Chiral phosphoric acid catalyzed 1,3-dipolar cycloadditions of aldehydes, diethyl α-aminomalonate, and nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2014.04.006

A one-pot three component 1,3-dipolar cycloaddition reaction of an aldehyde, α-aminomalonate, and nitroalkene has been developed through binaphthol derived chiral phosphoric acids. This reaction represents one of the most enantioselective catalytic approaches to access structurally diverse pyrrolidine derivatives.

Full text of DOI:10.1016/j.tetasy.2014.04.006

Tetrahedron: Asymmetry 25 (2014) 787–791
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral phosphoric acid catalyzed 1,3-dipolar cycloadditions
of aldehydes, diethyl
a-aminomalonate, and nitroalkenes
⇑
Wenqiang Luo, Yongjun Lin, Dengshan Yang, Long He
Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering, China West Normal University,
Nanchong 637002, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot three component 1,3-dipolar cycloaddition reaction of an aldehyde,
a-aminomalonate, and
Received 21 January 2014
Accepted 2 April 2014
Available online 2 June 2014
nitroalkene has been developed through binaphthol derived chiral phosphoric acids. This reaction repre-
sents one of the most enantioselective catalytic approaches to access structurally diverse pyrrolidine
derivatives.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
and nitroalkenes to the synthesis of multi-substituted pyrrolidine
derivatives in the presence of phosphoric acid (see Fig. 2).
Five-membered heterocycles, in particular highly substituted
pyrrolidines, have features that are widely found within a wide
variety of biologically active unnatural products, and in numerous
natural alkaloids (Fig. 1).1 Furthermore, they also serve as chiral
building blocks or intermediates in the synthesis of natural alka-
loids and medicinally relevant compounds, as well as organocata-
lysts in asymmetric catalysis.2 Consequently, the development of
efficient methods to construct enantiomerically pure pyrrolidine
frameworks is undoubtedly appealing in organic synthesis.
Among the synthetic approaches to access pyrrolidine
structural motifs,3,4 the 1,3-dipolar cycloaddition reaction of
azomethine ylides with electronically poor olefins represents one
of the most efficient synthetic methods to construct these valuable
heterocycles.5,6 Chiral phosphoric acids containing a strongly
acidic hydroxyl and Lewis basic phosphoryl oxygens pioneered
by Akiyama et al. and Terada’s et al.,7 as efficient bifunctional
catalysts have been widely applied to a large number of highly
enantioselective organic transformations over the past few
years.8,9 Nitroalkenes (electronically poor olefins) are broadly
applicable to asymmetric reactions. Cycloaddition reactions of
nitroalkenes with azomethine ylides catalyzed by metal-complexes
and chiral thioureas have also been reported on.6f,6m,6n,10 Despite
this great success, the chiral phosphoric acid catalyzed
cycloaddition of nitroalkenes has not received as much attention.
Herein we report a highly diastereo- and enantioselective one-
2. Results and discussion
Initially, we started our investigation using 4-nitrobenzalde-
hyde 3a, ethyl
a-aminomalonate 4, and trans-b-nitrostyrene 5a
in CH2Cl2 at room temperature in the presence of 3 Å molecular
sieves catalyzed by 10 mol % of chiral biphosphoric acid 1 devel-
oped by Gong et al.9a Unfortunately, chiral phosphoric acid 1,
which exhibited high enantioselectivity in reactions with maleates,
when catalyzing the reaction of nitroalkenes resulted in racemic
products (entry 1). A catalyst survey of monophosphoric acids
revealed that a substantial change of the 3,30-subtituents had a sig-
nificant effect on the reactivity and enantioselectivity of the cyclo-
addition. As shown in Table 1, most of the catalysts tested afforded
high yields but with disappointing enantioselectivities (entries 2 to
10 and 12). Phosphoric acid 2j gave the best result in the model
reaction (88% yield), however, poor enantioselectivity was
observed (54% ee, entry 11). It is worth noting that this reaction
exhibited excellent diastereoselectivity (>95/5) by 1H NMR analy-
sis of the crude product.
