Organocatalytic synthesis of quaternary stereocenter bearing a fluorine atom: enantioselective conjugate addition of α-fluoro-β-ketoesters to nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2009.06.003

The catalytic enantioselective conjugate addition reaction of α-fluoro-β-ketoesters to nitroalkenes promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro-β-ketoesters with nitroalkenes under mild reaction conditions affor

Full text of DOI:10.1016/j.tetlet.2009.06.003

Tetrahedron Letters 50 (2009) 4674–4676
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Tetrahedron Letters
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Organocatalytic synthesis of quaternary stereocenter bearing a fluorine
atom: enantioselective conjugate addition of
nitroalkenes
a-fluoro-b-ketoesters to
*
Yeonock Oh, 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 catalytic enantioselective conjugate addition reaction of
moted by chiral bifunctional organocatalysts is described. The treatment of
nitroalkenes under mild reaction conditions afforded the corresponding Michael adducts containing a
fluorinated quaternary stereogenic center with excellent enantioselectivity (up to >99% ee).
Ó 2009 Elsevier Ltd. All rights reserved.
a
-fluoro-b-ketoesters to nitroalkenes pro-
-fluoro-b-ketoesters with
Received 27 April 2009
Revised 27 May 2009
Accepted 1 June 2009
Available online 6 June 2009
a
Keywords:
Bifunctional organocatalyst
Asymmetric catalysis
Michael reaction
Nitroalkenes
a-Fluoro-b-ketoesters
Fluoroorganic compounds are of importance in organic synthesis
have been shown recently for enantioselective fluorination of
carbonyl compounds.11
because of their use as medicinals and agrochemicals and in funda-
mental studies of biochemical and metabolic processes.1 Strategic
fluorination is commonly used in medicinal chemistry to improve
the metabolic property and bioavailability.2 Chiral fluoroorganic
compounds are interesting and important materials with uses in
analytical, biological, and medicinal chemistry and also in the chem-
istry of polymers and materials.3 In particular, chiral organofluorine
compounds containing a fluorine atom bonded directly to a stereo-
genic center have been utilized in studies of enzyme mechanisms
and as intermediates in asymmetric syntheses.4
The construction of chiral fluorinated quaternary carbon centers
is one of the most challenging tasks in organic synthesis, and a
number of excellent examples for enantioselective fluorination of
tertiary carbon nucleophiles were reported by using chiral transi-
tion metal complexes and organocatalysts.5 The first catalytic
enantioselective fluorination was reported by Togni et al. using
chiral Ti-complexes.6 Based on this concept, several groups suc-
cessfully applied chiral Lewis acids such as BINAP–Pd(II) and tran-
sition metal–bis(oxazoline) complexes to the asymmetric
fluorination of active methine compounds.7–9 In 2002, we devel-
oped the first organocatalytic fluorination reactions using phase-
transfer catalyst as a promoter.10 Organocatalytic approaches using
proline and cinchona alkaloids and their derivatives as catalysts
Another approach is asymmetric carbon–carbon bond formation
of fluorocarbon nucleophiles to construct chiral fluorine-containing
quaternary carbons.12 Most recently, Lu and Wang independently
reported enantioselective Michael reaction of fluorinated methines
with nitroalkenes catalyzed by cinchona alkaloid-derived organo-
catalysts.13 These reports prompt us to disclose our results with
chiral bifunctional organocatalysts for the enantioselective conju-
gate addition of a-fluoro-b-ketoesters to nitroalkenes.
As part of the research program related to the development of
synthetic methods for the enantioselective construction of stereo-
genic carbon centers,14 we recently reported electrophilic amination
of
fluoromalonates to
describe the enantioselective asymmetric conjugate addition of
a
-fluoro-b-ketoesters15 and asymmetric Michael addition of
a
,b-unsaturated ketones.12a Herein, we wish to
a
-fluoro-b-ketoesters to nitroalkenes catalyzed by bifunctional
thiourea-type organocatalysts16 bearing both central and axial chi-
ral elements.
A survey of some reaction parameters was performed, and some
representative results are presented in Table 1. Our investigation
began with the catalytic enantioselective conjugate addition of
methyl 2-fluoro benzoylacetate (1a) to b-nitrostyrene (2a) in tolu-
ene at room temperature in the presence of 10 mol % of catalysts.
The nature of the ester group of
impact on the reactivity and selectivity (entries 1–4). When
employing i-propyl ester of an -fluoro-b-ketoester 1c, the
a-fluoro-b-ketoesters 1 has an
* Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
a
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.003

Y. Oh et al. / Tetrahedron Letters 50 (2009) 4674–4676
4675
Table 1
Table 2
Optimization of the reaction conditions
Variation of the nitroalkene
O
O
O
O
cat. I
O
O
cat.
