Highly enantioselective direct Michael addition of 1,3-dicarbonyl compounds to β-fluoroalkyl-α-nitroalkenes

Article abstract of DOI:10.1016/j.tet.2014.02.062

Cinchona alkaloid catalysts were used in the Michael addition reaction of 1,3-dicarbonyl compounds to β-fluoroalkyl-α-nitroalkenes for the first time. The catalytic system performed well over a broad scope of substrates including β-keto esters and 1,3-diketones with high diastereoselectivities and excellent enantioselectivities (up to 99% ee) under mild conditions. A wide range of useful fluorinated chiral building blocks was synthesized.

Full text of DOI:10.1016/j.tet.2014.02.062

Tetrahedron 70 (2014) 2523e2528
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective direct Michael addition of 1,3-dicarbonyl
compounds to b-fluoroalkyl-a-nitroalkenes
,
Yan Zhao a, Xiao-Jin Wang a, Yun Lin b, Chen-Xin Cai a, Jin-Tao Liu a
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
b College of Chemistry and Environment, Nanjing Normal University, Nanjing 210097, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Cinchona alkaloid catalysts were used in the Michael addition reaction of 1,3-dicarbonyl compounds to
Received 23 October 2013
Received in revised form 12 February 2014
Accepted 24 February 2014
Available online 2 March 2014
b
-fluoroalkyl-
a
-nitroalkenes for the first time. The catalytic system performed well over a broad scope of
-keto esters and 1,3-diketones with high diastereoselectivities and excellent
substrates including
b
enantioselectivities (up to 99% ee) under mild conditions. A wide range of useful fluorinated chiral
building blocks was synthesized.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
b
-Fluoroalkyl-a-nitroalkene
1,3-Dicarbonyl compound
Michael addition reaction
Cinchona alkaloid
1. Introduction
organofluorine molecules,8e10 despite the fact that they constitute
a very promising, highly reactive, yet easy-to-handle class of fluo-
The Michael addition reaction is one of the fundamental car-
bonecarbon bond formation reactions in organic synthesis and
offers an extremely powerful tool for the synthesis of highly
functionalized organic molecules.1e3 Accordingly, the development
of enantioselective catalytic protocols for this reaction has attracted
considerable attention. Of particular interest is the reaction of tri-
substituted carbon nucleophiles and electron-deficient olefins
giving Michael adducts containing adjacent quaternary and tertiary
stereocenters, which are key units in many complex natural prod-
ucts as well as valuable synthetic building blocks. However, this
requires high efficiency catalyst to impact both high enantiose-
lectivity and diastereoselectivity in a sterically demanding, and still
remains a great challenge.
Among the Michael acceptors, nitroalkenes are very attractive
because their addition reaction with nucleophiles provides a con-
venient access to nitroalkanes, which are versatile intermediates in
organic synthesis.2d The nitro functionality can be easily trans-
formed into amine,4 nitrile oxide,5 ketone or carboxylic acid,6 hy-
drogen,7 etc., providing a wide range of synthetically interesting
rinated building blocks. To our best knowledge, stereo-controlled
Michael reaction of -fluoroalkyl- -nitroalkenes still remains
a challenge for the chemists. In 2003, Zanda et al. reported the aza-
b
a
Michael reaction of 3,3,3-trifluoro-1-nitropropene and
a-amino
esters in the synthesis of fluorinated peptidomimetics.9 In 2006,
they reported further the Michael addition of ketone-derived en-
amines with
b-fluoroalkyl-a
-nitroalkenes.10 However, preformed
enamines were required in those reactions. Additionally, in the
enantioselective Michael addition reaction of carbonyl compounds
catalyzed by chiral enamines, 3,3,3-trifluoro-1-nitropropene was
marginally mentioned as a ‘difficult’ substrate featuring low yield
and enantioselectivity.11
Recently, asymmetric organocatalysis has processed astonish-
ingly and many kinds of catalysts, such as proline salts,12 chiral
metal complexes,13 and organocatalysts14 have been emerged for
the Michael addition reactions. The bifunctional organocatalysts
that can active both nucleophile and electrophile simultaneously
have been demonstrated as efficient enantioselective organo-
catalysts for the asymmetric conjugate addition of nitroalkenes.15
Therefore, readily available bifunctional catalysts based on the
cinchona alkaloid scaffold were under our consideration for the
asymmetric synthesis of fluorinated chiral compounds. In this pa-
per, we report the asymmetric Michael addition of 1,3-dicarbonyl
compounds. However, b-fluoroalkyl-a-nitroalkenes have been so
far scarcely studied and exploited in the synthesis of functionalized
* Corresponding author. E-mail address: jtliu@sioc.ac.cn (J.-T. Liu).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.062

2524
Y. Zhao et al. / Tetrahedron 70 (2014) 2523e2528
compounds to fluoroalkyl nitroolefins catalyzed by cinchona alka-
loid catalysts.