Studying the effect of temperature showed that the enantiose-
lectivity could be improved by performing the reaction at low tem-
perature (entries 12–15). The enantioselectivity was increased to
68% ee when the reaction was carried out at ꢀ10 °C (entry 14),
although the enantioselectivity did not improve and the yield
decreased at lower temperatures. Screening of different solvents
indicated that chloroform was the optimal choice (entries 16 to
18 and 14), affording the cycloaddition product 6a in 80% yield
and with 73% ee.
pot, three-component reaction of aldehydes,
a-aminomalonates,
⇑
Corresponding author. Tel.: +86 817 2568636.
E-mail address: longhe@cwnu.edu.cn (L. He).
http://dx.doi.org/10.1016/j.tetasy.2014.04.006
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

788
W. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 787–791
O
O
HOOC
OH
Me
H
N
H
H
COOH
H
OH
HN
H
N
MeO
MeO
Me
H
O
Me
N
H
COOH
N
H
H
(-)-coccinine
(+)-benzohydrindan
(-)-Lentiginosine
acromelic acid A
Figure 1. Representative natural products bearing the pyrrolidine framework.
Ar
2g, Ar = 2,4,6-(iPr)3C6H2
2h, Ar = 2,4,6-(CH3)3C6H2
2i Ar = 3,5-(CH3)2C6H3
2a
, Ar = Ph
2b, A r= 4-t-BuC6H4
2c, Ar = 4-NO2C6H4
2d
O
O
O
P
, Ar = 3,5-(CF3)2C6H3
2j
2l
OH
,
,
Ar = 9-anthracenyl
Ar = 9-phenanthrenyl
O
2e, Ar = 4-ClC6H4
O
O
O
P
OH
O
2f
,
A r= 2-naphthyl
Ar
P
O
O
2
HO
1
Figure 2. Chiral phosphoric acids evaluated in this study.
Table 1
Optimization of the reaction conditionsa
Ph
O2N
NO2
CO2Et
CO2Et
CO2Et
CO2Et
CHO
10 mol% catalyst
+
+
N
H
solvent, 3Å MS, temp
H2N
Ph
O2N
O2N
4
5a
3a
6a
Entry
Catalyst
Temp (°C)
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1
25
25
25
25
25
25
25
25
25
25
25
25
0
ꢀ10
ꢀ25
ꢀ10
ꢀ10
ꢀ10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1,2-DCE
CHCl3
77
74
77
77
78
88
77
84
60
33
88
89
80
79
45
76
80
71
1
7
7
2
24
1
2
4
9
1
54
24
63
68
68
70
73
26
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2j
2j
2j
9
10
11
12
13
14
15
16
17
18
2j
2j
2j
Toluene
a
b
c
The reaction was carried out on a 0.1 mmol scale in a solvent (1 mL) with 3 Å MS (100 mg) for 24–96 h, and the ratio of 3a/4/5a was 1.2:1:2.
Isolated yield.
ee values were determined by HPLC analysis and the absolute configuration was assigned by comparing specific rotations with literature values.10b
With the optimal conditions in hand, we first explored the
generality of the current protocol, the cycloaddition between
4-nitrobenzaldehyde, ethyl -aminomalonate, and different
reaction of aldehydes, ethyl a-aminomalonate, and a variety of
nitroalkenes, providing multi-substituted pyrrolidine derivatives
in high yields and with excellent diastereoselectivities with
moderate to high enantioselectivities.
a
nitroalkenes with electron withdrawing substituents, as well as
electron donating substituents on the phenyl motif. All of the reac-
tions proceeded smoothly and furnished the desired cycloaddition
adducts 6b–6h in high yields and with moderate to good
enantioselectivities (entries 1–7). The cycloaddition of a variety
of aldehydes also takes place with moderate to high enantioselec-
tivities (entries 8–13). However, electron rich benzaldehydes and
alkyl-substituted nitroolefins failed to afford the desired product
in the current catalytic system (entries 14–15).