O
O
F
F
(10 mol%)
(
NO2
OiPr
10 mol%)
NO2
+
Ph
OR
Ph
+
Ar
Ph
OiPr
Ph
Ph
OR
solvent, rt.
toluene, rt.
NO2
NO2
F
F
Ar
Ph
1
2a
3
2
1c
3
Yielda (%)
drb
eec (%)
Entry
1, R
Cat.
Solvent
Time (h)
Yielda (%)
drb
eec (%)
Entry
2, Ar
Time (h)
1
2
3
4
5
6
7
8
9
1a, Me
1b, Et
I
I
I
I
II
III
IV
I
I
I
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
m-Xylene
THF
Toluene
Toluene
23
20
40
57
24
32
80
32
32
41
48
60
3a, 95
3b, 97
3c, 98
3d, 56
3c, 95
3c, 93
3c, 10
3c, 82
3c, 93
3c, 61
3c, 83
3c, 88
3:1
88
96
98
98
À90
97
ndf
93
97
96
90
96
1
2
3
4
5
6
7
8
2b, o-Cl-Ph
2c, o-F-Ph
2d, p-Me-Ph
2e, p-OMe-Ph
2f, 2-Naphthyl
2g, 2-Furyl
94
94
115
115
48
44
44
72
3e, 93
3f, 96
3g, 98
3h, 94
3i, 84
3j, 84
3k, 98
3l, 91
3:1
4:1
>99
99
>99
98
93
98
2.9:1
4.3:1
2.3:1
4:1
1c, i-Pr
1d, t-Bu
1c, i-Pr
1c, i-Pr
1c, i-Pr
1c, i-Pr
1c, i-Pr
1c, i-Pr
1c, i-Pr
1c, i-Pr
3.6:1
3.5:1
3.8:1
1.6:1
2.8:1
3.3:1
3.1:1
ndf
2h, 2-Thienyl
2i, Isobutyl
88
91
5:1
2.8:1
5.4:1
7.9:1
5.4:1
a
Refers to the isolated mixture of diastereomers.
10
11d
12e
Determined by 1H NMR of the crude reaction mixture.
b
c
I
I
Enantiomeric excess of major diastereomer, determined by chiral HPLC analysis
with chiral columns (Chiralcel OD-H for 3j, Chiralpak AD-H for 3e–h, 3k–l, and IC
for 3i).
a
Refers to the isolated mixture of diastereomers.
Determined by 1H NMR of the crude reaction mixture.
Enantiomeric excess of major diastereomer, determined by chiral HPLC.
The reaction was carried out at À20 °C.
The reaction was carried out at À40 °C.
Not determined.
b
c
d
e
f
(1S,2S)-diaminocyclohexane unit in catalyst I are matched in this
reaction. Concerning the solvent (entries 3 and 8–10), there is a
little influence on the stereochemical outcome of the process.
Temperature effect was not significant, with a slightly lower
enantioselectivity being given at a lower temperature (entries 11
and 12). The absolute configuration of 3b was determined to be
(2S,3R) by comparing the chiral HPLC data and specific rotation
with those of an authentic sample.13
We then carried on with the evaluation of the generality of this
protocol under the optimized reaction conditions. The results of a
representative selection of aromatic and aliphatic nitroalkenes
for the catalytic enantioselective conjugate addition reaction are
corresponding adduct 3c was isolated with an excellent enantiose-
lectivity of 98% ee (entry 3). However, t-butyl ester 1d turned out
to be less effective; much longer reaction time was required to
achieve a moderate yield (entry 4). We surveyed chiral bifunctional
catalysts containing a tertiary amine as catalysts (Fig. 1). High
yields with excellent enantioselectivities were observed for
structurally variable bifunctional thiourea-type catalysts (entries
3 and 5–7). Under the standard reaction conditions, catalyst I
exhibited better enantioselectivity (98% ee, entry 3). Compared
with catalyst I, diastereomeric catalyst II gave the desired product
3c in a slightly lower enantioselectivity with the opposite of the
absolute configuration of the major enantiomer (90% ee, entry 5).
This suggests that the chirality of (R)-binaphthyl moiety and of
summarized in Table 2. The corresponding c-nitro-a-fluorocarbon-
yl compounds 3e–l were formed in high yields (84–98%), moderate
diastereoselectivities (1.6–4:1), and excellent enantioselectivities
(88% to >99%). The effect of the substituents of the aromatic nitro-
alkenes structures on the reaction efficiency was limited.
