Enantioselective decarboxylative Michael addition of β-ketoacids to nitroalkenes catalyzed by binaphthyl-derived organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2012.09.100

The catalytic enantioselective decarboxylative Michael addition reaction promoted by chiral bifunctional organocatalysts has been developed, allowing facile synthesis of the corresponding γ-nitro ketones with excellent enantioselectivity (up to 97% ee). The method reported represents a valuable approach utilizing β-ketoacids as synthetic equivalents of aryl methyl ketones.

Full text of DOI:10.1016/j.tetlet.2012.09.100

Tetrahedron Letters 53 (2012) 6569–6572
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Enantioselective decarboxylative Michael addition of b-ketoacids
to nitroalkenes catalyzed by binaphthyl-derived organocatalysts
⇑
Hyoung Wook Moon, 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 decarboxylative Michael addition reaction promoted by chiral bifunctional
Received 13 August 2012
Revised 13 September 2012
Accepted 21 September 2012
Available online 28 September 2012
organocatalysts has been developed, allowing facile synthesis of the corresponding c-nitro ketones with
excellent enantioselectivity (up to 97% ee). The method reported represents a valuable approach utilizing
b-ketoacids as synthetic equivalents of aryl methyl ketones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Organocatalysis
Michael addition
c
-Nitro ketones
Nitroalkenes
The Michael addition reaction is widely recognized as one of the
direct catalytic enantioselective Michael addition of aryl methyl
ketones to nitroalkenes.11 There are still some drawbacks to the
previously reported procedures, such as the high catalyst loading
and long reaction time required for good enantioselectivity.
Accordingly, the development of alternative catalysts for the direct
organocatalytic enantioselective decarboxylative Michael addition
of b-ketoacids to nitroalkenes is highly desirable. We envisioned
that the assembly of a structurally well-defined chiral 1,2-diamine
and binaphthyl scaffold with a H-bonding motif could activate
nitroalkenes and ketoacids as bifunctional organocatalysts. The ri-
gid binaphthyl structure can serve as an efficient stereocontrolling
axial chiral element.
As part of the research program related to the development of
synthetic methods for the enantioselective construction of stereo-
genic carbon centers,12 we recently reported enantioselective
Michael additions of active methylenes and methines.13 Herein,
we wish to describe the direct enantioselective decarboxylative
Michael addition of b-keto acids to nitroalkenes catalyzed by
bifunctional organocatalysts bearing both central and axial chiral
elements (see Fig. 1.).
To determine suitable reaction conditions for the catalytic
enantioselective decarboxylative Michael addition reaction of
b-ketoacids, we initially investigated the reaction system with
nitrostyrene (1a) and benzoylacetic acid (2a) in the presence of
10 mol % of catalyst in THF at room temperature. We first exam-
ined the impact of the structure of catalysts I–VI on the enantiose-
lectivities (21–85% ee, Table 1, entries 1–6). The best results were
obtained with catalyst III which is a binaphthyl-modified squara-
mide bifunctional organocatalyst bearing central and axial chiral
most important and fundamental methods for the formation of
C–C bonds in organic synthesis,1 and the development of asym-
metric version of this reaction has been a subject of intensive
research.2 In addition to the great success of catalysis with metal
complexes, the environmentally friendly organocatalyst-mediated
asymmetric Michael reaction has been explored in depth in recent
years.3,4 The Michael addition of nucleophiles to nitroalkenes rep-
resents a direct and appealing approach to the synthesis of chiral
nitroalkanes that are versatile intermediates in organic synthesis,
which can be transformed into an amine, nitrile oxide, ketone,
carboxylic acid, hydrogen group, and so on.5 In recent years, the
enantioselective decarboxylative additions of malonic acid
half-thioesters as ester enolate equivalents have received much
attention.6 Although
a number of reactions of malonic acid
half-thioesters as carbon nucleophiles to various electrophiles have
been reported,7 the corresponding b-ketoacids have received rela-
tively little attention as carbon nucleophiles. There have been a
few reported examples of decarboxylative aldol, alkylation, and
Mannich reactions of b-ketoacids as surrogates of ketones.8 The
Evans group has reported the first catalytic enantioselective
decarboxylative reaction of b-ketoacids with nitroalkenes in the
presence of chiral Ni(II) complexes.9 Very recently, The Ma and
Lu groups described organocatalytic enantioselective decarboxyla-
tive aldol-type reactions of b-ketoacids with trifluoromethyl
ketones and isatins.10 Recently, several groups have reported the
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.100

6570
H. W. Moon, D. Y. Kim / Tetrahedron Letters 53 (2012) 6569–6572
Table 1
Optimization of the reaction conditionsa
O
N
O
O
N
Ph
cat. (10 mol%)
solvent, rt, 3h
NO2
+
Ph
Ph
OH
NH
NO2
HN
Ph
N
S
1a
2a
S
NH
3a
HN
Entry
Cat.