4. Experimental
4.1. General
NMR spectra were recorded on a Brucker-400 MHz spectrome-
ter. Melting points were determined on a digital melting point
apparatus and are uncorrected. Infrared spectra were recorded on
a Nicolet MX-1E FT-IR spectrometer. HPLC analysis was performed
on Waters-Breeze (2487 Dual k Absorbance Detector and 1525 Bin-
ary HPLC Pump, UV detection monitored at 254 nm or 205 nm).
Chiralpak columns were purchased from Daicel Chemical
3. Conclusion
In conclusion, we have developed a chiral phosphoric acid
catalyzed one-pot, three component 1,3-dipolar cycloaddition

W. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 787–791
789
Table 2
Generality for nitroalkenes and aldehydesa
R2
O2N
R1
CO2Et
CO2Et
2j
10 mol%
NO2
R1CHO
+
+
CO2Et
CO2Et
CHCl3, -10 oC, 3Å MS
R2
H2N
N
H
5
4
3
6
Entry
R1
R2
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-BrC6H4
4-BrC6H4
3-NO2C6H4
4-ClC6H4
4-CNC6H4
4-CH3OC6H4
3-BrC6H4
3-ClC6H4
C6H5
4-BrC6H5
C6H5
4-BrC6H5
C6H5
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
84
90
85
81
71
74
71
92
88
90
86
76
42
—
77
65
70
74
70
56
57
62
70
53
84
74
23
—
9
4-BrC6H4
4-ClC6H4
10
11
12
13
14
15
4-CNC6H4
4-CNC6H4
C6H5
4-CH3OC6H4
4-NO2C6H4
C6H5
C6H5
i-Pr
d
—
—
a
b
c
The reaction was carried out on a 0.1 mmol scale in CHCl3 (1 mL) with 3 Å MS (100 mg) at ꢀ10 °C for 48–96 h, and the ratio of 3/4/5 was 1.2:1:2.
Isolated yield.
ee values were determined by HPLC analysis and the absolute configuration was assigned by comparing specific rotations with literature values.10b
None of the desired product was isolated, only affording the product from the intermolecular cycloaddition of azomethine ylides.
d
Industries, LTD. Optical rotations were determined at 589 nm
(sodium D line) by using a Perkin–Elmer-343 polarimeter.
4.4. Diethyl 3-(4-bromophenyl)-4-nitro-5-(4-nitrophenyl)pyrro-
lidine-2,2-dicarboxylate 6b
4.2. General procedure for the asymmetric 1,3-dipolar cyclo-
addition reactions (Table 2)
White solid, mp 142–145 °C, yield: 84%; (Flash column chroma-
tography eluent, petroleum ether/ethyl acetate 4:1); 1H NMR
(400 MHz, CDCl3)
d (ppm) 0.86 (t, J = 7.1 Hz, 3H), 1.29 (t,
To
a
solution of an aldehyde (0.12 mmol), catalyst 2j
J = 7.1 Hz, 3H), 3.28 (d, J = 5.4 Hz, 1H), 3.61–3.70 (m, 1H), 3.92–
3.95 (m, 1H), 4.27–4.43 (m, 2H), 5.05 (d, J = 7.7 Hz, 1H), 5.56–
5.67 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.59
(d, J = 8.6 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3); 13.42, 13.99, 51.12, 62.44, 62.47, 62.87, 92.72, 122.71,
123.64, 128.37, 130.25, 131.91, 133.16, 143.98, 148.25, 168.05,
(0.01 mmol), and 3 Å molecular sieves (100 mg) in CHCl3 (1.0 mL)
was added the amino ester (0.1 mmol), and then the nitroalkene
(0.2 mmol). The reaction mixture was stirred at ꢀ10 °C until the
reaction was complete (monitored by TLC). The reaction mixture
was then filtered to remove the molecular sieves, and the solid
powder was washed with ethyl acetate (5.0 mL). The resultant
solution was quenched with saturated aqueous NaHCO3 (5 mL)
and the aqueous layer was extracted with ethyl acetate (5 mL ꢁ 3).
