J?rgensen-Hayashi catalysts supported on poly(ethylene glycol)s as highly efficient and reusable organocatalysts for the enamine-catalyzed asymmetric Michael reaction

Article abstract of DOI:10.1039/c5ob01442e

A new kind of recyclable and reusable PEG-supported J?rgensen-Hayashi catalyst is synthesized for the first time and proven to be efficient for the enamine-catalyzed asymmetric Michael reaction with generally moderate to good diastereoselectivity and high

Full text of DOI:10.1039/c5ob01442e

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Organic & Biomolecular Chemistry
Journal Name
RSCPublishing
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DOI: 10.1039/C5OB01442E
ARTICLE
Jørgensen – Hayashi Catalyst Supported on
Poly(ethylene glycol)s as Highly Efficient and
Reusable Organocatalysts for Enamine-Catalyzed
Asymmetric Michael Reaction
Cite this: DOI:
10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Ai-Bao Xia, Can Zhang, Yan-Peng Zhang, Yan-Jun Guo, Xiao-Long Zhang,
Zhao-Bo Li and Dan-Qian Xu*,a
DOI: 10.1039/x0xx00000x
A new kind of recyclable and reusable PEG-supported Jørgensen
–
Hayashi catalyst is
www.rsc.org/
synthesized for the first time and proven to be efficient for the enamine-catalyzed
asymmetric Michael reaction with generally moderate to good diastereoselectivity and high
to excellent enantioselectivity (up to 6 : 1 dr, 99% ee). The prepared PEG-supported catalyst
can be recovered eight times and found to provide similar diastereoselectivity and
enantioselectivity to unsupported functional catalyst.
polyethylene glycol(PEG)-supported derivatives 2 through thiol–ene
Introduction
5g,
coupling for the first time (Figure 1)5f,
7, as well as their
The use of organocatalysis as a new powerful tool for the application in enamine-catalyzed asymmetric Michael reaction8.
asymmetric synthesis of pharmaceutical intermediates, biologically
active compounds, and natural products has grown in recent years.1 Results and discussion
Various efficient organocatalysts, such as the S-proline and its
derivatives, imidazolidine, and other chiral organocatalysts, have
O
been used in organocatalytic methods.2 However, high
Ph
OR
Ph
1a，R'=TMS
1b，R'=TES
Ph
organocatalyst loadings (10 mol% to 30 mol%) are generally
required in those transformations to afford ideal catalytic
performance. Furthermore, homogeneous organocatalysts cannot be
easily separated from reaction systems to further reuse them.
Therefore, the development of catalyst immobilization may aid us in
overcoming these problems, and it also holds great significance in
both economic and environmental concerns.3
(S) - α, α - diarylprolinol silyl ethers, also known as Jørgensen–
Hayashi catalysts, were proven to be promising organocatalysts,4 and
various different approaches for the immobilization of Jørgensen–
Hayashi catalyst have been reported. Whereas the use of insoluble
heterogeneous supports has gained widespread attention,5
immobilization on soluble homogeneous polymers has scarcely been
reported.6 For example, Zeitler and co-workers have reported on a
type of MeOPEG-supported Jørgensen–Hayashi catalyst through a
stable 1,2,3-triazole linkage, and the immobilized catalyst provides
unchanged reactivity and selectivity as compared with the
homogeneous catalyst6g. In this article, we report the synthesis of
N
OR'
Ph
N
H
H
1
2
(S) - α, α - diarylprolinol silyl ethers
O
JH1，R=TMS
JH2，R=TES
JH3，R=TBS
Ph
OR'
S
N
Ph
H
=PEG
Figure 1. Catalysts used in this study
As described in Scheme 1, the unsupported functional Jørgensen–
Hayashi catalyst 1 was accordingly synthesized and immobilized
onto the thiol PEG. The PEG-supported Jørgensen–Hayashi catalysts
2 could be obtained in a very good overall yield (> 41% from 3).6g
According to the elemental analysis of nitrogen, the loading of
functional Jørgensen–Hayashi catalyst 1a on PEG-supported 2aa,
2ab, 2ac, 2ad and 2ae was 0.65 mmol/g, 0.39 mmol/g, 0.17 mmol/g,
0.3 mmol/g and 0.19 mmol/g, respectively. And the loading of
functional Jørgensen–Hayashi catalyst 1b on PEG-supported 2bd
was 0.29 mmol/g.
unsupported functional Jørgensen–Hayashi catalyst
1 and its
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HO
Ph
O
Ph
Ph
O
HO
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DOI: 10.1039/C5OB01442E
OH
O
Ph
(a) ClCO2Et, K2CO3, 87% yield
(b) PhMgBr, THF, 62% yield
Cl
N
OH
N
N
(c) 3 equiv NaH, DMF
90% yield
O
H
O
EtO
trans-4-hydroxy-L-proline
3
4
(d) KOH,
EtOH / H2O,
86% yield
O
Ph
N
Ph
OH
H
5
(e) TMSCl, NEt3, CH2Cl2
70% yield
(e') TESOTf, NEt3, CH2Cl2
60% yield
O
O
Ph
OTES
Ph
Ph
OTMS
Ph
N
H
1b
N
H
1a
2aa
2ab
=PEG1000, n=1, R'=TMS
HO
=PEG2000, n=1, R'=TMS
(f) AIBN,
PhMe,
60℃
O
n1
O
Ph
OR'
Ph
2ac
2ad
=PEG5000, n=1, R'=TMS
=PEG3400, n=2, R'=TMS
S
> 90% yield
1
N
H
SH
n
=PEG
2
2ae
2bd
=PEG5000, n=2, R'=TMS
=PEG3400, n=2, R'=TES
O
n2
Scheme 1. Synthesis of the Unsupported Functional Jørgensen–Hayashi Catalyst 1 and the PEG-Immobilized 2 from trans-4-Hydroxy-L-
Proline
Table 1. Catalyst Screening and Reaction Optimizationa
O
Catalyst 2
PhCO2H
NO2
O
H
NO2
solvent, r.t.