Solvent
Yieldb (%)
eec (%)
CF3
F3C
CF3
1
2
3
4
5
6
7
8
I
II
III
IV
V
THF
THF
THF
THF
THF
THF
Et2O
Dioxane
EtOAc
PhMe
CH2Cl2
CHCl3
CHCl2CH2Cl
MeOH
i-PrOH
CHCl3/THF (1:1)
CHCl3/THF (4:1)
CHCl3/THF (9:1)
CHCl3/THF (1:4)
CHCl3/THF (4:1)
CHCl3/THF (4:1)
CHCl3/THF (4:1)
CHCl3/THF (4:1)
CHCl3/THF (4:1)
60
67
70
60
56
54
76
75
63
80
78
74
76
77
78
83
83
80
81
82
83
84
83
62
21
55
85
69
57
27
67
81
75
65
71
85
81
56
45
93
97
93
93
97
96
96
97
80
F3C
II
I
VI
III
III
III
III
III
III
III
III
III
III
III
III
III
III
III
III
III
III
N
N
9
HN
HN
10
11
12
13
14
15
16
17
18
19
20d
21e
22f
23g
24h
O
O
O
HN
HN
O
F3C
F3C
CF3
IV
CF3
III
Ph
Ph
Ph
N
HN
N
Ph
S
HN
HN
a
O
Reaction conditions: b-nitrostyrene (1a, 0.2 mmol), benzoylacetic acid (2a,
0.24 mmol), catalyst (0.02 mmol), CHCl3/THF (4:1, 2.0 mL) at room temperature.
b
HN
Isolated yield.
O
c
F3C
Enantiopurity was determined by HPLC analysis using Chiralpak AD-H column.
5 mol % Catalyst loading.
1 mol % Catalyst loading.
0.25 mol % Catalyst loading for 6 h.
0.1 mol % Catalyst loading for 6 h.
0.05 mol % Catalyst loading for 6 h.
CF3
d
e
F3C
f
CF3
g
V
VI
h
Figure 1. Structures of chiral organocatalysts.
yield and enantioselectivity was observed with alkyl-substituted
nitroalkene 1k (Table 2, entry 11). The absolute configuration of
the adducts 3 was determined for some derivatives by comparison
of their optical and HPLC properties with literature values.11
To examine the generality of the catalytic enantioselective
decarboxylative Michael addition reaction of the b-ketoacid
derivatives 2 by using chiral bifunctional organocatalyst III, we
studied the Michael addition of various b-ketoacids 2b–h with
b-nitrostyrene (1a). As seen from the results summarized in
elements.13f Different solvents were then tested in the presence of
10 mol % of catalyst III together with benzoylacetic acid (2a) and
b-nitrostyrene (1a) in order to improve the selectivity of the
reaction further. Aprotic solvents, such as THF, diethyl ether, ethyl
acetate, toluene, dichloromethane, chloroform, and 1,1,2-trichloro-
ethane were tolerated well in this conjugate addition without a
significant decrease in the enantioselectivities (65–85% ee, Table 1,
entries 3 and 7–13). Protic polar solvents also afforded products in
good yields, but the selectivities dropped significantly (Table 1, en-
tries 14 and 15). Remarkably, the use of co-solvent of chloroform
and THF gave high yields and excellent enantioselectivities (entries
16–19). Among the solvents probed, the best results (83% yield and
97% ee) were achieved when the reaction was conducted in chloro-
form/THF (4:1) (Table 1, entry 17). The present catalytic system
tolerates catalyst loading down to 5, 1, 0.25, or 0.1 mol % without
compromising the yield or the enantioselectivity (Table 1, entries
20–24).