To examine the generality of the catalytic enantioselective
conjugate addition reaction of
bifunctional organocatalyst I, we studied the addition of various
-fluoro-b-ketoesters 1 to b-nitrostyrene (2a).17 As it can be seen
a-fluoro-b-ketoesters 1 by using
a
from the results summarized in Table 3, the corresponding
N
N
products 3m–r were obtained in high to excellent yields, moderate
HN
HN
HN
HN
S
S
Table 3
Variation
a
-fluoro-b-ketoester
CF3
CF3
I
cat.
O
O
O
O
F
(10 mol%)
NO2
F3C
F3C
Ar
OiPr
NO2
+
Ph
Ar
OiPr
toluene, rt.
I
II
F
Ph
2a
3
1
Entry
Ar
Time (h)
Yielda (%)
drb
5:1
3.4:1
3.3:1
3.7:1
3.4:1
1.5:1
eec (%)
N
N
1
2
3
4
5
6
1e, m-Cl-Ph
1f, p-Br-Ph
1g, p-Me-Ph
1h, p-CF3-Ph
1i, 2-Naphthyl
1j, 2-Thienyl
44
23
111
66
38
42
3m, 96
3n, 93
3o, 93
3p, 93
3q, 96
3r, 95
91
94
83
93
97
91
HN
O
HN
HN
O
O
S
CF3
CF3
a
F3C
Refers to the isolated mixture of diastereomers.
b
c
Determined by 1H NMR of the crude reaction mixture.
F3C
Enantiomeric excess of major diastereomer, determined by chiral HPLC analysis
IV
III
with chiral columns (Chiralcel OD-H for 3m, 3n, Chiralpak AD-H for 3p, 3r, and IC
for 3o, 3q).
Figure 1. Structure of chiral thiourea-tertiary amine catalysts.

4676
Y. Oh et al. / Tetrahedron Letters 50 (2009) 4674–4676
3. (a) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu, M.
Organofluorine Compounds: Chemistry and Applications; Springer: Berlin, 2000;
(b)Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J. R., Welch, J.
T., Eds.ACS Symposium Series 639; American Chemical Society: Washington,
DC, 1996; p 4.
4. (a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds; Soloshonok, V. A.,
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Asymmetry 1990, 1, 661; (c)Asymmetric Fluoroorganic Chemistry: Synthesis,
Application, and Future Directions; Ramachandran, P. V., Ed.ACS Symposium
Series 746; American Chemical Society: Washington, DC, 2000.
I
cat.
O
O
O
O
F
(10 mol%)
NO2
OEt
+
Ph
CH2Cl2, rt, 5 h
OEt
NO2
F
1k
Ph
89% yield
d.r. = 1:1.1
95% e e(major), 90% ee (minor)
2a
3s
Scheme 1.
5. For reviews, see: (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2004, 104, 1;
(b) Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147; (c) Ma, J.-A.; Cahard, D.
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Angew. Chem., Int. Ed. 2006, 45, 2172; (h) Bobbio, C.; Gouverneur, V. Org. Biomol.
Chem. 2006, 4, 2065; (i) Shibata, N.; Ishimaru, T.; Nakamura, S.; Toru, T. J.
Fluorine Chem. 2007, 128, 469; (j) Brunet, V. A.; O’Hagan, D. Angew. Chem., Int.
Ed. 2008, 47, 1179; (k) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem.
Soc. Rev. 2008, 37, 1727.
N
H
O
R
6. Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359.
S
N
H
O
7. For b-keto esters (a) Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M.
J. Am. Chem. Soc. 2002, 124, 14530; (b) Hamashima, Y.; Takano, H.; Hotta, D.;
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Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2005, 44, 4204.
N
CF3
F
O
OR
H
N
O
Ar
CF3
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(b) Park, E. J.; Kim, H. R.; Joung, C. W.; Kim, D. Y. Bull. Korean Chem. Soc. 2004, 25,
1451.
Figure 2. Proposed stereochemical model.
9. For b-keto phosphonates (a) Bernardi, L.; Jørgensen, K. A. Chem. Commun.
2005, 1324; (b) Hamashima, Y.; Suzuki, T.; Shimura, Y.; Shimizu, T.;
Umebayashi, N.; Tamura, T.; Sasamoto, N.; Sodeoka, M. Tetrahedron Lett.
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diastereoselectivities, and excellent enantioselectivities (83–97%
ee).
We examined the catalytic enantioselective conjugate addition
10. Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545.