H
Et
6a
Et
7a
8aa
drd
eee (%)
Entry
Cat
solvent
time (day)
Cb (%)
Yc (%)
1
2
3
1a
1b
none
none
none
none
none
none
none
none
none
none
PhMe
(CH2Cl)2
EtOH
MeOH
H2O
1
1
1
1
1
7
7
7
7
7
4
4
4
2
2
2
2
2
> 99
95
95
90
88
89
89
85
1.8:1
1.9:1
2.6:1
2.6:1
2.6:1
94
92
94
89
88
JH1
JH2
JH3
2aa
2ab
2ac
2ad
2ae
2ad
2ad
2ad
2ad
2ad
2ad
2ad
2ad
4
92
5
6
7
8
88
< 5
< 5
15
64
41
10
60
37
35
73
87
86
85
55
87
31
1.1:1
3:1
2:1
5:1
10:1
2:1
2.7:1
1.5:1
1.5:1
5:1
99
98
99
87
90
86
90
87
90
97
92
9
10
11
12
13
14
15
16
17
18
41
86
> 99
> 99
> 99
> 99
> 99
67
(CH2Cl)2 : H2O (1:1)
(CH2Cl)2 : H2O (3:1)
(CH2Cl)2 : H2O (5:1)
4.6:1
a
Unless otherwise stated, the reaction was conducted by stirring in solvent (0.25 mL) using 6a (0.5 mmol) and 7a (0.1 mmol) with 5 mol% catalyst and 10
b
c
d
mol% PhCO2H at room temperature. The conversion, determined by GC-MS. Isolated yield of 8aa. The dr value of syn:anti, determined through HPLC
analysis on a Chiralcel OD-H. e The ee value of the syn isomer, determined through HPLC analysis on a Chiralcel OD-H.
2 | J. Name., 2012, 00, 1‐3
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ARTICLE
position also yielded the addition product 8fa with high
The unsupported functional Jørgensen–Hayashi catalysts 1,
regular Jørgensen-Hayashi catalysts JH and the PEG-supported
Jørgensen–Hayashi catalysts 2 were then evaluated for the enamine-
catalyzed asymmetric Michael reaction of butyraldehyde 6a and
trans-β-nitrostyrene 7a without solvent at room temperature (Table 1,
entries 1–10). Pleasingly, using catalysts 1a, 1b, JH1, JH2 and JH3,
Michael product 8aa was obtained as the major product with
significant similar diastereo- and enantiocontrol (Table 1, entries 1–
5). Furthermore, among the tested PEG-supported Jørgensen–
Hayashi catalysts (entries 6–10), 2ad (entry 9), which exhibited
slightly better diastereoselectivity and enantioselectiviy than the
unsupported functional catalyst 1 (entry 1), was found to be the best
catalyst among the supported catalysts for the reaction, providing
8aa in 64% conversion, 3:1 dr with corresponding 98%, and 67% ee.
Subsequent evaluation of solvent effects improved the yield to 87%
when (CH2Cl)2:H2O (3:1) was used as the solvent (entries 11–18).
After obtaining the optimized reaction conditions, a series of
experiments were performed to investigate the substrate scope
for the enamine-catalyzed asymmetric Michael reaction of
enantioselectivity (85% ee) (Table 2, entry 6). In addition, also
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the nitrodiene 7h with aldehyde 6a was also successfully
DOI: 10.1039/C5OB01442E
converted to the conjugate addition product in good yield and
excellent enantioselectivity (Table 2, entry 14). These results
demonstrate that the PEG-supported Jørgensen–Hayashi
catalyst 2ad is a highly efficient catalyst.
Next, the recyclability and stability of the PEG-supported
catalyst 2ad was examined. The recycling experiment was
performed at the premise of recovering the PEG-supported catalyst
by using acid-based extraction method. After the Michael reaction,
the recovered PEG-supported catalyst was extracted from the
aqueous phase, dried, and then directly subjected to the next run. As
shown in Table 3, the PEG-supported catalyst 2ad can be reused for
at least eight times without losing the enantioselectivity (94 to 99%
ee) and diastereoselectivity (dr 4:1 to 5:1). After the seventh run, due
to the hydrolysis of the silyl ether, we could observe a significant
decrease in catalytic activity, although diastereoselectivity and
enantioselectivity maintained. But after simply treating the
deactivation PEG-supported catalyst 2ad with ClSi(CH3)3 in CH2Cl2,
the catalytic activity of the 2ad can be recovered effectively(Table 3,
entry 9). 5d, 5i The JH1 was also tested in the recycling experiment, in
the fourth run with the recovered catalyst, quite low yield (only 14%)
with constant level of diastereo- and enantioselectivity was observed
(Table 3, entry 4). And when the PEG-supported catalyst 2bd with
more robust TES was used, it can be reused for eight times without
losing the enantioselectivity (99% ee) and diastereoselectivity (dr 9:1
to 10:1). .
aldehydes
Table 2, different combinations of
react smoothly in the presence of 5 mol% of the supported
catalyst 2ad to afford the expected adducts in moderate to
6
and trans-β-nitrostyrenes
7. As summarized in
6
and were allowed to
7
8
excellent yields (40% to 95%), moderate to good
diastereoselectivities (1:1 to 6:1 dr) and high to excellent
enantioselectivities (syn isomer, 85% to 99% ee). Variations in
the aldehydes
6
(Table 2, entries 1–6) as well as in the
nitroolefins 7a
–7g (Table 2, entries 7–13) are well tolerated.
Aldehyde 6f with more sterically demanding moiety in the β-
Table 2. Scope of the enamine-catalyzed asymmetric Michael reactiona
5 mol % catalyst 2ad
10 mol % PhCO2H
O
O
R2
NO2
NO2
R2
H
H
(CH2Cl)2 : H2O (3 : 1)
r.t.