Table 3, the corresponding
c-nitro ketones 3l–r were obtained
in excellent yields with excellent enantioselectivities. A range
of electron-donating and electron-withdrawing substitutents on
the b-aryl ring of the b-ketoacids 2b–e provided reaction prod-
ucts in high yields and excellent enantioselectivities (87–97%
ee, Table 3, entries 1–4). The heteroaryl- and naphthyl-
substituted b-ketoacids 2f and 2g provided the products with
high selectivity (93% and 83% ee, Table 3, entries 5 and 6). The
b-alkyl-substituted b-ketoacid, 3-oxobutanoic acid (2h), was also
an acceptable starting material and provided the corresponding
Michael adducts in high yield and with excellent enantioselectiv-
ity (91% ee, Table 3, entry 7).
We then explored the possibility of using a wide range of nitro-
alkene derivatives 1 with benzoylacetic acid (2a) in the presence of
0.1 mol % of catalyst III in THF at room temperature (Table 2).14
A
The present method is operationally simple and efficient and,
thus, may be valuable for practical chemical synthesis. As shown
in Scheme 1, when benzoylacetic acid (2a) was treated with
nitroalkene 1g under the optimal reaction conditions, the reaction
range of electron-donating and electron-withdrawing substituents
on the aryl ring of the nitrostyrenes 1b–g provided the reaction
products in high yields (78–89%) and with excellent enantioselec-
tivities (87–97%, Table 2, entries 1–7). The heteroaryl- and
naphthyl-substituted nitroalkenes 1h–j provided the products
with high selectivity (Table 2, entries 8–10). However, diminished
proceeded smoothly to afford the desired
c-nitro ketone 3g at the
gram scale with 76% yield and 91% ee. (Scheme 1).

H. W. Moon, D. Y. Kim / Tetrahedron Letters 53 (2012) 6569–6572
6571
Table 2
tivities (up to 97% ee) were observed for all the substrates exam-
ined in this work. We believe that this method provides a
practical entry for the preparation of chiral c-nitro ketone deriva-
tives. Further study of this catalytic enantioselective decarboxyla-
tive addition reaction of b-ketoacids with various carbon
electrophiles is in progress.
Variation of the nitroalkenes 1a
O
R
O
O
cat. III (0.1 mol%)
Ph
NO2
+
R
Ph
OH
CHCl3/THF (4:1)
NO2
rt, 6 h
2a
3
1
Yieldb (%)
eec (%)
Acknowledgment
Entry
1, R
1a, Ph
1b, 2-NO2C6H4
1c, 4-FC6H4
1d, 4-ClC6H4
1e, 4-BrC6H4
1f, 4-MeC6H4
1g, 4-MeOC6H4
1h, 2-Furyl
1i, 2-Thienyl
1j, 2-Naphthyl
1k, PhCH2CH2
1
2
3
4
5
6
7
8
3a, 83
3b, 82
3c, 88
3d, 89
3e, 87
3f, 80
3g, 78
3h, 80
3i, 83
3j, 81
3k, 70
97
93
90
93
87
91
90
92
91
93
76
This research was supported in part by the Soonchunhyang
University Research Fund.
References and notes
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9
10
11d
a
Reaction conditions: nitroalkene
1
(0.2 mmol), benzoylacetic acid (2a,
3. For selected recent reviews for bifunctional organocatalysts, see: (a) Connon, S.
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0.24 mmol), catalyst (0.2
lmol), CHCl3/THF (4:1, 2.0 mL) at room temperature.
b
Isolated yield.
c
Enantiopurity was determined by HPLC analysis using Chiralpak AD-H (for 3a
and 3c–k) and IA (for 3b) columns.
d
This reaction was conducted using 10 mol % catalyst at room temperature for
15 h.
Table 3
Variation of the b-ketoacids 2a
O
O
O
R
cat. III (0.1 mol%)
NO2
+
Ph
R
OH
NO2
6. (a) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678;
(b) Pan, Y.; Tan, C.-H. Synthesis 2011, 2044.
CHCl3/THF (4:1)
Ph
1a
rt, 6 h
2
3
7. (a) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125, 2852; (b)
Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am.
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Entry
2, R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
2b, 4-MeC6H4
2c, 4-MeOC6H4
2d, 4-BrC6H4
2e, 2-ClC6H4
2f, 2-Thienyl
2g, 2-Naphthyl
2h, Me
3l, 83
97
87
95
91
93
83
91
3m, 80
3n, 80
3o, 84
3p, 85
3q, 84
3r, 87
a
Reaction conditions: b-nitrostyrene (1a, 0.2 mmol), b-ketoacid 2 (0.24 mmol),
catalyst (0.2 mol), CHCl3/THF (4:1, 2.0 mL) at room temperature.
l
b
Isolated yield.