catalyst loading afforded the adduct with 93:7 dr and 99% ee.
Lowering temperature to 0 ꢀC gave the same result (Table 1, entries
7e13). Therefore, the optimal conditions were set as follows: car-
rying out the reaction in toluene at room temperature using 5 mol %
3c as catalyst.
2. Results and discussion
Under the optimal conditions, the scopes of
b-fluoroalkyl-a-
Our initial investigation involved the screening different cin-
chona alkaloid catalysts for the addition reaction of trans-3,3,3-
trifluoro-1-nitropropene (1a) to cyclic keto ester 2a at room tem-
perature. As summarized in Table 1, all cinchona alkaloids 3 pro-
vided the addition product 4a in good yields in 12 h at room
temperature, although the stereoselectivity of the reaction varied
from catalyst to catalyst. Using natural cinchona alkaloid 3a as
catalyst, the reaction afforded good diastereoselectivity but poor
enantioselectivity in tetrahydrofuran (THF) (Table 1, entry 1).
Enantioselectivity of the reaction was improved dramatically by
using 9-OH protected catalyst 3b, but the diastereoselectivity was
not increased in toluene (Table 1, entry 2). In order to achieve better
results in terms of both diastereoselectivity and enantioselectivity,
the 60-hydroxy cinchona alkaloids were examined as these catalysts
have shown great potential as bifunctional organocatalysts for
asymmetric conjugate addition reactions.16,17 To our delight, ex-
cellent diastereoselectivity and enantioselectivity were obtained
when 60-hydroxy cinchona alkaloid 3c or 3d was used (Table 1,
entries 3 and 4). In the case of 3e, high diastereoselectivity and
moderate enantioselectivity were afforded (Table 1, entry 5).
Compound 3f, an effective chiral catalyst in some asymmetric re-
actions developed recently,18 afforded 93:7 dr and 92% ee (Table 1,
entry 6). Further examination of solvent revealed that toluene was
the best solvent for this reaction. Using 3c as catalyst, 5 mol % of
nitroalkenes 1 and 1,3-dicarbonyl compounds 2 were examined
next. As shown in Table 2, reactions of various fluoroalkyl nitro-
alkenes (1bed) with 2a afforded the expected products (4bed)
with excellent diastereoselectivities and enantioselectivities (Table
2, entries 2e4). It should be noted that the reaction required 140 h
for achieving full conversion when 3,3-difluoro-1-nitropropene 1b
was used as the substrate (entry 2). Diethyl malonate 2b showed
lower reactivity under the optimal conditions, which may be at-
tributed to a less favored coordination. By increasing the catalyst
loading to 10 mol %, the reaction of 2b with 1a gave the corre-
sponding product 4e with 99% ee (Table 2, entry 5) in 36 h. High
enantioselectivities were also obtained in the reactions of ethyl
acetoacetate (2c) and acetylacetone (2d) under the optimal con-
ditions (Table 2, entries 6 and 7). In the reaction of 2c, the enoli-
zation of adduct 4f took place easily and decreased the
diastereoselectivity. Furthermore, the reaction was applied suc-
cessfully to bicyclic compound 2e and the corresponding addition
product 4h was obtained with high stereoselectivity (89:11 dr, 99%
ee). It is worth mentioning that low or moderate stereoselectivities
were reported regarding the Michael addition reaction of 2e.15b,19
Besides ethyl esters, benzyl ester 2f was also investigated. How-
ever, even using 10 mol % 3c as catalyst, the reaction was very slow
and a little drop in enantioselectivity was observed, partially due to
the steric effect (Table 2, entry 9).
To determine the absolute configuration of chiral products 4, we
also tried the transformation of the product. To our delight, com-
pound 4c could be successfully reduced by zinc dust and further
converted into the corresponding nitrone 5c20 in 36% yield with
92% ee (Scheme 1). After recrystallization, the ee value reached 96%.
