
O
R2
R2
1a
0.5 mol%
NO2
R1
R2
R2
NO2
NH2OH·HCl
+
NO2
NO2
R1
DCM, rt, 36 h
R1
R1
EtOH, 60 oC, 12 h
2
3
4
R1 = aromatic ring.
3a: R2 = CH3,; 3b: R2 = Ph.
4
7
Entry
2
3
4
Yield (%)b
ee (%)c
R1 = H, p-Me, p-MeO, m-MeO, p-F, p-CF3
R1 = Ph 2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
4a
4b
4c
4d
4e
4f
4g
4h
4i
89
75
78
87
85
84
86
87
83
85
92
84
81
>99
98
>99
>99
>99
99
96
98
99
99
Entry
4
7
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
R
1 = 4-F-Ph 2b
R1 = 4-Cl-Ph 2c
R1 = 2-Br-Ph 2d
1
2
3
4
5
6
4a
4b
4f
4g
4h
4j
7a
7b
7c
7d
7e
7f
91
85
88
85
89
88
99
99
>99
>99
>99
>99
R1 = 2,4-di-Cl-Ph 2e
R1 = 4-Me-Ph 2f
R1 = 4-MeO-Ph 2g
R
1 = 3-MeO-Ph 2h
9
R1 = 2-furyl 2i
R1 = 4-CF3-Ph 2j
R1 = Ph 2a
a
Reaction conditions: unless otherwise noted, a mixture of 4 (0.1 mmol) and
10
11
12
13
4j
4k
4l
NH2OHÁHCl (10.4 mg, 0.15 mmol) in ethanol (2 mL) was stirred at 60 °C for 12 h.
95
92
91
b
Isolated yield.
R1 = 4-MeO-Ph 2g
R1 = 2-furyl 2i
c
Determined by HPLC analysis using a chiralpac AS-H column.
4m
a
Reaction conditions: 1,3-dicarbonyl compound 3 (0.4 mmol) was added to an
agitated solution of nitroolefin 2 (0.2 mmol) and catalyst 1a (0.5 mol %) in DCM
reoisomer in excellent ee (entries 1–6). When 5b–d were used in
the Michael addition reaction, products 6g–k were obtained with
moderate diastereoselectivity in 95–99% ee (entries 7–11).
The relative and absolute configurations of the Michael adducts
4 were determined to be (S) by comparison of the specific rotation
with those reported in the literature.3h,5g,7a
To further illustrate the synthetic potential of this methodology,
the synthesis of chiral isoxazole derivatives was performed. As
shown in Table 4, the asymmetric Michael addition products 4
were treated with hydroxylamine hydrochloride in ethanol to gen-
erate 7a–f in up to 91% yield and with >99% enantioselectivity,
which have potential activity in the inhibition of factor Xa and hu-
man b-adrenergic receptors.9,10 The formation of 7a was confirmed
by X-ray crystallography (Fig. 1).11
(1.5 mL) at room temperature for 36 h.
b
Isolated yield.
c
Determined by HPLC analysis using a chiralpak AD-H or chiralcel OD-H column.
5 to a variety of aromatic nitroalkenes was also effective in forming
adduct 6 with excellent diastereoselectivity and enantioselectivity,
with values at approximately 99% ee being uniformly observed.
Substrate 5a gave the desired products 6a–f as almost one diaste-
Table 3
Scope of asymmetric Michael addition of nitroalkenes 2 with ketoester 5 catalyzed by
a
1a
O
O
O
O
OR3
NO2
1a
0.5 mol% , DCM
OR3
NO2
R2
+
R1
R2
rt, 36 h
R1
2
5
6
R
R
R
1 = aromatic ring
2 = cyclopentyl, cyclohexyl.
3 = Me, Et, t-Bu.
Entry
2
5
6
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
2a
2c
2e
2h
2j
5a
5a
5a
5a
5a
5a
5b
5b
5b
5c
5d
O
6a
6b
6c
6d
6e
6f
6g
6h
6i
86
82
84
85
75
72
74
73
70
76
74
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
5.3:1
>99
>99
>99
>99
98
>99
98
>99
97
2ke
2a
2g
2ke
2a
2a
9
10
11
6j
6k
97
97/95
11:9
O
O
O
O
O
O
O
O
OEt
O-t-Bu
OEt
5a
5d
5b
5c
a
Reaction conditions: 1,3-dicarbonyl compound 5 (0.4 mmol) was added to an
agitated solution of nitroolefin 2 (0.2 mmol) and catalyst 1a (0.5 mol %) in DCM
(1.5 mL) at room temperature for 36 h.
b
Isolated yield.
c
The syn/anti ratio was determined by 1H NMR.
d
Values of the major isomer were determined by HPLC using a chiralpak AD-H or
chiralcel OD-H column.
e
2-(2-Nitrovinyl)thiophene was used.