8. (a) Rohr, K.; Mahrwald, R. Org. Lett. 1878, 2011, 13; (b) Yang, C. F.; Wang, J. Y.;
Tian, S.-K. Chem. Commun. 2011, 8343; (c) Yang, C. F.; Shen, C.; Wang, J. Y.; Tian,
S.-K. Org. Lett. 2012, 14, 3092.
c
Enantiopurity was determined by HPLC analysis using Chiralpak AD-H (for 3l–
q) and (S,S)-Whelk-O1 (for 3r) columns.
9. Evans, D. A.; Mito, S.; Shair, M. D. J. Am. Chem. Soc. 2007, 129, 11583.
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46, 3115; (d) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659; (e) Lee, J. H.;
Bang, H. T.; Kim, D. Y. Synlett 2008, 1821; (f) Lee, J. H.; Kim, D. Y. Adv. Synth.
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Korean Chem. Soc. 2011, 32, 1195; (k) Lee, H. J.; Kang, S. H.; Kim, D. Y. Bull.
Korean Chem. Soc. 2011, 32, 1125; (l) Lee, H. J.; Kim, J. H.; Kim, D. Y. Bull. Korean
Chem. Soc. 2011, 32, 785; (m) Moon, H. W.; Kim, D. Y. Bull. Korean Chem. Soc.
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NO2
O
MeO
Ph
NO2
1g (1.20 g)
cat. III (0.1 mol%)
+
CHCl3/THF (4:1)
MeO
rt, 9 h
O
O
3g
Ph
OH
2a (1.32 g)
(76% yield, 91% ee)
Scheme 1. Gram scale Michael addition of benzoylacetic acid (2a) with nitroalkene
1g.
In conclusion, we have developed a highly efficient catalytic
enantioselective decarboxylative Michael addition reaction of b-
ketoacids to nitroalkenes using 0.1 mol % of a binaphthyl-derived
chiral bifunctional organocatalyst. The desired
were obtained in good to high yields, and excellent enantioselec-
c-nitro ketones

6572
H. W. Moon, D. Y. Kim / Tetrahedron Letters 53 (2012) 6569–6572
13. (a) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847; (b)
Moon, H. W.; Kim, D. Y. Tetrahedron Lett. 2010, 51, 2906; (c) Kang, S. H.; Kwon,
B. K.; Kim, D. Y. Tetrahedron Lett. 2011, 52, 3247; (d) Kang, Y. K.; Suh, K. H.; Kim,
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(4:1, 2.0 mL) was added benzoylacetic acid (2a, 39.4 mg, 0.24 mmol) at room
temperature. The reaction mixture was stirred for 6 h at room temperature.
After completion of the reaction, the resulting solution was concentrated in
vacuo and the obtained residue was purified by flash chromatography (EtOAc/
Hexane, 1:5) to afford the 44.7 mg (83%) of the Michael adduct 3a. (S)-4-nitro-
1,3-diphenylbutan-1-one (3a): ½a D23
ꢂ
= ꢁ10.3(c = 1.00, CHCl3); 1H NMR (200 MHz,
CDCl3) d 7.93–7.89 (m, 2H), 7.62–7.37 (m, 3H), 7.35–7.20 (m, 5H), 4.84 (dd,
J = 12.2, 6.1 Hz, 1H), 4.70 (dd, J = 12.2, 7.8 Hz, 1H), 4.31–4.15 (m, 1H), 3.50–3.40
(m, 2H); 13C NMR (50 MHz, CDCl3) d 196.82, 139.05, 136.31, 133.56, 129.02,
128.70, 127.98, 127.84, 127.42, 79.52, 41.48, 39.24; HPLC (90:10, n-hexane: i-
PrOH, 220 nm, 1.0 mL/min) Chiralpak AD-H, tR = 8.6 min (major), tR = 10.5 min
(minor), 97% ee.
14. Typical procedure for the Michael addition reaction of benzoylacetic acid (2a) with
b-nitrostyrene (1a): To
0.2 mmol) and catalyst III (100
a stirred solution of nitrostyrene (1a, 29.8 mg,
l
L, 2 ꢀ 10ꢁ3 M, 0.2
lmol) in chloroform/THF