The absolute configuration of 5c was unambiguously confirmed by
X-ray diffraction analysis21 (Fig. 1). Therefore, the stereochemical
outcome of the corresponding Michael adduct 4 could be deduced
from that of 5c as (Sa, Rb).
Table 1
Catalyst screening and reaction condition optimization
Based on the above experimental results and related liter-
ature,13a a possible transition state was proposed for this reaction as
shown in Fig. 2. As a bifunctional organocatalyst, catalyst 3c may
active keto ester and nitroolefin simultaneously in this reaction: the
tertiary amine activates keto ester by stabilizing the enol in-
termediate through hydrogen bonding, and 60-hydroxy of the cat-
alyst activates nitroolefin and also orientates keto ester with the
hydrogen bonding network.
3. Conclusion
Entrya
3
X
Solvent
drc
86:14
85:15
93:7
>95:5
93:7
>95:5
>95:5
>95:5
>95:5
94:6
Yield (%)d
ee (%)e
In summary, we have developed a facile method for the asym-
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
3d
3d
3d
3c
3c
3c
3c
20
20
20
20
20
20
20
10
5
THF
83
84
81
76
83
89
87
88
83
82
81
84
84
4
54
96
94
44
92
91
91
91
99
99
99
99
metric Michael addition of
b-fluoroalkyl-a-nitroalkenes and 1,3-
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
dicarbonyl compounds with high efficiency and excellent stereo-
selectivities. Catalyzed by organocatalysts derived from cinchona
alkaloid, the reaction took place under mild conditions and affor-
ded a series of fluorinated building blocks, which might be useful in
the synthesis of biologically active molecules.
7b
8b
9b
10
11b
12
13b
10
10
5
4. Experimental section
4.1. General
95:5
93:7
95:5
5
a
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), 3 (X mol %), solvent, rt, 12 h.
The reaction was carried out at 0 ꢀC.
All manipulations were performed under a nitrogen atmosphere
using standard Schlenk techniques. Alkenes 1aed were prepared
following literature procedures.10 Melting points were uncorrected.
1H NMR spectra were recorded in CDCl3 on a Bruker AM-300
b
c
Determined by 19F NMR of the crude product.
Isolated total yield.
d
e
The ee values were determined by HPLC analysis of product 4a.

Y. Zhao et al. / Tetrahedron 70 (2014) 2523e2528
2525
Table 2
The scope of the Michael addition reaction
Entrya
1
2
Time (h)
4
drb
Yield (%)c
84
ee (%)d
1
1a
2a
12
140
16
93:7
99
94
91
97
99
2
1b
1c
1d
1a
2a
2a
2a
2b
>95:5
93:7
>95:5
d
85
80
90
79
3
4
14
5e
36
6
7
1a
1a
2c
12
12
d
d
82
85
99
93
2d
8
1a
1a
2e
2f
12
89:11
94:6
81
77
99
82
9e
120
a
Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), 3c (5 mol %), toluene, rt.
Determined by 19F NMR of the crude products.
Isolated total yield.
The ee values were determined by HPLC analysis of product 3.
10 mol % of 3c was used.
b
c
d
e

2526
Y. Zhao et al. / Tetrahedron 70 (2014) 2523e2528
CHCl3). 1H NMR (300 MHz, CDCl3)
d
: 5.22 (d, J¼15.3 Hz, 1H),
4.75e4.68 (m, 1H), 4.20 (t, J¼7.8 Hz, 2H), 3.94e3.86 (m, 1H),
2.76e2.73 (m, 1H), 2.55e2.34 (m, 2H), 2.15e2.04 (m, 3H), 1.27 (t,
J¼7.8 Hz, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢂ64.32 (d,
J¼7.6 Hz, 3F) ppm. 13C NMR (100 MHz, CDCl3)
d: 210.61, 167.44,
125.69 (q, JCeF¼281.4 Hz), 71.10, 63.15, 58.65, 45.64 (q,
JCeF¼26.8 Hz), 37.30, 31.64, 19.55, 13.96 ppm. IR (film)
n: 2988, 1760,
1733, 1568, 1236, 1128 cmꢂ1. MS (70 eV) m/z (%): 297 (Mþ), 193
(100.00). HRMS: calcd for C11H14F3NO5: 297.0824, found: 297.0830.