R1
R1
6
7
8
drc
eed
(%)
Entry
1
R1 / 6
R2 / 7
8 / yieldb (%)
8aa / 87
(syn:anti)
Et / 6a
C6H5 / 7a
5:1
97
2
3
Pr / 6b
Butly / 6c
Pentyl / 6d
Hexyl / 6e
i-Pr / 6f
Et / 6a
C6H5 / 7a
C6H5 / 7a
C6H5 / 7a
C6H5 / 7a
C6H5 / 7a
8ba / 90
8ca / 93
8da / 70
8ea / 92
8fa / 40
8ab / 85
8ac / 91
8ad / 86
8ae / 88
8af / 75
8cc / 95
8cg / 57
8ah / 68
5:1
4:1
4:1
5:1
1:1
6:1
1:1
3:1
3:1
2:1
5:1
3:1
2:1
87
91
99
96
85
98
92
99
99
98
99
99
89
4
5e
6
7e
8
4-CH3-C6H4 / 7b
4-Br-C6H4 / 7c
Et / 6a
9e
10e
11
12
13
14
Et / 6a
3-Br-C6H4 / 7d
2-Br-C6H4 / 7e
Et / 6a
Et / 6a
2-Thienyl / 7f
Butly / 6c
Butly / 6c
Et / 6a
4-Br-C6H4 / 7c
4-Cl-C6H4 / 7g
4-Br-C6H4CH=CH / 7h
a
Unless otherwise stated, the reaction was conducted by stirring in 0.25 mL solvent using 6 (0.5 mmol) and 7 (0.1 mmol) with 5 mol% catalyst 2ad and 10
b
c
mol% PhCO2H at room temperature for 2 days. In the case of racemic samples, 50 mol% DL-proline were used in DMF. Isolated yield. Determined by
chiral-phase HPLC. The ee value of the syn isomer, determined by chiral-phase HPLC. The ee value of the syn isomer was determined by chiral HPLC
analysis after conversion of the aldehyde into the corresponding alcohol by reduction with NaBH4.
d
e
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Table 3. Recycling of 2ad for the enamine-catalyzed asymmetric Michael reaction of 6c with 7aa
View Article Online
DOI: 10.1039/C5OB01442E
O
5 mol % catalyst 2ad
10 mol % PhCO2H
O
NO2
H
NO2
H
(CH2Cl)2 : H2O (3 : 1)
r.t.
6c
7a
8ca
recycle
method
yield of 8cab (%)
drc (syn:anti)
5:1
eec (%)(syn)
A
B
C
A
B
C
A
B
C
A
B
C
A
B
C
A
C
A
C
A
C
A
C
A
79
60
96
99
4:1
82
9:1
99
79
5:1
96
1
2
3
4
58
4:1
99
80
9:1
99
78
4:1
99
58
4:1
99
79
9:1
99
67
5:1
99
59
5:1
99
78
9:1
99
71
5:1
98
14
5:1
99
76
9:1
99
69
4:1
94
5
6
7
76
10:1
5:1
99
65
95
76
10:1
5:1 (5:1)d
10:1
5:1 (5:1)e
9:1
99
55(71)d
97 (97)d
75
99
46(71)e
75
97 (97)e
99
8
9f
69
5:1
95
a Method A: unless otherwise stated, the reaction was conducted by stirring in 5 mL solvent using 6c (2.4 mmol) and 7a (2 mmol) with 5 mol% catalyst 2ad
b
and 10 mol% PhCO2H at room temperature in 2 days. Method B: JH1 was used as the catalyst. Method C: 2bd was used as the catalyst. Isolated yield of
8ca. c Determined through HPLC analysis on a Chiralcel OD-H. d Reaction time = 3 days. e Reaction time = 5 days. f Using the reactivated catalyst 2ad.
The 1H NMR and 13C NMR spectra were recorded in deuterated
Conclusions
solvents and are reported in ppm relative to tetramethylsilane.
GC−MS experiments were performed on a GC system with a
mass selective detector. HRMS data were measured on a
LC/TOF-MS with ESI source or GC/TOF-MS with EI source.
Elemental analyses of N, C, and H, and IR spectra were
In summary, a novel recyclable, and reusable PEG-supported
Jørgensen–Hayashi catalyst is synthesized for the first time.
The catalyst is proven to be efficient catalyst for the enamine-
catalyzed asymmetric Michael reaction of a wide range of
aldehydes with both nitroolefins and nitrodiene. Moderate to
excellent yield (40% to 95%), moderate to good
diastereoselectivities (1:1 to 6:1 dr), and high to excellent
enantioselectivities (87% to 99% ee) are achieved using only 5
mol% PEG-supported catalyst loading. The prepared PEG-
supported catalyst can be recovered eight times and found to
provide similar diastereoselectivity and enantioselectivity to
unsupported functional catalyst. Further study on the wide
application of this efficient strategy for the synthesis of
potentially valuable chiral molecules is under investigation in
our laboratory.
performed for catalysts 2aa
,
2ab
,
2ac
,
2ad, 2ae and 2bd
.
Column chromatography
and
flash
chromatography
experiments were performed on silica gel (200-300 mesh)
eluting with ethyl ether and petroleum ether. TLC experiments
were carried out on glass-backed silica plates. In each case,
enantiomeric ratio was determined on a chiral column in
comparison with authentic racemates by chiral HPLC.
Compound
3 was synthesized according to the reference 6g.
Conventional procedure for the synthesis of PEG-supported
Jørgensen–Hayashi catalysts 2
Experimental
Synthesis of compound 4
Sodium hydride (1.69 g, 0.044 mmol, 4.4 equiv., 60 (ω%) ) was
General information
4 | J. Name., 2012, 00, 1‐3
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added in a N2-filled round-bottom flask containing 30 mL dried combined organic layer was washed with brine and dried over
anhydrous Na2SO4 and the solvent was removed under reduced
DMF at room temperature with stirring for 10 min. Then, the
solution of 3 (3.41 g, 0.01 mmol, 1 equiv.) in 9 mL of dried DMF
was added in 30 min at 0 °C. After an hour, 1-(chloromethyl)-4-
vinylbenzene (1.67 g, 0.011 mmol, 1.1 equiv.) was added slowly
using a septum. The resulting reaction mixture was allowed to react
with stirring at ambient temperature. Subsequently, the reaction was
quenched with diethyl ether (10 mL) and water (10 mL). The layers
were separated and the aqueous phase was extracted with diethyl
ether several times. The combined organic layers were washed with
water, dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate 8/1 to 5/1) to
afford the product 4, yield: 18.5 g, 90 %; yellow oil; 1H NMR (500
MHz, CDCl3): δ = 7.58−7.56 (m, 2H), 7.45−7.42 (m, 2H), 7.41−7.37
(m, 6H), 7.35−7.27 (m, 4H), 6.76−6.72 (q, J = 11.0, 17.5 Hz, 1H),
5.81−5.78 (m, 1H), 5.31−5.28 (m, 1H), 4.90−4.93 (q, J = 5.0, 11.5
Hz, 1H), 4.48 (s, 2H), 4.18 (t, J = 5.5 Hz, 1H), 4.08−4.05 (q, J = 5.5,
12.5 Hz, 1H), 3.38−3.35 (m, 1H), 1.96−1.92 (q, J = 5.0, 13.5 Hz,
1H), 1.25−1.19 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ =
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pressure. The residue was purified by silica gel column
chromatography (petroleum ether/ethyl DeOthI:e1r0.150/319/Cto5OB30/114)42tEo
afford the product
NMR (500 MHz, CDCl3): δ = 7.52−7.50 (m, 2H), 7.41−7.38 (m,
4H), 7.32−7.24 (m, 8H), 6.77−6.71 (q, = 11.0, 18.0 Hz, 1H),
5.77 (d, = 18.0 Hz, 1H), 5.26 (d, = 10.5 Hz, 1H), 4.42 (t,
1.