Figure 1. X-ray crystal structure of 7a.

B. Liu et al. / Tetrahedron: Asymmetry 24 (2013) 1276–1280
1279
3H), 3.59 (s, 2H), 3.19 (s, 2H), 2.64 (s, 2H), 2.27 (s, 1H), 1.53 (d,
J = 25.8 Hz, 4H). 13C NMR (100 MHz, DMSO-d6) d 182.13, 181.82,
175.25, 167.30, 166.41, 157.81, 156.22, 155.22, 147.72, 144.27,
143.66, 143.12, 142.16, 131.58, 131.43, 129.37, 128.93, 127.59,
127.47, 127.37, 124.50, 121.86, 119.02, 115.07, 114.21, 101.56,
58.79, 58.75, 55.68, 52.80, 42.77, 27.29, 26.22. HRMS Calcd for
3. Conclusion
In conclusion, we have developed a new class of chiral squara-
mides as multiple H-bond donor organocatalysts that show excel-
lent activity and enantioselectivity in the asymmetric Michael
addition of nitroolefins to 1,3-dicarbonyl compounds. The Michael
adducts were further transformed into optically active isoxazole
derivatives in high yield and with high enantioselectivity. Further
application of these squaramides to other asymmetric transforma-
tions is currently underway.
C
45H40N4O5 (M+H)+: 717.2999. Found: 717.3069.
Compound 1b pale white solid, 71% yield, mp: 257–259 °C. 1H
NMR (400 MHz, DMSO-d6) d 8.79 (s, 1H), 8.17 (s, 1H), 7.98 (d,
J = 9.0 Hz, 1H), 7.89–7.83 (m, 3H), 7.79 (s, 3H), 7.59 (d, J = 4.1 Hz,
1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.22 (t, J =
7.2 Hz, 2H), 7.15–7.09 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.81
(d, J = 8.4 Hz, 1H), 5.98 (s, 2H), 5.05–4.96 (m, 2H), 4.91 (d,
J = 13.1 Hz, 2H), 3.95 (s, 3H), 3.51 (s, 2H), 3.18 (s, 2H), 2.68–2.56
(m, 2H), 2.25 (s, 1H), 1.52 (d, J = 28.0 Hz, 4H). 13C NMR (100 MHz,
4. Experimental
4.1. Materials and methods
DMSO-d6)
d 195.95, 191.40, 182.32, 167.54, 166.67, 157.83,
Unless otherwise noted, reagents and materials were obtained
from commercial suppliers and used without further purification.
All solvents were purified according to reported procedures. Reac-
tions were run in oven dried glassware under an Ar atmosphere.
Reactions were monitored by thin layer chromatography (TLC)
and column chromatography purifications were performed using
230–400 mesh silica gel. 1H and 13C NMR spectra were measured
on Bruker DRX and DMX spectrometers at 400 MHz for 1H spectra
and 100 MHz for 13C spectra and calibrated from residual solvent
signal. Enantiomeric excesses (ee) were determined by HPLC anal-
ysis using a SHIMADZU Series instrument with Daicel Chiralpak
AD-H or Chiralcel OD-H columns, as indicated.
154.33, 147.72, 144.26, 142.14, 134.27, 133.59, 131.88, 131.42,
129.35, 128.22, 127.96, 127.67, 127.51, 125.89, 125.71, 124.35,
122.68, 122.19, 121.88, 119.04, 116.20, 114.21, 109.50, 101.62,
79.15, 58.86, 55.70, 55.59, 43.83, 27.31, 26.24. HRMS Calcd for
C
45H40N4O5 (M+H)+: 717.2999. Found: 717.4857.
Compound 1c pale white solid, 77% yield, mp: 236–238 °C.