The chiral HPLC analytical data: Chiralpak AD-H column, detected
at 214 nm, eluent: n-hexane/iso-propanol¼100/1, 0.7 mL/min, re-
tention times: tR (minor)¼20.98 min, tR (major)¼23.28 min.
Scheme 1. Transformation of 4c to 5c.
4.2.2. (S)-Ethyl 1-((R)-1,1-difluoro-3-nitropropan-2-yl)-2-
oxocyclopentanecarboxylate (4b). Colorless oil; ½a D24
þ4.84 (c 1.25,
ꢁ
CHCl3). 1H NMR (300 MHz, CDCl3)
d
: 6.07 (td, J¼55.8, 5.1 Hz, 1H);
5.03e4.97 (m, 1H), 4.71e4.64 (m, 1H), 4.20 (t, J¼7.5 Hz, 2H),
3.52e3.45 (m, 1H), 2.62e2.34 (m, 3H), 2.19e2.04 (m, 3H), 1.27 (t,
J¼7.5 Hz, 3H) ppm. 19F NMR (282 MHz, CDCl3)
: ꢂ116.5 (ddd,
d
J¼291.0, 54.7, 18.9 Hz, 1F), ꢂ120.7 (ddd, J¼291.0, 55.8, 18.6 Hz,
1F) ppm. 13C NMR (100 MHz, CDCl3)
JCeF¼244.2 Hz), 70.36, 62.59, 58.51, 44.08 (t, JCeF¼20.1 Hz), 37.37,
31.90, 19.32, 13.72 ppm. IR (film) : 2985, 1755, 1727, 1564, 1371,
d: 211.91, 168.69, 115.16 (t,
n
1236 cmꢂ1. MS (70 eV) m/z (%): 463 (Mþ), 55 (100.00). HRMS: calcd
for C11H15F2NO5: 279.0918, found: 279.0920. The chiral HPLC ana-
lytical data: Chiralpak AD-H column, detected at 214 nm, eluent: n-
hexane/iso-propanol¼95/5, 0.7 mL/min, retention times: tR
(minor)¼15.08 min, tR (major)¼16.91 min.
4.2.3. (S)-Ethyl 1-((R)-1-chloro-1,1-difluoro-3-nitropropan-2-yl)-2-
oxocyclopentanecarboxylate (4c). Colorless oil; ½a D24
ꢂ21.7 (c 1.09,
ꢁ
CHCl3). 1H NMR (300 MHz, CDCl3)
d: 5.37e5.31 (m, 1H), 4.45 (dd,
Fig. 1. The X-ray crystal structure of 5c.
J¼16.5, 6.0 Hz, 1H), 4.21e4.04 (m, 3H), 2.83e2.77 (m, 1H),
2.49e2.34 (m, 2H), 2.21e2.02 (m, 3H), 1.28 (t, J¼6.9 Hz, 3H) ppm.
19F NMR (282 MHz, CDCl3)
d
: ꢂ48.3 (d, J¼167.5 Hz, 1F), ꢂ51.3 (dd,
J¼167.5, 16.6 Hz, 1F) ppm. 13C NMR (100 MHz, CDCl3)
d: 210.19,
167.00, 128.96 (t, JCeF¼295.9 Hz), 71.97, 62.92, 59.59, 51.30 (t,
JCeF¼22.3 Hz), 37.04, 31.59, 19.30, 13.68 ppm. IR (film)
n: 2984,
1758, 1731, 1565, 1405, 1119 cmꢂ1. MS (70 eV) m/z (%): 313 (Mþ),
55 (100.00). HRMS: calcd for C11H14ClF2NO5: 313.0529, found:
313.0521. The chiral HPLC analytical data: Chiralpak AD-H col-
umn, detected at 214 nm, eluent: n-hexane/iso-propanol¼98/2,
0.7 mL/min, retention times: tR (minor)¼13.91 min, tR (major)¼
15.25 min.
Fig. 2. Proposed transition state.