1a, yield: 3.2 g, 70 %; colorless liquid; 1H
J
J
J
J =
5.5 Hz, 3H), 3.84−3.83 (m, 1H), 3.05−3.03 (m, 1H), 2.88−2.85
(m, 1H), 1.78−1.75 (m, 2H), 0.06 (s, 9H) ppm; 13C NMR (125
MHz, CDCl3): δ = 146.5, 145.3, 138.1, 137.0, 136.6, 128.5 (×2),
127.9 (×2), 127.7 (×2), 127.6 (×2), 127.5 (×2), 127.0, 126.9,
126.3 (×2), 113.8, 82.8, 79.0, 70.6, 63.8, 52.8, 34.3, 2.2 (×3)
ppm; (ESI+) m/z 458.21; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C29H36NO2Si 458.2516; Found 458.2515. 1b, yield:
3.0 g, 60 %; colorless liquid; 1H NMR (500 MHz, CDCl3): δ =
7.64−7.63 (m, 2H), 7.51−7.47 (m, 4H), 7.41−7.36 (m, 8H),
6.87−6.81 (q,
J = 11.0, 17.5 Hz, 1H), 5.87 (d, J = 18.0 Hz, 1H),
5.36 (d, = 11 Hz, 1H), 4.54−4.46 (m, 3H), 3.85 (m, 1H),
J
3.15−2.98 (m, 1H), 2.85−2.82 (m, 1H), 1.95−1.78 (m, 2H),
1.10−0.94 (m, 9H), 0.70−0.63 (m, 2H), 0.51−0.46 (m, 4H) ppm;
13C NMR (125 MHz, CDCl3): δ = 145.5, 145.2, 138.2, 136.9,
136.6, 128.8 (×2), 128.0 (×2), 127.8 (×2), 127.6 (×2), 127.2
160.4, 143.0, 140.2, 137.4, 137.2, 136.4 (×2), 128.7 (×2), 128.5 (×2), (×2), 127.0, 126.9, 126.2 (×2), 113.7, 82.6, 79.3, 70.6, 63.9,
52.9, 34.5, 7.2 (×3), 6.5 (×3) ppm; (ESI+) m/z 500.27; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C32H42NO2Si 500.2985;
Found 500.2983.
128.0 (×2), 127.8, 126.4 (×2), 126.1 (×2), 125.5 (×2), 114.2, 85.8,
78.4, 71.1, 67.5, 53.8, 36.2 ppm; GC−MS: m/z 411.2 (100), 165.1,
91.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H26NO3
412.1913; Found 412.1922.
Synthesis of PEG-supported Jørgensen
2
–
Hayashi catalysts
Synthesis of compound 5
A N2-filled three-necked round-bottom flask was charged with
A mixture of
1 (0.038 g, 0.082 mmol, 1.1 equiv.), PEG-SH
(0.075 mmol, 1 equiv.), AIBN (0.012 g, 0.075 mmol, 1 equiv.)
in toluene (1.5 mL) was stirred at 60 °C for 1d, then the
reaction mixture was precipitated with diethyl ether, filtered,
4
(4.11 g, 0.01 mmol) in 25 mL ethanol. Potassium hydroxide
(1.12 g, 0.02 mmol, 2 equiv.) in water (4.6 mL) was added in a
drop-wise manner. After being stirred for 30 h at 45 °C, the
reaction was diluted with ethyl acetate. The layers were
separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was washed with brine and
dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography (petroleum ether/ethyl acetate 8/1 to
and dried under vacuum. In the case of SH-PEG-SH,
1 ( 0.072
g, 0.157 mmol, 2.1 equiv.) and AIBN (0.024 g, 0.15 mmol, 2
equiv.) were used. Anal. Calcd. for 2aa Found: C, 58.40; H,
8.41; N, 0.91. IR (KBr): γmax/cm-1 3731
,
2924
Anal. Calcd. for 2ab Found: C, 56.80; H, 8.51; N, 0.55. IR
(KBr): γmax/cm-1 3731
2869 1108 950 707. Anal. Calcd. for
, , ,
1105 951 757.
,
,
,
,
2ac Found: C, 54.80; H, 9.10; N, 0.24. IR (KBr): γmax/cm-1
3731, 3504, 1110, 955, 759. Anal. Calcd. for 2ad Found: C,
54.80; H, 8.32; N, 0.42. IR (KBr): γmax/cm-1 3429, 2885, 1112,
956, 760. Anal. Calcd. for 2ae Found: C, 54.70; H, 8.40; N,
0.27. IR (KBr): γmax/cm-1 3430, 2876, 1109, 953, 732. Anal.
Calcd. for 2bd Found: C, 54.81; H, 8.33; N, 0.41. IR (KBr):
4/1) to afford the product
mp: 70.4 °C; 1H NMR (500 MHz, CDCl3): δ = 7.62 (
Hz, 2H), 7.53 (t, = 1.0 Hz, 2H), 7.43 (d, = 8.5 Hz, 2H),
7.36−7.30 (m, 6H), 7.24−7.19 (m, 2H), 6.79−6.73 (q, = 10.5,
17.5 Hz, 1H), 5.78 (d, = 17.5 Hz, 1H), 5.28 (d, = 11.0 Hz,
1H), 4.63−4.60 (q, = 6.5, 9.5 Hz, 1H), 4.49−4.44 (m, 2H),
5, yield: 16.6 g, 86 %; white solid,
d
, J = 7.0
J
J
J
J
J
J
γ
max/cm-1 3443, 2874, 1112, 951, 706.