The combined organic layers were then dried over anhydrous
Na2SO4. After evaporation under reduced pressure, the residue was
purified through flash column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate 4:1–2:1) to yield pure products.
170.90; IR (KBr):
c 3364, 2953, 1719, 1586, 1547, 1335, 1282,
1202, 1102, 1003, 896, 724, 671; Enantiomeric excess: 77%, deter-
mined by HPLC (Daicel Chirapak AS-H, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 15.26 min (minor),
tR = 34.47 min (major); [a]
20 = +55.4 (c 0.39, CH2Cl2).
D
4.5. Diethyl 4-nitro-3-(3-nitrophenyl)-5-(4-nitrophenyl)pyrro-
lidine-2,2-dicarboxylate 6c
4.3. Diethyl 4-nitro-5-(4-nitrophenyl)-3-phenylpyrrolidine-2,2-
dicarboxylate 6a
White solid, mp 155–158 °C, yield: 90%; (Flash column chro-
matography eluent, petroleum ether/ethyl acetate 3:1); 1H NMR
White solid, mp 128–130 °C, yield: 76%; (Flash column chroma-
(400 MHz, CDCl3)
d (ppm) 0.79 (t, J = 7.2 Hz, 3H), 1.22 (t,
tography eluent, petroleum ether/ethyl acetate 4:1); 1H NMR
J = 7.2 Hz, 3H), 3.27 (d, J = 5.5 Hz, 1H), 3.60–3.68 (m, 1H), 3.92–
4.00 (m, 1H), 4.20–4.36 (m, 2H), 5.09 (d, J = 8.6 Hz, 1H), 5.56
(q, J = 8.8 Hz, 1H), 5.68 (t, J = 8.8 Hz, 1H), 7.47 (q, J = 8.1 Hz,
1H), 7.54 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 7.8 Hz, 1H), 8.11–8.16
(m, 4H); 13C NMR (100 MHz, CDCl3); 12.48, 12.95, 50.09, 61.35,
61.59, 61.69, 74.25, 91.18, 122.37, 122.56, 122.63, 127.50,
127.82, 134.31, 135.05, 142.83, 147.30, 147.35, 166.79, 169.58;
IR (KBr): 3353, 3094, 2970, 2925, 1738, 1626, 1568, 1500,
1456, 1332, 1264, 1206, 1140, 1060, 867, 745, 657; Enantiomeric
excess: 65%, determined by HPLC (Daicel Chirapak AS-H,
hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C,
254 nm): tR = 25.56 min (minor), tR = 52.41 min (major);
(400 MHz, CDCl3)
d (ppm) 0.78 (t, J = 7.1 Hz, 3H), 1.29 (t,
J = 7.1 Hz, 3H), 3.28 (d, J = 5.4 Hz, 1H), 3.53–3.58 (m, 1H), 3.90–
3.95 (m, 1H), 4.29–4.41 (m, 2H), 5.13 (d, J = 7.0 Hz, 1H),
5.59–5.67 (m, 2H), 7.30–7.35 (m, 5H), 7.61 (d, J = 8.6 Hz, 1H),
8.19 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3); 13.31, 51.84,
62.25, 62.36, 63.39, 75.92, 93.42, 123.64, 128.33, 128.51, 128.53,
128.79, 134.45, 144.07, 148.23, 168.22, 171.06; IR (KBr):
c 3366,
2977, 1716, 1612, 1574, 1514, 1445, 1333, 1283, 1194, 1103,
1063, 862, 712; Enantiomeric excess: 72%, determined by HPLC
(Daicel Chirapak AS-H, hexane/isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 °C, 254 nm): tR = 13.98 min (minor), tR = 26.67 min
(major); [a]
20 = +29.3 (c 0.43, CH2Cl2).
D
[a]
20 = +47.1 (c 0.87, CH2Cl2).