4.2.4. (S)-Ethyl 1-((R)-6-chloro-3,3,4,4,5,5,6,6-octafluoro-1-
nitrohexan-2-yl)-2-oxocyclopentanecarboxylate (4d). Colorless oil;
spectrometer (300 MHz) with TMS as internal standard. 19F NMR
spectra were taken on a Bruker AM-300 (282 MHz) spectrometer
using CFCl3 as external standard. 13C NMR spectra were taken on
a Bruker AM-400 (100 MHz) spectrometer. IR spectra were ob-
tained with a Nicolet AV-360 spectrophotometer. Mass spectra
were obtained on a Finnigan GCeMS 4021 spectrometer. Unless
otherwise mentioned, solvents and reagents were purchased from
commercial sources and used as received.
½
a 2D4
ꢁ
þ14.82 (c 1.12, CHCl3). 1H NMR (300 MHz, CDCl3)
d: 5.05 (dq,
J¼15.7, 1.5 Hz, 1H), 4.74e4.68 (dd, J¼16.8, 3.0 Hz, 1H), 4.29e4.14 (m,
3H), 2.79e2.77 (m, 1H), 2.45 (t, J¼8.1 Hz, 2H), 2.17e2.10 (m, 3H),
1.25 (t, J¼6.9 Hz, 3H) ppm. 19F NMR (282 MHz, CDCl3)
: ꢂ68.18 (s,
d
2F), ꢂ106.5 (dd, J¼282.5, 15.8 Hz, 1F), ꢂ110.2 (dd, J¼282.5, 6.8 Hz,
1F), ꢂ119.7e119.9 (m, 2F), ꢂ122.8e124.0 (m, 2F) ppm. 13C NMR
(100 MHz, CDCl3)
d
: 210.48, 167.87, 122.6 (q, JCeF¼276.5 Hz), 121.6
(q, JCeF¼278.4 Hz), 118.3 (q, JCeF¼276.2.4 Hz), 70.80 (t, JCeF¼5.2 Hz),
4.2. Typical procedure
63.63, 62.75, 42.09 (t, JCeF¼19.3 Hz), 36.95, 19.18, 13.46 ppm. IR
(film) n
: 2987, 1760, 1731, 1570, 1383, 1130 cmꢂ1. MS (70 eV) m/z (%):
To a stirred solution of nitroalkene 1a (44 mg, 0.31 mmol) and
cyclic keto ester 2a (47 mg, 0.3 mmol) in toluene (3 mL), was added
catalyst 3c (6.2 mg, 0.015 mmol) at room temperature. The mixture
was stirred for 12 h (monitored by TLC). After removal of the sol-
vent, the residue was subjected to fast column chromatography on
silica gel (petroleum ether/ethyl acetate¼10:1e6:1) to give 4a.
463 (Mþ), 55 (100.00). HRMS: calcd for C14H14ClF8NO5: 463.0433,
found: 463.0434. The chiral HPLC analytical data: Chiralpak AD-H
column, detected at 214 nm, eluent: n-hexane/iso-propanol¼98/
2, 0.7 mL/min, retention times: tR (minor)¼7.24 min, tR (major)¼
8.22 min.
4.2.5. (R)-Diethyl
2-(1,1,1-trifluoro-3-nitropropan-2-yl)malonate
ꢁ
4.2.1. (S)-Ethyl 2-oxo-1-((R)-1,1,1-trifluoro-3-nitropropan-2-yl)cy-
(4e). Colorless oil; ½a D24
þ1.21 (c 1.16, CHCl3). 1H NMR (300 MHz,
clopentanecarboxylate (4a). Colorless oil; ½a D24
ꢁ
ꢂ15.68 (c 1.38,
CDCl3) d: 5.02e4.77 (m, 2H), 4.31e4.21 (m, 4H), 4.09e4.01 (m, 1H),

Y. Zhao et al. / Tetrahedron 70 (2014) 2523e2528
2527
3.89 (d, J¼3.9 Hz,1H),1.30 (t, J¼7.2 Hz, 6H) ppm. 19F NMR (282 MHz,
1172 cmꢂ1
.
ESI-MS (m/z): 377 (MþþH2O). HRMS: calcd for
CDCl3)
d
: ꢂ69. 8 (d, J¼7.2 Hz, 3F) ppm. 13C NMR (100 MHz, CDCl3)
d:
C16H16F3NO5Na: 382.0868, found: 382.0872. The chiral HPLC ana-
166.31, 165.98, 126.67 (q, JCeF¼279.1 Hz), 70.49, 63.05, 62.62, 48.22,
lytical data: Chiralpak AD-H column, detected at 214 nm, eluent: n-
hexane/iso-propanol¼90/10, 0.7 mL/min, retention times: tR
(minor)¼10.42 min, tR (major)¼11.88 min.
