Highly enantioselective conjugate addition of fluoromalonates to nitroalkenes using bifunctional organocatalysts

Article abstract of DOI:10.1016/j.jfluchem.2009.06.002

The enantioselective conjugate addition of fluoromalonates to aromatic nitroalkenes catalyzed by chiral amine-thiourea bifunctional organocatalysts generated a stereocenter at the carbon bearing the aromatic group and an adjacent prochiral center from the

Full text of DOI:10.1016/j.jfluchem.2009.06.002

Journal of Fluorine Chemistry 130 (2009) 759–761
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
Highly enantioselective conjugate addition of fluoromalonates to nitroalkenes
using bifunctional organocatalysts
*
Bo Kyung Kwon, Sun Mi Kim, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history:
The enantioselective conjugate addition of fluoromalonates to aromatic nitroalkenes catalyzed by chiral
amine-thiourea bifunctional organocatalysts generated a stereocenter at the carbon bearing the
aromatic group and an adjacent prochiral center from the fluoromalonate. Treatment of fluoromalonates
with aromatic nitroalkenes under mild reaction conditions afforded the corresponding 2-fluoro-2-(2-
nitro-1-arylethyl)malonates with high yields (72–93%) and excellent enantioselectivities (91–98% ee).
ß 2009 Elsevier B.V. All rights reserved.
Received 29 April 2009
Received in revised form 28 May 2009
Accepted 2 June 2009
Available online 7 June 2009
Keywords:
Bifunctional organocatalysts
Michael reaction
Nitroalkenes
Asymmetric reactions
Fluoromalonates
1. Introduction
catalytic asymmetric conjugate additions of active methine
compounds to nitroalkenes in the presence of chiral metal
The chemistry of bioactive organofluorine compounds is a
rapidly developing area of research because of their importance
in biochemical and medicinal application [1–4]. Introduction of
fluorine atom into biologically active compounds often leads to
improvement of their biological characteristics due to unique
properties of the fluorine atom [5–7]. Chiral organofluorine
compounds have been utilized in studies of enzyme mechanisms
and as intermediates in asymmetric syntheses [8,9]. The Michael
addition reaction is widely recognized as one of the most
general and versatile methods for formation of C–C bonds in
organic synthesis [10–12], and the development of enantiose-
lective catalytic protocols for this reaction has been subject of
intensive research [13,14]. In addition to the great success
catalyzed by metal complexes, the powerful and environmen-
tally friendly organocatalyst-mediated asymmetric Michael
reaction has been explored intensively in recent years [15–
21]. Michael reaction of nucleophiles to nitroalkenes represents
a direct and most appealing approach to chiral nitroalkanes that
are versatile intermediates in organic synthesis, which can be
transformed into an amine, nitrile oxide, ketone, carboxylic acid,
hydrogen, etc. [22–25]. Recently, several groups presented the
complexes or organocatalysts [26–40]. To the our best knowl-
edge, although catalytic enantioselective Michael additions of
active methine compounds such as malonates [26–32],
b-
ketoesters [33–37], and 1,3-diketones [38–40] have reported, up
to now there is one examples of these reactions with
fluoromalonates using chiral Mg-box complex [42]. However,
a highly enantioselective Michael addition of fluoromalonates to
nitroalkenes remains elusive; although, if successfully promoted
with a practically accessible chiral catalyst under air- and
moisture-tolerant conditions, it could provide a highly attrac-
tive, convergent approach toward optically active
fluoromalonates [57].
g-nitro
2. Results and discussion
As part of research program related to the development of
synthetic methods for the enantioselective construction of
stereogenic carbon centers [41,43–50], we recently reported
chiral amine-thiourea I (Fig. 1) to be a highly selective catalyst
for the enantioselective amination of active methines [51,52].
We envision that the rigid binaphthyl structure can serve as an
efficient stereocontrolling axial chiral element. In this commu-
nications, we wish to describe the direct asymmetric Michael
reaction of fluoromalonates to nitroalkenes with catalyzed by
environmentally benign bifunctional organocatalysts bearing
* Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.06.002