D

790
W. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 787–791
4.6. Diethyl 3-(4-chlorophenyl)-4-nitro-5-(4-nitrophenyl)pyr-
rolidine-2,2-dicarboxylate 6d
7.35–7.44 (m, 2H), 7.45 (d, J = 6.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3); 13.42, 13.99, 51.29, 62.47, 62.51,
62.98, 75.63, 92.83, 122.76, 123.63, 127.48, 128.40, 130.31,
131.52, 131.68, 136.52, 143.93, 148.26, 167.97, 170.86; IR (KBr):
Colorless foam, yield: 85%; (Flash column chromatography elu-
ent, petroleum ether/ethyl acetate 4:1); 1H NMR (400 MHz, CDCl3)
d (ppm) 0.86 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 3.28 (d,
J = 5.3 Hz, 1H), 3.62–3.70 (m, 1H), 3.95–4.03 (m, 1H), 4.26–4.43
(m, 2H), 5.07 (d, J = 7.7 Hz, 1H), 5.57–5.67 (m, 2H), 7.27 (d,
J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H),
8.18 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3); 12.40, 12.97,
50.04, 61.40, 61.45, 61.85, 74.53, 91.79, 122.61, 127.35, 127.91,
128.93, 131.62, 133.60, 142.99, 147.22, 167.05, 169.89; IR (KBr):
c
3322, 2979, 2890, 1725, 1601, 1545, 1518, 1474, 1346, 1287,
1207, 1145, 1112, 1046, 858, 778, 694; Enantiomeric excess: 56%,
determined by HPLC (Daicel Chirapak AS-H, hexane/isopropa-
nol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 12.79 min
(minor), tR = 27.73 min (major); [a]
20 = +24.5 (c 0.4, CH2Cl2).
D
4.10. Diethyl 3-(3-chlorophenyl)-4-nitro-5-(4-nitrophenyl)pyr-
rolidine-2,2-dicarboxylate 6h
c
3356, 2977, 1742, 1685, 1591, 1437, 1371, 1288, 1229, 1105,
1040, 857, 773, 707; Enantiomeric excess: 70%, determined by
HPLC (Daicel Chirapak AS-H, hexane/isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 °C, 254 nm): tR = 13.51 min (minor), tR = 34.38 min
White solid, mp 154–157 °C, yield: 71%; (Flash column chroma-
tography eluent, petroleum ether/ethyl acetate 5:1); 1H NMR
(400 MHz, CDCl3)
d (ppm) 0.85 (t, J = 7.2 Hz, 3H), 1.29 (t,
(major); [a]
20 = +27.8 (c 0.78, CH2Cl2).
D
J = 7.1 Hz, 3H), 3.29 (d, J = 5.3 Hz, 1H), 3.65–3.69 (m, 1H), 3.94–
3.98 (m, 1H), 4.27–4.38 (m, 2H), 5.07 (d, J = 7.5 Hz, 1H), 5.57–
5.67 (m, 2H), 7.23–7.33 (m, 4H), 7.60 (d, J = 8.7 Hz, 2H), 8.18 (d,
J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3); 13.39, 13.98, 51.31,
62.45, 62.51, 62.98, 75.61, 92.82, 123.62, 126.91, 128.73, 134.69,
4.7. Diethyl 3-(4-cyanophenyl)-4-nitro-5-(4-nitrophenyl)pyrro-
lidine-2,2-dicarboxylate 6e
White solid, mp 136–138 °C, yield: 81%; (Flash column chroma-
136.25, 143.95, 148.25, 167.99, 170.86; IR (KBr):
c 3348, 2977,
tography eluent, petroleum ether/ethyl acetate 3:1); 1H NMR
1738, 1658, 1591, 1378, 1258, 1223, 1105, 1040, 855, 707;
Enantiomeric excess: 57%, determined by HPLC (Daicel Chirapak
AS-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 12.21 min (minor), tR = 26.66 min (major);
(400 MHz, CDCl3)
d (ppm) 0.85 (t, J = 7.2 Hz, 3H), 1.28 (t,
J = 7.2 Hz, 3H), 3.31 (d, J = 5.6 Hz, 1H), 3.59–3.68 (m, 1H), 3.97–
4.05 (m, 1H), 4.27–4.43 (m, 2H), 5.14 (d, J = 8.0 Hz, 1H), 5.59–
5.62 (m, 1H), 5.68 (q, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.59
(d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3); 13.48, 13.97, 51.35, 62.51, 62.67,
62.72, 75.45, 92.13, 112.62, 118.06, 123.67, 128.41, 129.57,
[a]
20 = +25.9 (c 0.66, CH2Cl2).