41.27 (q, JCeF¼29.1 Hz), 13.82 ppm. IR (film)
n: 2987, 1736, 1567,
1381, 1183 cmꢂ1. ESI-MS (m/z): 319 (MþþH2O); HRMS: calcd for
C
10H14F3NO6Na: 324.0665, found: 324.0665. The chiral HPLC ana-
lytical data: Chiralpak IC column, detected at 214 nm, eluent: n-
hexane/iso-propanol¼90/10, 0.7 mL/min, retention times: tR
(major)¼7.30 min, tR (minor)¼13.47 min.
4.2.10. The preparation of 5c. Compound 4c (157 mg, 0.5 mmol)
and NH4Cl (27 mg, 0.5 mmol) were dissolved in H2O/dioxane (1:2,
3.0 mL) and the mixture was cooled to 5 ꢀC. Under vigorous stirring,
Zn powder (130 mg, 2.0 mmol) was added. After stirring for 30 min,
the mixture was allowed to warm to room temperature and was
stirred at room temperature overnight. The resulted mixture was
filtered and the solid was washed with MeOH (10 mL). The liquid
phase was evaporated to its half volume and extracted with CHCl3
(3ꢃ5 mL), dried (MgSO4), and evaporated. The residue was purified
by flash column chromatography (ethyl acetate/EtOH¼5:1) to give
5c.
4.2.6. (3R)-Ethyl 2-acetyl-4,4,4-trifluoro-3-(nitromethyl)butanoate
(4f). Colorless oil; ½a D24
ꢁ
ꢂ8.13 (c 1.25, CHCl3). 1H NMR (300 MHz,
CDCl3) d: 13.71 (s, 0.3H), 5.00e4.72 (m, 2H), 4.35e4.00 (m, 3.70H),
2.40 (s, 0.90H), 2.34 (s, 1.2H), 2.21 (s, 0.9H), 1.37e1.25 (m, 3H) ppm.
19F NMR (282 MHz, CDCl3)
d
: ꢂ68.0 (d, J¼8.1 Hz, 0.9F), ꢂ69.1 (d,
J¼8.5 Hz, 0.9F), ꢂ69.6 (d, J¼9.8 Hz, 1.2F) ppm. 13C NMR (100 MHz,
CDCl3) d: 200.30, 198.03, 180.06, 171.42, 166.50, 165.91, 125.52 (q,
JCeF¼279.2 Hz),125.42 (q, JCeF¼279.1 Hz),125.21 (q, JCeF¼279.1 Hz),
72.93, 70.31, 70.26, 62.91, 62.73, 61.39, 53.32, 53.79, 41.40 (q,
JCeF¼29.7 Hz), 41.34 (q, JCeF¼27.6 Hz), 40.17 (q, JCeF¼28.3 Hz), 31.23,
4.2.11. (3R,3aS)-3-(Chlorodifluoromethyl)-3a-(ethoxycarbonyl)-
2,3,3a,4,5,6-hexahydrocyclopenta[b]pyrrole 1-oxide (5c). White
28.68, 19.74, 13.78, 13.70 ppm. IR (film)
n
: 1745, 1725, 1566, 1381,
solid, mp: 142e144 ꢀC; ½a D24
ꢁ
ꢂ104.3 (c 0.97, EtOH). 1H NMR
1254, 1128 cmꢂ1. MS (70 eV) m/z (%): 271 (Mþ, 0.58), 43 (100.00).
HRMS: calcd for C9H12F3NO5: 271.0668, found: 271.0670. The chiral
HPLC analytical data: Chiralpak AD-H column, detected at 214 nm,
eluent: n-hexane/iso-propanol¼95/5, 0.7 mL/min, retention times:
tR (major)¼6.58 min, tR (minor)¼6.88 min.
(300 MHz, CDCl3)
d
: 4.85 (t, J¼12.0 Hz, 1H), 4.32e4.17 (m, 3H),
3.39e3.10 (m, 1H), 2.80e2.73 (m, 1H), 2.67e2.56 (m, 1H), 2.46e2.36
(m, 1H), 2.29e2.01 (m, 2H), 1.64e1.53 (m, 1H), 1.31 (t, J¼6.9 Hz,
3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢂ67.3 (d, J¼8.1 Hz, 2F) ppm.