4.09−4.07 (m, 1H), 3.20−3.16 (m, 2H), 1.86−1.80 (m, 1H),
1.74−1.70 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ =
147.8, 145.0, 138.0, 137.1, 136.6, 128.3 (×2), 128.0 (×2), 127.8
(×2), 126.6, 126.4, 126.3 (×2), 126.0 (×2), 125.5 (×2), 113.9,
79.5, 76.9, 70.6, 63.5, 52.6, 33.0 ppm; (ESI+) m/z 386.28;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H28NO2
386.2115; Found 386.2119.
Conventional procedure for the asymmetric Michael
reaction catalyzed by 2d
Solvent (0.25 mL) was added to a mixture of aldehydes
6 (0.5
mmol) with nitroolefins or nitrodiene (0.1 mmol) in the
7
presence of 5 mol% catalyst 2ad and 10 mol% PhCO2H at
room temperature with vigorous stirring. After 2 days, the
reaction mixture was extracted with DCM, washed with water,
dried, and concentrated. The residue was purified by flash
chromatography on silica gel (ethyl ether/petroleum ether = 1:3
Synthesis of compound 1
Fresh triethylamine (1.31 g, 0.013 mmol, 1.3 equiv.) was added
slowly to a solution of
5 (3.85 g, 0.01 mmol, 1 equiv.) in
as eluent) to yield the faintly yellow liquid products
8.
anhydrous dichloromethane (30 mL) under N2-atmosphere.
After being stirred for 10 min, fresh chlorotrimethylsilane (1.19
g, 0.011 mmol, 1.1 equiv.) or TESOTf (2.91 g, 0.011 mmol, 1.1
equiv.) was added in a drop-wise manner at 0 °C. The reaction
was allowed proceed with stirring at ambient temperature for a
further 3 days. Subsequently, the mixture was poured into ice
water followed by extraction with dichloromethane. The
Enantiomeric ratio was determined by HPLC analysis on a
chiral column.
(2R,3R)-2-ethyl-4-nitro-3-phenylbutanal (8aa) 5a
yield: 19.2
.
mg, 87 %; 97 % ee; 5:1 dr; yellow liquid; The enantiomeric
excess was determined by HPLC on Daicel Chiralpak OD-H
with hexane/i-PrOH (95:5) as the eluent, Flow: 1.0 mL/min;
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1‐3 | 5

Organic & Biomolecular Chemistry
Page 6 of 8
ARTICLE
Journal Name
UV = 224 nm; tsyn
= 37.573 min, tsyn
= 32.482 min; (2R,3R)-2-isopropyl-4-nitro-3-phenylbutanal (8fa) 5a
major
.
yield:
minor
tantiminor = 58.752 min, tantimajor = 34.854 min; 1H NMR (500 MHz, 9.40 mg, 40 %; 85 %; 47 % ee; 1:1 dr; white solid, mp: 114.4
View Article Online
DOI: 10.1039/C5OB01442E
CDCl3): δ = 9.72 (d,
J = 2.5 Hz, 1H), 7.36−7.34 (m, 2H), °C; The enantiomeric excess was determined by HPLC on
7.31−7.28 (m, 1H), 7.19−7.17 (m, 2H), 4.74−4.61 (m, 2H), Daicel Chiralpak IC-H with hexane/i-PrOH (95:5) as the eluent,
3.84−3.77 (m, 1H), 2.71−2.66 (m, 1H), 1.55−1.46 (m, 2H), Flow: 1.0 mL/min; UV = 212nm; tsynminor = 29.745 min, tsyn
major
1
0.82 (t,
203.1, 136.8, 129.1 (×2), 128.1, 128.0 (×2), 78.5, 53.4, 42.8, NMR (500 MHz, CDCl3): δ = 9.91(d,
20.4, 10.7 ppm; GC−MS: m/z 145.1, 117.1, 104.1, 91.1 (100), 7.36−7.33 (m, 2H), 7.30−7.27 (m, 1H), 7.21−7.20 (m, 2H),
77.1. 4.70−4.55 (m, 1H), 3.94−3.89 (m, 1H), 2.80−2.77 (m, 1H),
(R)-2-((R)-2-nitro-1-phenylethyl)pentanal (8ba) 5a
yield: 21.2 1.73−1.69 (m, 1H), 1.09 (d, = 7.0 Hz, 3H), 0.87 (t, = 7.0 Hz,
J
= 7.5 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ = = 33.878 min; tantiminor = 14.439 min, tantimajor = 19.159 min; H
J
= 2.0 Hz, 1H),
.
J
J
mg, 90 %; 87 % ee; 5:1 dr; yellow liquid; The enantiomeric 3H); 13C NMR (125 MHz, CDCl3): δ = 204.4, 137.2, 129.1 (×2),
excess was determined by HPLC on Daicel Chiralpak OD-H 128.0 (×3), 79.0, 58.7, 42.0, 27.9, 21.6, 16.9 ppm; GC−MS:
with hexane/i-PrOH (90:10) as the eluent, Flow: 1.0 mL/min; m/z 145.2 (100), 104.2, 117.2, 131.2, 91.2.
UV = 228 nm; tsyn
= 22.518 min, tsyn
= 24.932 min; (2R,3R)-2-ethyl-4-nitro-3-p-tolylbutanal (8ab) 8h
major
.
yield: 19.98
tantiminor = 20.212 min, tantimajor = 34.877 min; 1H NMR (500 MHz, mg, 98 %; 43 % ee; 6:1 dr; yellow liquid; The product was
CDCl3): δ = 9.72 (d, = 3.0 Hz, 1H), 7.38−7.34 (m, 2H), converted to the corresponding alcohol with NaBH4 and
minor
J
7.33−7.30 (m, 1H), 7.20−7.18 (m, 2H), 4.74−4.64 (m, 2H), enantiomeric excess was determined by HPLC on Daicel
3.81−3.77 (m, 1H), 2.74−2.70 (m, 1H), 1.51−1.47 (m, 1H), Chiralpak OD-H with hexane/i-PrOH (97:3) as the eluent, Flow:
1.39−1.32 (m, 2H), 1.22−1.18 (m, 1H), 0.82 (t,
J
= 7.0Hz, 3H); 1.0 mL/min; UV = 212 nm; tsyn
= 59.725 min, tsyn
=
minor
major
13C NMR (125 MHz, CDCl3): δ = 203.2, 136.9, 129.1 (×2), 63.937 min; tanti
= 47.476 min, tanti
= 51.595 min; H
1
minor
major
128.2, 128.0 (×2), 78.4, 53.9, 43.3, 29.5, 19.8, 13.9 ppm; NMR (500 MHz, CDCl3): δ = 9.72 (d,
J = 3.0 Hz, 1H),
GC−MS: m/z 145.2 (100), 117.2, 104.2, 91.2, 77.2.