11. (a) Enders, D.; Hüttl, M. R. M. Synlett 2005, 991; (b) Marigo, M.; Fielenbach, D.;
of alkyl
organocatalyst
10 mol % of catalyst I, the reaction proceeded to afford the
tro- -fluorocarbonyl compound 3s after 5 h in 89% yield, 1.1:1
a
-fluoro-b-ketoesters 1k with b-nitrostyrene (2a) using
at room temperature. In the presence of
-ni-
I
Braunton, A.; Kjꢀrsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44,
c
3703; (c) Steiner, D. D.; Mase, N.; Barbas, C. F., III Angew. Chem., Int. Ed. 2005, 44,
3706; (d) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826;
(e) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 15051; (f) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Nakamura, S.;
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J. Am. Chem. Soc. 2007, 129, 6394; (c) Furukawa, T.; Shibata, N.; Mizuta, S.;
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S.; Yu, C.; Song, X.; Wang, W. Chem. Commun. 2009, 2136.
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Y.; Huh, S. C. Tetrahedron 2001, 57, 8933; (c) Park, E. J.; Kim, M. H.; Kim, D. Y. J.
Org. Chem. 2004, 69, 6897; (d) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47,
4265; (e) Kang, Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y. Synlett 2007, 1135; (f)
Cho, M. J.; Kang, Y. K.; Lee, N. R.; Kim, D. Y. Bull. Korean Chem. Soc. 2007, 28,
2191; (g) Kim, S. M.; Kang, Y. K.; Cho, M. J.; Mang, J. Y.; Kim, D. Y. Bull. Korean
Chem. Soc. 2007, 28, 2435; (h) Lee, J. H.; Bang, H. T.; Kim, D. Y. Synlett 2008,
1821; (i) Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29, 2036; (j) Kang, Y. K.; Kim,
D. Y. Bull. Korean Chem. Soc. 2008, 29, 2093; (k) Mang, J. Y.; Kwon, D. G.; Kim, D.
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Korean Chem. Soc. 2009, 30, 829.
a
dr, and 95% ee (Scheme 1). The absolute configuration of com-
pound 3s was determined by comparing the specific rotation and
chiral HPLC data with those of an authentic sample.13b
Although the reason for the observed enantioselectivity is still
unclear, we believe that a nitro group of the nitroalkene is
activated by a thiourea moiety through hydrogen bonding, and
a-fluoro-b-ketoester is activated by the basic nitrogen atom in
tertiary amine (Fig. 2). These interactions control the stereochem-
ical outcome of the reaction and accelerate the reaction rate.
In conclusion, we have developed a highly efficient catalytic
enantioselective conjugate addition reaction of
a-fluoro-b-ketoest-
ers using bifunctional organocatalyst I. The desired
c
-nitro- -flu-
a
orocarbonyl compounds were obtained in good to high yields,
moderate diastereoselectivities, and excellent enantioselectivities
(up to >99% ee). A quaternary stereocenter bearing a fluorine atom
and an adjacent stereogenic carbon center are created with an
excellent level of enantioselectivity and in high yields in the conju-
gate addition process. Further study on the asymmetric synthesis
of fluorine-containing compounds is underway.
15. (a) Mang, J. Y.; Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29, 2091; (b) Mang, J. Y.;
Kwon, D. G.; Kim, D. Y. J. Fluorine Chem. 2009, 130, 259.
16. (a) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659; (b) Jung, S. H.; Kim, D. Y.
Tetrahedron Lett. 2008, 49, 5527; Recently, Shao et al. reported the asymmetric
Michael reaction of 2,4-pentandione promoted by catalyst I, see: (c) Peng, G.-
Z.; Shao, Z.-H.; Fan, B.-M.; Song, H.; Li, G.-P.; Zhang, H. B. J. Org. Chem. 2008, 73,
5202.
References and notes
17. General procedure for the conjugate addition of
nitrostyrene: To stirred solution of -fluoro b-ketoester
and catalyst (13.3 mg, 0.02 mmol) in toluene (0.4 mL) was added b-
a
-fluoro-b-ketoesters to b-
1. (a) Hudlicky, M.; Pavlath, A. E. Chemistry of Organic Fluorine Compounds II;
American Chemical Society: Washington, DC, 1995; (b) Filler, R.; Kobayashi, Y.
Biomedicinal Aspect of Fluorine Chemistry; Kodansha Ltd, Elsevier Biochemical
Press: Tokyo, New York, 1982; (c) Kirk, K. L. J. J. Fluorine Chem. 2006, 127, 1013;
(d) Isanobor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303; (e) Muller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881; (f) Kirk, K. L. Org. Process Res. Dev.
2008, 12, 305.
a
a
1
(0.2 mmol)
I
nitrostyrene (2a, 29.8 mg, 0.2 mmol) at room temperature. The reaction
mixture was stirred for 23–115 h at room temperature. The mixture was
diluted with saturated NH4Cl solution (30 mL) and extracted with ethyl
acetate (2 Â 30 mL). The combined organic layers were dried over MgSO4,
filtered, concentrated, and purified by flash chromatography to afford the
2. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320.
c
-nitro a-fluoro b-ketoester 3.