D
4.11. Diethyl 5-(4-bromophenyl)-4-nitro-3-phenylpyrrolidine-
2,2-dicarboxylate 6i
132.42, 139.42, 143.75, 148.31, 167.84, 170.57; IR (KBr):
c 3368,
3072, 2984, 2927, 2234, 1736, 1698, 1629, 1478, 1426, 1361,
1281, 1222, 1182, 1102, 1043, 865, 813, 762, 689; Enantiomeric
excess: 74%, determined by HPLC (Daicel Chirapak IA-H,
hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C,
254 nm): tR = 15.30 min (minor), tR = 45.10 min (major);
White solid, mp 138–140 °C, yield: 92%; (Flash column chroma-
tography eluent, petroleum ether/ethyl acetate 6:1); 1H NMR
(400 MHz, CDCl3)
d (ppm) 0.76 (t, J = 7.2 Hz, 3H), 1.27 (t,
J = 7.2 Hz, 3H), 3.21 (d, J = 5.4 Hz, 1H), 3.49–3.57 (m, 1H), 3.86–
3.93 (m, 1H), 4.26–4.39 (m, 2H), 5.11 (d, J = 6.9 Hz, 1H), 5.44–
5.48 (m, 1H), 5.57 (q, J = 7.0 Hz, 1H), 7.29–7.33 (m, 7H), 7.45 (d,
J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3); 13.32, 14.00, 51.93,
62.07, 62.23, 63.83, 75.94, 93.55, 122.92, 128.33, 128.59, 128.94,
[a]
20 = +61.4 (c 0.7, CH2Cl2).
D
4.8. Diethyl 3-(4-methoxyphenyl)-4-nitro-5-(4-nitrophenyl)pyr-
rolidine-2,2-dicarboxylate 6f
131.6, 134.91, 135.79, 168.43, 171.11; IR (KBr):
c 3375, 3001,
White solid, mp 134–136 °C, yield: 71%; (Flash column chroma-
2924, 1746, 1565, 1481, 1462, 1362, 1267, 1211, 1140, 1044,
1012, 845, 745, 705; Enantiomeric excess: 62%, determined by
HPLC (Daicel Chirapak IA-H, hexane/isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 °C, 254 nm): tR = 8.47 min (minor), tR = 14.72 -
tography eluent, petroleum ether/ethyl acetate 3:1); 1H NMR
(400 MHz, CDCl3)
d (ppm) 0.85 (t, J = 7.2 Hz, 3H), 1.29 (t,
J = 7.2 Hz, 3H), 3.26 (d, J = 5.4 Hz, 1H), 3.61–3.68 (m, 1H), 3.38 (s,
3H), 3.93–4.00 (m, 1H), 4.28–4.41 (m, 2H), 5.04 (d, J = 7.4 Hz,
1H), 5.56–5.66 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 9.2 Hz,
2H), 7.59 (d, J = 8.7 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3); 13.46, 14.01, 51.21, 55.35, 62.26, 62.29, 63.00,
75.72, 93.43, 114.14, 123.61, 126.07, 128.34, 129.68, 144.25,
min (major); [a]
20 = 24.1 (c 0.86, CH2Cl2).