1H NMR (400 MHz, DMSO-d6) d 8.79 (s, 1H), 8.11 (s, 1H), 7.99
(d, J = 9.1 Hz, 1H), 7.93–7.72 (m, 5H), 7.60 (s, 1H), 7.46 (d,
J = 8.7 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.23 (t, J = 6.9 Hz, 2H),
7.18–7.09 (m, 2H), 6.83 (dd, J = 15.6, 8.5 Hz, 2H), 5.99 (s, 2H),
5.16–4.82 (m, 4H), 3.95 (s, 3H), 3.46 (s, 2H), 3.18 (s, 2H),
2.64 (s, 2H), 2.26 (s, 1H), 1.53 (d, J = 27.8 Hz, 4H). 13C NMR
(100 MHz, DMSO-d6) d 182.79, 182.40, 167.13, 158.32, 154.76,
148.24, 144.75, 142.69, 138.82, 134.74, 134.14, 134.05, 131.93,
129.85, 128.71, 128.46, 128.29, 128.17, 126.40, 126.25, 124.81,
123.27, 123.18, 122.70, 122.38, 119.48, 116.64, 114.74, 114.12,
102.09, 81.18, 59.32, 57.85, 56.19, 49.90, 44.29, 27.80, 26.74.
4.1.1. Procedure for the synthesis of squaramides catalyst 1a
A solution of binaphthol derived amine (0.1 mmol) in DCM
(5 mL) with TEA (0.2 mmol) was stirred at room temperature for
30 min, after which a solution of quinine–squaramide (1.2 mmol)
in DCM was added. After 48 h, the reaction mixture was cconcen-
trated and subjected to column chromatography to afford product
1a (78%) as a pale white solid.
HRMS Calcd for
717.5936.
C
45H40N4O5 (M+H)+: 717.2999. Found:
Compound 1d pale white solid, 75% yield, mp: 257–259 °C. 1H
NMR (400 MHz, DMSO-d6) d 8.79 (d, J = 4.3 Hz, 2H), 8.30 (s, 1H),
7.98 (d, J = 9.2 Hz, 1H), 7.92–7.77 (m, 5H), 7.65 (s, 1H), 7.44 (dd,
J = 9.1, 2.3 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.23 (t, J = 7.2 Hz, 2H),
7.14 (t, J = 7.5 Hz, 2H), 6.85 (dd, J = 24.0, 8.4 Hz, 2H), 6.13 (s, 1H),
5.84 (ddd, J = 17.2, 11.0, 6.4 Hz, 1H), 5.23 (d, J = 17.6 Hz, 1H), 5.09
(d, J = 10.5 Hz, 1H), 4.93 (s, 2H), 3.96 (s, 3H), 3.65 (s, 2H), 3.26 (s,
2H), 2.26 (s, 1H), 1.99 (s, 1H), 1.90 (s, 3H), 1.57 (s, 3H). 13C NMR
N
NH2HCl
O
O
OH
OH
OMe
H
EtO
N
H
+
N
quinine-squaramide
DCM TEA
amine
(100 MHz, CDCl3)
d 181.90, 181.45, 167.06, 166.22, 157.76,
157.46, 154.02, 147.51, 147.46, 147.31, 143.89, 143.31, 141.84,
133.92, 133.23, 131.07, 128.99, 128.92, 127.80, 127.59, 127.32,
125.53, 125.37, 123.98, 123.82, 121.77, 121.55, 118.69, 115.79,
113.88, 101.21, 59.38, 55.33, 45.29, 43.47, 26.95, HRMS Calcd for
N
C
45H40N4O5 (M+H)+: 717.2999. Found: 717.6101.
O
O
Compound 1e pale white solid, 76% yield, mp: 259–261 °C. 1H
NMR (400 MHz, DMSO-d6) d 9.97 (s, 1H), 9.59 (s, 1H), 9.04 (s, 2H),
8.50 (s, 1H), 8.45 (s, 1H), 8.38 (d, J = 7.4 Hz, 1H), 8.13 (d, J = 8.2 Hz,
1H), 7.88 (dd, J = 13.8, 8.6 Hz, 5H), 7.84–7.72 (m, 3H), 7.39 (d,
J = 8.9 Hz, 1H), 7.23 (t, J = 7.3 Hz, 2H), 7.16–7.10 (m, 2H), 6.83 (dd,
J = 12.8, 8.7 Hz, 2H), 6.39 (s, 1H), 5.91–5.80 (m, 1H), 5.46 (d,
J = 17.4 Hz, 1H), 5.28 (d, J = 9.7 Hz, 1H), 4.99–4.87 (m, 2H), 4.60 (s,
1H), 3.81 (s, 1H), 2.79 (s, 1H), 1.87 (t, J = 24.5 Hz, 4H), 1.46 (s, 1H).