7.16−7.13 (m, 2H), 7.08−7.06 (m, 2H), 4.72−4.59 (m, 2H),
(R)-2-((R)-2-nitro-1-phenylethyl)hexanal (8ca) 5a
.
yield: 21.16 3.77−3.76 (m, 1H), 2.67−2.65 (m, 1H), 2.33 (s, 3H), 1.53−1.50
mg, 93 %; 91 % ee; 4:1 dr; yellow liquid; The enantiomeric (m, 2H), 0.84 (t,
J
= 7.0 Hz, 3H) ppm; 13C NMR (125 MHz,
excess was determined by HPLC on Daicel Chiralpak OD-H CDCl3): δ = 203.3, 137.9, 133.7, 129.8 (×2), 127.9 (×2), 78.7,
with hexane/i-PrOH (90:10) as the eluent, Flow: 1.0 mL/min; 55.1, 42.4, 21.0, 20.4, 10.7 ppm; GC−MS: m/z 159.2, 143.2,
UV = 228 nm; tsyn
= 17.039 min, tsyn
= 20.918 min; 118.2 (100), 117.2, 91.2.
minor
major
tantiminor = 18.612 min, tantimajor = 29.811 min; 1H NMR (500 MHz, (2R,3R)-3-(4-bromophenyl)-2-ethyl-4-nitrobutanal (8ac) 8e
CDCl3): δ = 9.71 (d, = 3.0 Hz, 1H), 7.37−7.34 (m, 2H), yield: 27.21 mg, 92 %; 75 % ee; 1:1 dr; yellow liquid; The
.
J
7.32−7.29 (m, 1H), 7.20−7.18 (m, 2H), 4.74−4.63 (m, 2H), enantiomeric excess was determined by HPLC on Daicel
3.81−3.77 (m, 1H), 2.73−2.69 (m, 1H), 1.51− 1.47 (m, 1H), Chiralpak IC-H with hexane/i-PrOH (95:5) as the eluent, Flow:
1.43−1.40 (m, 1H), 1.28−1.19 (m, 2H), 1.18−1.13 (m, 2H), 1.0 mL/min; UV = 228 nm; tsynminor= 41.210 min, tsyn
major
1
0.79 (t,
203.3, 136.9, 129.1 (×2), 128.1, 128.0 (×2), 78.4, 53.9, 43.2, NMR (500 MHz, CDCl3): δ = 9.71 (d,
28.5, 27.0, 22.5, 13.6 ppm; GC−MS: m/z 145.2 (100), 117.2, 7.49−7.47 (m, 2H), 7.08−7.07 (m, 2H), 4.74−4.57 (m, 2H),
105.2, 104.2, 91.2. 3.80−3.75 (m, 1H), 2.69−2.64 (m, 1H), 1.57−1.45 (m, 2H),
(R)-2-((R)-2-nitro-1-phenylethyl)heptanal (8da) 5a = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ =
yield: 0.83 (t,
J
= 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = =44.663 min; tanti
= 36.397 min, tanti
= 26.531 min; H
minor
major
J
= 2.5 Hz, 1H),
.
J
18.41 mg, 70 %; 99 % ee; 4:1 dr; yellow liquid; The 204.8, 136.0, 132.4 (×2), 129.8 (×2), 122.2, 78.3, 54.7, 42.2,
enantiomeric excess was determined by HPLC on Daicel 20.4, 10.6 ppm; GC−MS: m/z 223.0, 115.1 (100), 103.1, 91.1,
Chiralpak OD-H with hexane/i-PrOH (90:10) as the eluent, 77.1.
Flow: 1.0 mL/min; UV = 228 nm; tsynmajor = 19.745 min; tanti
(2R,3R)-3-(3-bromophenyl)-2-ethyl-4-nitrobutanal
(8ad).
minor
= 26.491 min, tanti
= 17.652 min; 1H NMR (500 MHz, yield: 25.71 mg, 86 %; 99 % ee; 99:1 dr; yellow liquid; The
major
CDCl3): δ = 9.69 (d,
J = 2.5 Hz, 1H), 7.36−7.33 (m, 2H), product was converted to the corresponding alcohol with
7.31−7.28 (m, 1H), 7.19−7.18 (m, 2H), 4.74−4.63 (m, 2H), NaBH4 and enantiomeric excess was determined by HPLC on
3.82−3.77 (m, 1H), 2.72−2.70 (m, 1H), 1.49−1.47 (m, 1H), Daicel Chiralpak OD-H with hexane/i-PrOH (97:3) as the
1.39−1.38 (m, 1H), 1.28−1.11 (m, 6H), 0.81 (t,
J
= 7.0 Hz, 3H); eluent, Flow: 0.6 mL/min; UV = 228 nm; tsynmajor =80.238 min;
1
13C NMR (125 MHz, CDCl3): δ = 203.2, 136.8, 129.0 (×2), tanti
= 58.952 min, tanti
= 62.618 min; H NMR (500
minor
major
128.0 (×3), 78.4, 53.8, 43.1,31.5, 27.2, 26.0, 22.1, 13.7 ppm; MHz, CDCl3): δ = 9.70 (d,
J = 2.5 Hz, 1H), 7.44−7.41 (m, 1H),
GC−MS: m/z 117.1 (100), 115.1, 104.1, 77.1, 91.1.