13C NMR (100 MHz, CDCl3)
d:
168.28, 153.40, 125.70 (t,
JCeF¼293.1 Hz), 67.16, 63.01, 62.77, 56.50 (t, JCeF¼25.0 Hz), 34.77,
4.2.7. (R)-3-(1,1,1-Trifluoro-3-nitropropan-2-yl)pentane-2,4-dione
26.49, 21.81, 13.88 ppm. IR (film) n
: 2947, 1733, 1644, 1238 cmꢂ1. EI
(4g). Yellow solid; mp: 47e49 ꢀC; ½a D24
ꢁ
þ39.86 (c 0.89, CHCl3). 1H
(m/z): 281 (Mþ). HRMS: calcd for C11H14ClF2NO3: 281.0630, found:
281.0631. The chiral HPLC analytical data: Chiralpak IC column,
detected at 214 nm, eluent: n-hexane/iso-propanol¼70/30, 0.7 mL/
min, retention times: tR (minor)¼19.31 min, tR (major)¼22.36 min.
NMR (300 MHz, CDCl3)
d
: 4.83 (dd, J¼13.8, 1.7 Hz, 1H), 4.67 (dd,
J¼11.6, 7.0 Hz, 1H), 4.38 (d, J¼5.7 Hz, 1H), 3.96e3.90 (m, 1H), 2.44 (s,
3H), 2.35 (s, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢂ68.9 (d,
J¼8.7 Hz, 3F) ppm. 13C NMR (100 MHz, CDCl3)
d: 200.86, 198.36,
125.67 (q, JCeF¼279.4 Hz), 70.21, 61.88, 41.43 (q, JCeF¼28.1 Hz),
Acknowledgements
31.98, 29.71 ppm. IR (film)
n: 2931, 1736, 1711, 1565, 1380,
1249 cmꢂ1. MS (70 eV) m/z (%): 241 (Mþ), 43 (100.00). HRMS: calcd
for C8H10F3NO4: 241.0562, found: 241.0564. The chiral HPLC ana-
lytical data: Chiralpak AD-H column, detected at 214 nm, eluent: n-
hexane/iso-propanol¼90/10, 0.7 mL/min, retention times: tR
(major)¼12.68 min, tR (minor)¼13.31 min.
Financial support from the National Natural Science Foundation
of China (No. 21172243) and the Natural Science Foundation of the
Education Commission of Jiangsu Province (Grant No.
07KJB150059) is gratefully acknowledged.
Supplementary data
4.2.8. (S)-Ethyl 1-oxo-2-((R)-1,1,1-trifluoro-3-nitropropan-2-yl)-2,3-
dihydro-1H-indene-2-carboxylate (4h). Yellow oil; ½a D24
þ87.77 (c
ꢁ
Copies of 1H NMR, 13C NMR, 19F NMR, and HPLC spectra for the
products are available. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2014.02.062.
0.99, CHCl3). 1H NMR (300 MHz, CDCl3)
d: 7.80e7.67 (m, 2H),
7.56e7.42 (m, 2H), 5.33 (dd, J¼15.9, 1.2 Hz, 1H), 4.95e4.87 (m, 1H),
4.28e4.11 (m, 3H), 3.90 (d, J¼17.1 Hz, 1H), 3.35 (d, J¼17.1 Hz, 1H),
1.27e1.15 (m, 3H) ppm. 19F NMR (282 MHz, CDCl3)
d
: ꢂ63.9 (d,
J¼5.92 Hz, 3F) ppm. 13C NMR (100 MHz, CDCl3)
d: 197.78, 167.57,
References and notes
152.47, 136.38, 133.33, 128.33, 126.25, 125.53 (q, JCeF¼281.1 Hz),
125.43, 71.14, 63.14, 59.18, 45.58 (q, JCeF¼26.8 Hz), 34.96,
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13.65 ppm. IR (film) n
: 2987,1743,1722,1568,1243 cmꢂ1. MS (70 eV)
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5.07e5.00 (m, 3H), 4.61e4.50 (m, 1H), 3.87e3.78 (m, 1H),
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F
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JCeF¼281.5 Hz), 69.76, 67.51, 57.48, 44.42 (q, JCeF¼26.9 Hz), 36.03,
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n

2528
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These data can be obtained free of charge via www.ccdc.cam.ac.uk.