13C NMR (100 MHz, DMSO-d6) d 182.92, 173.09, 170.82, 167.55,
158.29, 154.50, 151.24, 148.22, 144.65, 141.15, 134.74, 133.80,
131.89, 129.84, 128.71, 128.42, 128.14, 127.30, 126.47, 126.18,
124.73, 124.57, 123.25, 122.73, 122.54, 119.26, 116.51, 114.97,
113.83, 101.72, 60.23, 59.51, 56.08, 49.44, 45.78, 43.99, 27.65,
25.60. HRMS Calcd for C44H39N4O4 (M+H)+: 687.2893. Found:
687.2968.
OMe
H
N
H
N
H
N
OH
OH
1a
Compound 1a pale white solid, 78% yield, mp: 223–225 °C. 1H
NMR (400 MHz, DMSO-d6) d 8.78 (d, J = 3.9 Hz, 1H), 8.13 (s, 1H),
7.98 (d, J = 9.2 Hz, 1H), 7.92–7.82 (m, 3H), 7.78 (s, 2H), 7.58 (d,
J = 11.0 Hz, 2H), 7.45 (d, J = 9.1 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H),
7.27–7.17 (m, 2H), 7.14 (d, J = 7.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H),
6.81 (d, J = 8.5 Hz, 1H), 5.99 (s, 2H), 5.13–4.75 (m, 4H), 3.94 (s,

1280
B. Liu et al. / Tetrahedron: Asymmetry 24 (2013) 1276–1280
4.1.2. General procedure for the asymmetric Michael addition
In a 10 mL round-bottomed flask, 1,3-dicarbonyl compound 3
(0.4 mmol) was added to an agitated solution of nitroolefin 2
(0.2 mmol) and catalyst 1a (0.7 mg, 0.001 mmol) in 1 mL of dicho-
lomethane at room temperature. After 36 h, the reaction was mon-
itored by TLC, condensed under reduced pressure and subjected to
flash chromatography column to give the pure product 4.
Calcd for C14H13F3N2O3 (M)+: 314.0878, Found: 314.0882. 13C
NMR (100 MHz, CDCl3) d 166.76, 158.68, 140.99, 127.46, 126.28,
126.24, 126.21, 126.17, 110.91, 76.90, 37.74, 11.70, 10.87. Chir-
alpak AS-H column (250 Â 4.6 mm), 10% i-PrOH/ hexane; 0.8 mL/
min, 230 nm; tmajor = 22.198 min, tminor = 25.897 min, ee > 99%.
Acknowledgments
4.1.3. General procedure for the synthesis of 7a
This work was supported by the NSFC (91017005, 81172935),
Key Project of Ministry of Education (313040), and the Research
Fund for the Doctoral Program of Higher Education of China
(20100141110021) and the Fundamental Research Funds for the
Central Universities (2012306020202).
A mixture of 4a (50 mg, 0.2 mmol) and NH2OHÁHCl (97 mg,
0.3 mmol) was stirred in ethanol (2 mL). The reaction was then
stirred at 60 °C for 12 h. The reaction was completed by TLC and
the mixture was purified directly by flash column chromatography
to provide 7a as a pale yellow oil.
Compound 7a pale yellow oil, 91% yield, 1H NMR (400 MHz,
CDCl3) d 7.33 (dd, J = 7.1, 3.1 Hz, 3H), 7.14 (d, J = 7.3 Hz, 2H), 5.04
(dd, J = 11.9, 6.3 Hz, 1H), 4.84 (ddd, J = 16.0, 10.7, 8.0 Hz, 2H),
2.38 (s, 3H), 2.12 (s, 3H). 13C NMR (100 MHz, CDCl3) d 166.50,
158.95, 136.88, 129.22, 127.96, 126.96, 111.54, 77.36, 37.91,
11.67, 10.88. HRMS Calcd for C13H14N2O3 (M)+: 246.1004, Found:
246.1006. Chiralpak AS-H column (250 Â 4.6 mm), 10% i-PrOH/
hexane; 0.8 mL/min, 230 nm; tmajor = 32.640 min, tminor = 40.727
min, ee = 99%.