7.36−7.35 (m, 1H), 7.24−7.18 (m, 1H), 7.14−7.13 (m, 1H),
(R)-2-((R)-2-nitro-1-phenylethyl)octanal (8ea) 8f
.
yield: 25.48 4.74−4.59 (m, 2H), 3.82−3.75 (m, 1H), 2.70−2.65 (m, 1H),
mg, 96 %; 11% ee; 5:1 dr; yellow liquid; The product was 1.57−1.46 (m, 2H), 0.84 (t,
J
= 7.5 Hz, 3H); 13C NMR (125
converted to the corresponding alcohol with NaBH4 and MHz, CDCl3): δ = 202.7, 139.4, 131.4, 131.1, 130.7, 126.7,
enantiomeric excess was determined by HPLC on Daicel 123.1, 78.1, 54.7, 42.2, 20.4, 10.6 ppm; GC−MS: m/z 169.0,
Chiralpak AD-H with hexane/i-PrOH (95:5) as the eluent, Flow: 115.1 (100), 103.1, 91.1, 77.1. HRMS (EI-TOF) m/z: [M]+
1.0 mL/min; UV = 208 nm; tsyn
= 12.866 min, tsyn
=
Calcd for C12H14BrNO3 299.0157; Found 299.0163.
= 14.199 min; H (2R,3R)-3-(2-bromophenyl)-2-ethyl-4-nitrobutanal (8ae) 8e
major
minor
major
11.493 min; tanti
= 16.479 min, tanti
.
1
minor
NMR (500 MHz, CDCl3): δ = 9.67 (d,
J = 2.5 Hz, 1H), yield: 26.31 mg, 88 %; 99 % ee; 3:1 dr; yellow liquid; The
7.34−7.31 (m, 2H), 7.28−7.25 (m, 1H), 7.18−7.17(m, 2H), enantiomeric excess was determined by HPLC on Daicel
4.72−4.61 (m, 2H), 3.81−3.76 (m, 1H), 2.72−2.67 (m, 1H), Chiralpak OD-H with hexane/i-PrOH (90:10) as the eluent,
1.48−1.10 (m, 10H), 0.81 (t,
J
= 6.0 Hz, 3H); 13C NMR (125 Flow: 1.0 mL/min; UV = 232 nm; tsynmajor = 29.997 min; tanti
minor
MHz, CDCl3): δ = 203.3, 136.9, 129.1 (×2), 128.0 (×3), 78.4, = 41.356 min, tanti
= 28.786 min; 1H NMR (500 MHz,
major
53.9, 43.2, 31.4, 28.5, 27.3, 26.4, 22.4, 14.0 ppm; GC−MS: m/z CDCl3): δ = 9.73 (d,
J = 2.0 Hz, 1H), 7.61−7.60 (m, 1H),
145.1 (100), 105.1, 104.1, 91.1, 78.1.
7.33−7.30 (m, 1H), 7.22−7.18 (m, 1H), 7.17−7.13 (m, 1H),
4.87−4.67 (m, 2H), 4.38−4.37 (m, 1H), 2.93 (s, 1H), 1.66−1.57
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 8
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
(m, 1H), 1.56−1.47 (m, 1H), 0.67 (t,
J
= 15.0 Hz, 3H); 13C After 2 days, 50 mL ethyl ether and 20mL (0.1 (ω %)) aqueous
NMR (125 MHz, CDCl3): δ = 202.9, 136.3, 133.9, 129.5 (×2), NaOH solution were added in the reaction solution. Then the
View Article Online
128.1 (×2), 77.4, 54.4, 41.3, 19.6, 11.6 ppm; GC−MS: m/z layers were separated and the aqueous phase was extracted by
DOI: 10.1039/C5OB01442E
184.1 (100), 169.1, 115.1, 104.2, 77.2.
(2R,3S)-2-ethyl-4-nitro-3-(thiophen-2-yl)butanal
CH2Cl2 (25 mL×3), simply dried over anhydrous Na2SO4 and
then subjected to the next run directly. And the PEG supported
(8af) 8g
.
yield: 17.03 mg, 98 %; 70 % ee; 2:1 dr; yellow liquid; The catalysts can be easily recovered in quantitative yields for each
product was converted to the corresponding alcohol with run.
NaBH4 and enantiomeric excess was determined by HPLC on
Daicel Chiralpak OD-H with hexane/i-PrOH (98:2) as the Reactivating of the deactivation catalyst 2ad
eluent, Flow: 0.5 mL/min; UV = 228nm; tsynminor = 123.112 min, Fresh triethylamine (1.3 eq) was added slowly to a solution of
tsynmajor = 129.573 min; tantiminor = 113.667 min, tantimajor = 105.861 the recovered deactivation PEG-supported catalyst 2ad (1
min; 1H NMR (500 MHz, CDCl3): δ = 9.717(d,
J = 2.0 Hz, 1H), equiv.) in anhydrous DCM (10 mL) under N2-atmosphere.
7.25−7.23 (m, 1H), 6.96−6.94 (m, 1H), 6.91−6.90 (m, 1H), After being stirred for 10 min, fresh chlorotrimethylsilane (2
4.75−4.62 (m, 2H), 4.20−4.14 (m, 1H), 2.72−2.67 (m, 1H), equiv.) was added in a drop-wise manner at 0 °C. The reaction
1.69−1.61 (m, 2H), 0.87 (t,
J
= 7.5 Hz, 3H); 13C NMR (125 was allowed proceed with stirring at ambient temperature for a
MHz, CDCl3): δ = 202.5, 139.5, 127.2, 127.1, 125.3, 78.9, 55.8, further 3 days. Subsequently, the mixture was poured into ice
38.4, 20.3, 10.9 ppm; GC−MS: m/z 180.1, 151.1, 110.1 (100), water followed by extraction with DCM. The combined organic
137.1, 97.1.
layer was washed with brine, dried over anhydrous Na2SO4,
concentrated, and dissolved in toluene. The mixture was further
(R)-2-((R)-1-(4-bromophenyl)-2-nitroethyl)hexanal
(8cc).
yield: 31.07 mg, 95 %; 99 % ee; 5:1 dr; yellow liquid; The precipitated with diethyl ether, filtered, and dried under vacuum
enantiomeric excess was determined by HPLC on Daicel to obtain the reactivated catalyst 2ad
.