D
4.12. Diethyl 3,5-bis(4-bromophenyl)-4-nitropyrrolidine-2,2-
dicarboxylate 6j
148.19, 159.71, 168.31, 171.22; IR (KBr):
c 3353, 2979, 2875,
White solid, mp 104–106 °C, yield: 88%; (Flash column chroma-
1747, 1618, 1587, 1558, 1528, 1449, 1359, 1270, 1230, 1041,
881, 822; Enantiomeric excess: 70%, determined by HPLC (Daicel
Chirapak AS-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 27.51 min (minor), tR = 41.98 min (major);
tography eluent, petroleum ether/ethyl acetate 6:1); 1H NMR
(400 MHz, CDCl3)
d (ppm) 0.84 (t, J = 7.2 Hz, 3H), 1.26 (t,
J = 7.2 Hz, 3H), 3.21 (d, J = 5.4 Hz, 1H), 3.58–3.67 (m, 1H), 3.91–
3.99 (m, 1H), 4.23–4.39 (m, 2H), 5.04 (d, J = 7.6 Hz, 1H),
5.42–5.45 (m, 1H), 5.55 (q, J = 8.0 Hz, 1H), 7.21 (d, J = 6.8 Hz, 2H),
7.26 (q, J = 8.4 Hz, 2H), 7.44–7.47 (m, 4H); 13C NMR (100 MHz,
CDCl3); 13.43, 13.99, 51.18, 62.27, 62.35, 63.31, 75.52, 92.83,
122.51, 123.00, 128.98, 130.32, 131.66, 131.82, 133.64, 135.74,
[a]
20 = +46.4 (c 0.7, CH2Cl2).
D
4.9. Diethyl 3-(3-bromophenyl)-4-nitro-5-(4-nitrophenyl)pyrro-
lidine-2,2-dicarboxylate 6g
168.26, 170.94; IR (KBr):
c 3365, 2983, 2926, 1745, 1554,
White solid, mp 164–167 °C, yield: 74%; (Flash column chroma-
tography eluent, petroleum ether/ethyl acetate 4:1); 1H NMR
1489, 1410, 1364, 1285, 1201, 1155, 1071, 1031, 1011, 858, 807,
737; Enantiomeric excess: 70%, determined by HPLC (Daicel
Chirapak IA-H, hexane/isopropanol = 70/30, flow rate 1.0 mL/min,
T = 30 °C, 254 nm): tR = 11.02 min (minor), tR = 17.08 min (major);
(400 MHz, CDCl3)
d (ppm) 0.86 (t, J = 7.2 Hz, 3H), 1.29 (t,
J = 7.2 Hz, 3H), 3.29 (d, J = 5.2 Hz, 1H), 3.67–3.74 (m, 1H), 3.95–
4.01 (m, 1H), 4.29–4.41 (m, 2H), 5.06 (d, J = 7.4 Hz, 1H), 5.58–
5.67 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.20 (q, J = 7.8 Hz, 2H),
[a]
20 = +43.4 (c 1.0, CH2Cl2).
D

W. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 787–791
791
4.13. Diethyl 5-(4-chlorophenyl)-4-nitro-3-phenylpyrrolidine-2,
2-dicarboxylate 6k
(m, 1H), 7.28–7.36 (m, 8H), 7.40–7.43 (m, 2H); 13C NMR
(100 MHz, CDCl3); 13,4, 13.9, 50.9, 62.3, 62.4, 62.9, 74.5, 93.0,
115.6, 115.8, 123.6, 128.5, 130.2, 130.3, 144.0, 148.2, 161.4,
White solid, mp 142–144 °C, yield: 90%; (Flash column chroma-
163.9, 168.1, 171.0; IR (KBr): c 3357, 2983, 2928, 2235, 1737, 1486,
tography eluent, petroleum ether/ethyl acetate 6:1); 1H NMR
1406, 1364, 1281, 1211, 1048, 819; Enantiomeric excess: 23%,
determined by HPLC (Daicel Chirapak OD-H, hexane/isopropanol =
90/10, flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 12.45 min
(400 MHz, CDCl3)
d (ppm) 0.77 (t, J = 7.2 Hz, 3H), 1.27 (t,
J = 7.2 Hz, 3H), 3.21 (d, J = 5.4 Hz, 1H), 3.49–3.58 (m, 1H), 3.86–
3.94 (m, 1H), 4.27–4.39 (m, 2H), 5.12 (d, J = 6.9 Hz, 1H), 5.46–
5.50 (m, 1H), 5.57 (q, J = 7.2 Hz, 1H), 7.29–7.37 (m, 9H); 13C NMR
(100 MHz, CDCl3); 13.32, 13.99, 51.93, 62.06, 62.23, 63.79, 75.94,
93.62, 128.33, 128.60, 128.63, 128.70, 134.69, 134.93, 135.25,
(major), tR = 16.36 min (minor); [a]
20 = 26.6 (c 0.43, CH2Cl2).