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Compound 7b pale yellow oil, 85% yield, 1H NMR (400 MHz,
CDCl3) d 7.15–6.91 (m, 4H), 4.93 (dd, J = 12.0, 6.7 Hz, 1H), 4.75
(dt, J = 15.9, 9.2 Hz, 2H), 2.30 (s, 3H), 2.04 (s, 3H). 13C NMR
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d 166.46, 163.37, 160.90, 158.82, 132.65,
128.71, 128.62, 116.31, 116.10, 111.43, 77.39, 37.32, 11.70, 10.86.
HRMS Calcd for C13H13N2O3F (M)+: 264.0910, Found: 264.0913.
Chiralpak AS-H column (250 Â 4.6 mm), 10% i-PrOH/hexane;
0.8 mL/min, 230 nm; tmajor = 43.823 min, tminor = 82.588 min,
ee = 99%.
Compound 7c pale yellow oil, 88% yield, 1H NMR (400 MHz,
CDCl3) d 7.15 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 5.01 (dd,
J = 12.2, 6.7 Hz, 1H), 4.81 (ddd, J = 16.3, 10.9, 8.2 Hz, 2H), 2.37 (s,
3H), 2.33 (s, 3H), 2.12 (s, 3H). 13C NMR (100 MHz, CDCl3) d
166.40, 158.98, 137.77, 133.78, 129.85, 126.82, 111.66, 77.48,
37.60, 21.00, 11.67, 10.88. HRMS Calcd for C14H16N2O3 (M)+:
260.1161,
Found:
260.1162.
Chiralpak
AS-H
column
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11. CCDC 938486 7a contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(250 Â 4.6 mm), 10% i-PrOH/hexane; 0.8 mL/min, 230 nm;
tmajor = 35.252 min, tminor = 57.917 min, ee > 99%.
Compound 7d pale yellow oil, 85% yield, 1H NMR (400 MHz,
CDCl3) d 6.98 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.92 (dd,
J = 12.2, 6.9 Hz, 1H), 4.72 (ddd, J = 16.4, 10.8, 8.3 Hz, 2H), 3.72 (s,
3H), 2.30 (s, 3H), 2.05 (s, 3H). 13C NMR (100 MHz, CDCl3) d
166.31, 159.10, 158.97, 128.72, 128.07, 114.52, 111.74, 77.61,
55.34, 37.29, 11.69, 10.88. HRMS Calcd for C14H16N2O4 (M)+:
276.1110,
Found:
276.1112.
Chiralpak
AS-H
column
(250 Â 4.6 mm), 10% i-PrOH/hexane; 0.8 mL/min, 230 nm;
tmajor = 59.722 min, tminor = 103.352 min, ee > 99%.
Compound 7e pale yellow oil, 89% yield, 1H NMR (400 MHz,
CDCl3) d 7.22–7.15 (m, 1H), 6.76 (dd, J = 8.2, 2.2 Hz, 1H), 6.65 (d,
J = 7.8 Hz, 1H), 6.58 (s, 1H), 4.94 (dd, J = 12.2, 6.6 Hz, 1H), 4.74
(ddd, J = 16.2, 10.8, 8.2 Hz, 2H), 3.71 (s, 3H), 2.31 (s, 3H), 2.06 (s,
3H). 13C NMR (100 MHz, CDCl3) d 166.51, 160.12, 158.94, 138.43,
130.27, 119.07, 113.61, 112.50, 111.44, 77.32, 55.30, 37.85, 11.69,
10.89. HRMS Calcd for
C
14H16N2O4 (M)+: 276.1110, Found:
276.1115. Chiralpak AS-H column (250 Â 4.6 mm), 10% i-PrOH/
hexane; 0.8 mL/min, 230 nm; tmajor = 55.472 min, tminor = 58.858 -
min, ee > 99%.
Compound 7f pale yellow oil, 88% yield, 1H NMR (400 MHz,
CDCl3) d 7.63 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.29 (d,
J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 5.06 (dd, J = 16.4, 11.0 Hz,
1H), 5.06 (dd, J = 16.4, 11.0 Hz, 1H), 4.94–4.80 (m, 2H), 4.92–4.84
(m, 2H), 2.39 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 2.13 (s, 3H). HRMS