Chiralpak AD-H with hexane/i-PrOH (95:5) as the eluent, Flow:
1.0 mL/min; UV = 228 nm; tsyn
= 16.159 min, tsyn
=
minor
major
Acknowledgements
13.972 min; tantimajor = 19.652 min; 1H NMR (500 MHz, CDCl3):
δ = 9.68 (d, = 7.0 Hz, 1H), 7.49−7.47 (m, 2H), 7.08−7.07 (m,
2H), 4.72−4.59 (m, 2H), 3.79−3.74 (m, 1H), 2.71−2.66 (m, 1H),
1.48−1.37 (m, 2H), 1.26−1.14 (m, 4H), 0.79 (t, = 7.0 Hz, 3H);
J
Financially supported by the NSFC (21202149), the Foundation of
Public Projects of Zhejiang Province (2014C31144), Zhejiang Key
Course of Chemical Engineering and Technology, and Zhejiang Key
Laboratory of Green Pesticides and Cleaner Production Technology.
J
13C NMR (125 MHz, CDCl3): δ = 202.8, 136.0, 132.2 (×2),
129.7 (×2), 122.1, 78.1, 53.6, 42.5, 28.4, 27.0, 22.5, 13.6 ppm;
GC−MS: m/z 184.0, 115.1 (100), 103.1, 91.1, 77.1. HRMS (EI-
TOF) m/z: [M]+ Calcd for C14H17BrO 280.0463 [M − HNO2]+;
Found 280.0473.
Notes and references
a
Catalytic Hydrogenation Research Centre, State Key Laboratory Breeding
Base of Green Chemistry-Synthesis Technology, Zhejiang University of
Technology, Hangzhou, 310014, China; E-mail: chrc@zjut.edu.cn.
Electronic Supplementary Information (ESI) available: experimental
procedures, characterizations, NMR spectra and HPLC spectra are available.
See DOI: 10.1039/b000000x/
(R)-2-((R)-1-(4-chlorophenyl)-2-nitroethyl)hexanal
(8cg).
yield: 16.13 mg, 57 %; 99 % ee; 3:1 dr; yellow liquid; The
enantiomeric excess was determined by HPLC on Daicel
Chiralpak OD-H with hexane/i-PrOH (97:3) as the eluent, Flow:
1.0 mL/min; UV = 228 nm; tsyn
= 30.762 min, tanti
=
minor
major
32.548 min; tantimajor = 37.866 min; 1H NMR (500 MHz, CDCl3):
δ = 9.70 (d, = 5.0 Hz, 1H), 7.35−7.32 (m, 2H), 7.15−7.12 (m,
2H), 4.73−4.60 (m, 2H), 3.80−3.75 (m, 1H), 2.71−2.67 (m, 1H),
1.49−1.40 (m, 2H), 1.25−1.16 (m, 4H), 0.81 (t, = 5.0 Hz, 3H);
1
(a) B. List and J. W. Yang, Science 2006
C. C. C. Johansson, A. McNally and N. C. Vo, Drug Discovery
Today 2007 12, 8; (c) D. W. C. MacMillan, Nature 2008 455, 304;
(d) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev. 2009 38, 2178;
(e) E. Marqués-López, R. P. Herrera and M. Christmann, Nat. Prod.
Rep. 2010 27, 1138; (f) J. Alemán and S. Cabrera, Chem. Soc. Rev.
2013 42, 774.
(a) Special Issue on Organocatalysis: Chem. Rev. 2007
For selected book, see: (b) A. Berkessel and H. Gróger, Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2004 For
selected reviews, see: (c) A. Moyano and R. Ríos, Chem. Rev. 2011
111, 4703; (d) Ł. Albrecht, H. Jiang and K. A. Jørgensen, Angew.
Chem. Int. Ed. 2011 50, 8492; (e) C. Bhanja, S. Jena, S. Nayak and S.
Mohapatra, Beilstein J. Org. Chem. 2012 , 1668; (f) J. Duan and P.
Li, Catal. Sci. Technol. 2014 , 311.
For selected reviews, see: (a) Special Issue on Recoverable Catalysts
and Reagents: Chem. Rev. 2002 102, issue 10; (b) Special Issue on
Multiphase Catalysis, Green Solventsand Immobilization: Adv. Synth.
Catal. 2006 348, issue 12-13; (c) Special Issue on Facilitated
Synthesis: Chem.Rev. 2009 109, issue 2; (d) T. E. Kristensen and T.
, 313, 1584; (b) M. J. Gaunt,
J
,
,
J
13C NMR (125 MHz, CDCl3): δ = 202.8, 135.4, 131.1, 129.4
(×2), 129.4 (×2), 78.2, 53.7, 42.5, 28.4, 27.1, 22.5, 13.6 ppm;
GC−MS: m/z 179.0, 138.0 (100), 115.1, 103.1, 77.1. HRMS
(EI-TOF) m/z: [M]+ Calcd for C14H17ClO 236.0968 [M −
HNO2]+; Found 236.0979.
,
,
,
2
, 107, issue 17;
(2R,3S,E)-5-(4-bromophenyl)-2-ethyl-3-(nitromethyl)pent-
4-enal (8ah). yield: 22.10 mg, 68 %; 90 % ee; 2:1 dr; yellow
liquid; The enantiomeric excess was determined by HPLC on
Daicel Chiralpak IC-H with hexane/i-PrOH (95:5) as the eluent,
;
,
Flow: 1.0 mL/min; UV = 228 nm; tsynminor = 37.184 min, tsyn
major
= 41.757 min; tantiminor = 31.478 min, tantimajor = 25.638 min; H
1
,
NMR (500 MHz, CDCl3): δ = 9.69 (d,
7.43−7.41 (m, 2H), 7.20−7.18 (m, 2H), 6.48−6.45 (m, 1H),
6.00−5.59 (q, = 9.5, 16.0 Hz, 1H), 4.58−4.46 (m, 2H),
3.56−3.31 (m, 1H), 2.51−2.47 (m, 1H), 1.79−1.66 (m, 2H),
0.97 (t,
= 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ =
J = 2.0 Hz, 1H),
,
8
,
4
J
3
4
J
,
202.6, 134.8, 133.8, 131.7 (×2), 128.0 (×2), 124.6, 122.0, 77.6,
54.2, 40.9, 20.0, 11.1 ppm; GC−MS: m/z 171.1, 129.1 (100),
141.1, 115.1, 77.1. HRMS (EI-TOF) m/z: [M]+ Calcd for
C14H16BrNO3 325.0314; Found 325.0302.
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Hansen, Eur. J. Org. Chem. 2010, 3179.
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