D
Acknowledgments
168.44, 171.12; IR (KBr):
c
3357, 2981, 1739, 1549, 1490, 1442,
We are grateful for financial support from NSFC (No. 21102116)
and Innovative Research Team in College of Sichuan Province (No.
14TD0016).
1366, 1279, 1211, 1155, 1087, 1052, 1009, 849, 761, 698; Enantio-
meric excess: 53%, determined by HPLC (Daicel Chirapak IA-H, hex-
ane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 °C, 254 nm):
tR = 8.03 min (minor), tR = 13.39 min (major); [
a
]
D
20 = +19.3 (c 0.76,
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c
3357, 2993, 2235, 1727, 1609, 1549, 1484, 1406, 1374, 1283,
1211, 1147, 1048, 1008, 853, 809; Enantiomeric excess: 84%, deter-
mined by HPLC (Daicel Chirapak IA-H, hexane/isopropanol = 70/30,
flow rate 1.0 mL/min, T = 30 °C, 254 nm): tR = 13.61 min (minor),
tR = 31.59 min (major); [a]
20 = +59.3 (c 0.82, CH2Cl2).
D
4.15. Diethyl 5-(4-cyanophenyl)-4-nitro-3-phenylpyrrolidine-2,
2-dicarboxylate 6m
Colorless foam, yield: 76%; (Flash column chromatography elu-
ent, petroleum ether/ethyl acetate 5:1); 1H NMR (400 MHz, CDCl3)
d (ppm) 0.77 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 3.25 (d,
J = 5.5 Hz, 1H), 3.53–3.57 (m, 1H), 3.89–3.93 (m, 1H), 4.28–4.40
(m, 2H), 5.11 (d, J = 7.1 Hz, 1H), 5.53–5.56 (m, 1H), 5.62 (q,
J = 7.7 Hz, 1H), 7.30–7.35 (m, 5H), 7.54 (d, J = 8.2 Hz, 2H), 7.63 (d,
J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3); 13.31, 13.99, 51.81,
62.22, 62.33, 63.61, 93.38, 112.74, 118.47, 128.14, 128.48, 128.53,
128.78, 132.26, 134.49, 142.20, 168.26, 171.06; IR (KBr):
c 3356,
2921, 2227, 1755, 1561, 1458, 1362, 1287, 1219, 1135, 1032,
853, 745, 698; Enantiomeric excess: 74%, determined by HPLC
(Daicel Chirapak AS-H, hexane/isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 °C, 254 nm): tR = 13.35 min (minor), tR = 18.84 -
min (major); [a]
20 = +28.6 (c 0.67, CH2Cl2).
D
4.16. Diethyl-4-nitro-3,5-diphenylpyrrolidine-2,2-dicarboxylate
6n
Colorless foam, yield: 42%; (Flash column chromatography elu-
ent, petroleum ether/ethyl acetate 8:1); 1H NMR (400 MHz, CDCl3)
d (ppm) 0.76 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 3.22 (d,
J = 5.4 Hz, 1H), 3.51–3.56 (m, 1H), 3.86–3.91 (m, 1H), 4.27–4.39
(m, 2H), 5.14 (d, J = 6.7 Hz, 1H), 5.48–5.52 (m, 1H), 5.58–5.62