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B.K. Kwon et al. / Journal of Fluorine Chemistry 130 (2009) 759–761
Table 1
Optimazation of the reaction conditions
.
Entry
Cat.
Solvent
Time (day)
Yielda (%)
eeb (%)
1
I
Toluene
Toluene
Toluene
Toluene
THF
5
80
81
83
91
80
85
93
91
93
73
75
97
43
65
79
85
85
67
96
95
93
96
94
87
2
II
5
3
III
IV
IV
IV
IV
IV
IV
IV
IV
IV
5
4
5
5
7
6
CH3CN
CH2Cl2
DCE
7
7
2
8
3
9
CH2Br2
CH2Cl2
CH2Cl2
CH2Cl2
3
10c
11d
12e
6
10
15 h
a
Isolated yield.
b
Enantiopurity was determined by HPLC analysis using with a Chiralpak AD-H
column.
c
This reaction was carried out at ꢀ25 8C.
d
e
This reaction was carried out at ꢀ40 8C.
This reaction was carried out at 40 8C.
Fig. 1. Structures of various chiral organocatalysts.
excess (93–96% ee, entries 7–9). Temperature effect was also
significant, with a slightly lower enantioselectivity being given at
temperatures either lower or higher than room temperature
(entries 10–12). However, the yield was higher if the reaction
proceeded at higher temperature (entry 12). To examine the
generality of the catalytic asymmetric Michael reaction of
fluoromalonates 1 by using new bifunctional organocatalyst
IV, we studied the addition of fluoromalonates 1 to wide range of
para-substituted aromatic and heteroaromatic nitroalkenes 2. As
it can be seen by the results summarized in Table 2, the
corresponding products 3a–k were obtained in high to excellent
yields with excellent enantioselectivities (91–98% ee). The
absolute configuration of 3 was determined by comparing chiral
HPLC data and specific rotation with authentic samples [57].
both central and axial chiral elements. A survey of some reaction
parameters was performed, and some representative results are
presented in Table 1. Our investigation began with the catalytic
asymmetric Michael addition of ethyl fluoromalonate (1a) with
b
-nitrostyrene (2a). When the reaction was performed in
toluene at room temperature in the presence of 10 mol% catalyst
I, product 3a was isolated in high yield with 43% ee (Table 1,
entry 1). We first examined the impact of the structure of
catalysts I–IV on enantioselectivities (Table 1, 43–85% ee, entries
1–4). The best results have been obtained with catalyst IV.
Concerning the solvents (entries 4–9), the use of halogenated
solvents gave the good results in the yield and the enantiomeric
Table 2
Catalytic enantioselective Michael reaction of fluoromalonates
.
Entry
1, R
2, Ar
Time (d)
Yielda (%)
eeb (%)
1
Et
Ph
2
5
4
5
3
4
6
4
5
4
5
3a, 93
3b, 80
3c, 75
3d, 80
3e, 78
3f, 72
3g, 78
3h, 80
3i, 85
3j, 77
3k, 75
96
98
93
97
95
95
97
97
97
98
91
2
Et
4-F-Ph
3c
4
Et
2-F-Ph
Et
4-Cl-Ph
4-Br-Ph
4-Me-Ph
4-OMe-Ph
2-furyl
5c
6c
7d
8c
9
Et
Et
Et
Et
Me
Me
Me
2-NO2-Ph
2-thienyl
1-naphthyl
10c
11c
a
Isolated yield.
b
c
Enantiopurities were determined by HPLC analysis using with chiral columns (Chiralcel OD-H for 3g, Chiralpak AD-H for 3a–f and 3h–k).
This reaction was carried out at ꢀ25 8C.
d
This reaction was carried out using a catalyst III.

B.K. Kwon et al. / Journal of Fluorine Chemistry 130 (2009) 759–761
761
3. Conclusions
4.93 (dd, J = 13.4, 4.8 Hz, 1H), 7.29–7.32 (m, 5H); 13C NMR (50 MHz,
CDCl3) 13.6, 13.9, 47.3 (d, J = 18.3 Hz), 62.9, 63.6, 75.5 (d,
J = 5.8 Hz), 94.5 (d, J = 200.2 Hz), 128.8, 129.0, 129.2, 132.9,
163.6 (d, J = 26.1 Hz), 164.6 (d, J = 25.5 Hz); Rt HPLC (80:20, n-
hexane: i-PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H, tR = 5.4 min
(minor), 6.1 min (major). 96% ee.
In conclusion, we have developed a highly efficient catalytic
asymmetric Michael reaction of fluoromalonates 1 to nitroalkenes
2 using bifunctional organocatalyst IV [57]. The desired g-nitro-a-
fluoro carbonyl compounds 3 were obtained in good to high yields
and excellent enantioselectivities (91–98% ee) were observed. We
believe that this method provides an efficient route for the
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the product IV (83%, 268 mg). ½a D28
ꢁ
¼ ꢀ132:8 (c = 1.0, CHCl3); 1H
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(m, 2H), 7.53–7.35(m, 3H), 7.30–7.09(m, 4H), 6.59(s, 1H), 4.19–3.78
(m, 1H), 3.98 (d, J = 12.2 Hz, 2H), 3.50 (d, J = 12.2 Hz, 2H), 2.98–2.68
(m, 1H), 2.35–2.12 (m, 1H), 1.82–1.57 (m, 3H), 1.57–1.10 (m, 4H);
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(q, JC–F = 32.1 Hz), 130.5, 128.2, 126.5, 126.0, 125.7, 125.4, 123.3 (q,
JC–F = 270.8 Hz), 116.9, 113.1, 66.8, 51.2, 50.7, 33.1, 26.8, 25.3, 24.3;
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4.3. General procedure for asymmetric conjugate addition of
fluoromalonates 1 to nitroalkenes 2
To a stirred solution of fluoromalonate 1 (0.2 mmol) and
catalyst IV (6.5 mg, 0.01 mmol) in dichloromethane (0.5 mL) was
added nitroalkene 2 (0.1 mmol) at room temperature. After being
stirred for 2–6 d, the reaction mixture was concentrated. The
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate = 5/1) to afford desired product 3.3a: ½a D20
¼
ꢁ
14:9 (c = 1.2, CHCl3); 1H NMR (200 MHz, CDCl3) 1.01 (t, J = 6.9 Hz,
3H), 1.35 (t, J = 7.0 Hz, 3H), 3.93–4.18 (m, 2H), 4.32–4.42 (m, 2H),
4.57 (ddd, J = 30.3, 9.5, 4.8 Hz, 1H), 4.81 (dd, J = 13.4, 9.5 Hz, 1H),