Enantioselective organocatalytic conjugate addition of α-nitroacetate to α,β-unsaturated ketones in water

Article abstract of DOI:10.1016/j.tetlet.2010.03.105

The catalytic enantioselective conjugate addition reaction of α-nitroacetate to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of α-nitroacetate to α,β-unsaturated ketones under aqueous-phase reaction c

Full text of DOI:10.1016/j.tetlet.2010.03.105

Tetrahedron Letters 51 (2010) 2906–2908
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective organocatalytic conjugate addition of a-nitroacetate
to
a,b-unsaturated ketones in water
*
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 conjugate addition reaction of
promoted by chiral bifunctional organocatalysts is described. The treatment of
unsaturated ketones under aqueous-phase reaction conditions afforded the corresponding Michael
adducts with high enantioselectivity. The conjugate addition adducts are easily converted to chiral d-keto
nitroalkanes and d-keto esters.
a
-nitroacetate to
a
,b-unsaturated ketones
-nitroacetate to ,b-
Received 11 February 2010
Revised 23 March 2010
Accepted 25 March 2010
Available online 29 March 2010
a
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bifunctional organocatalysts
Asymmetric catalysis
Michael reaction
a-Nitroacetate
Nitromethylation
Enantioselective construction of stereogenic carbon center is a
formidable challenge in organic synthesis. The Michael addition
reaction is widely recognized as one of the most general methods
for the formation of C–C bonds in organic synthesis,1 and the
development of enantioselective catalytic conjugate addition reac-
tion has been the subject of intensive research.2 In addition to the
great success catalyzed by metal complexes, the powerful and
environmentally friendly organocatalyst-mediated asymmetric
conjugate addition reaction has been explored intensively in recent
years.3,4 Enantioselective organocatalytic conjugate addition reac-
The development of enantioselective organocatalytic methodology
in an aqueous medium has become the most desirable area of or-
ganic chemistry, due to the favorable features of water as an inex-
pensive, safe, and environmentally benign medium.9
As part of the research program related to the development of
synthetic methods for the enantioselective construction of stereo-
genic carbon centers,10 we recently reported asymmetric conjugate
addition reaction of active methylenes and methines.11 Herein, we
wish to describe the enantioselective asymmetric conjugate addi-
tion of
a-nitroacetate to a,b-unsaturated ketones promoted by
tion of nitroalkanes to
a
,b-unsaturated carbonyl compounds repre-
bifunctional organocatalysts containing chiral primary amines in
water. The products resulted from a conjugate addition reaction
will generate chiral d-keto nitroalkanes and d-keto esters, which
can be conveniently elaborated in organic synthesis.
sents 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.5 Although a number of catalytic enantioselective
Validation of the feasibility of the proposed Michael addition
conjugate addition reaction of nitroalkanes to
tones have been reported,6 up to now there are few examples of
these reactions with
-nitroacetate using chiral organocatalysts.7
However, an enantioselective conjugate addition of -nitroacetate
to ,b-unsaturated ketones catalyzed by chiral primary amine
a
,b-unsaturated ke-
process started by evaluating a model reaction between a-nitroac-
etate (2) and (E)-4-phenylbut-3-en-2-one (1a) in the presence of
20 mol % bifunctional catalysts (Fig. 1) and 40 mol % of benzoic
acid as additive in water at room temperature. As shown in
Table 1, 9-amino-9-deoxyepicinchona alkaloids (I–VI) effectively
promoted the addition in high yield and high enantioselectivity
(entries 1–6). While chiral primary amine organocatalysts (VII–
X) bearing both central and axial chiral elements gave low ee val-
ues (entries 7–10). The best result has been obtained with 9-ami-
no-9-deoxyepicinchonine (IV). Based on the exploratory studies,
we decided to select catalyst IV for further optimization of reaction
conditions. We examined our investigations by examining the
reactivity and selectivity with organocatalyst IV in the presence
of different acids, such as benzoic acid, substituted benzoic acids,
a
a
a
organocatalysts remains elusive; although, if successfully
promoted with a practically accessible chiral catalyst under mild
conditions, it could provide
a highly attractive, convergent
approach toward optically active d-keto nitroalkanes and d-keto
esters. Recently, chiral primary amines have emerged as new and
powerful catalysts for enantioselective organocatalytic reactions.8
* 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 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.105

H. W. Moon, D. Y. Kim / Tetrahedron Letters 51 (2010) 2906–2908
2907
Table 2
R
N
Enantioselective conjugate addition of
a
-nitroacetate to
a
,b-unsaturated ketones
R
N
NH2
N
O2N
CO2Et
N
O2N
CO2Et
O
O2N
R1
H2O, EtOH
Et3N
5 h, 50 o
IV
cat.
(20 mol%)
NH2
2
O
PhCO2H (40 mol%)
+
C
R2
H2O, rt
O
R1
R2
I, R = H
IV
V
, R = H
R1
R2
4
II
e
e
3
, R = OM
, R = OM
III, R = OH
VI, R = OH
1
O
O
O
Ar
Me
R
Ph
1a
, Ar = Ph
1g, R = Ph
1h, R = Me
N
N
1b, Ar = p-F-C6H4
1c
1i
Ph
, Ar = p-OMe-C6H4
H2N
1d, Ar = p-NEt2-C6H4
1e, Ar = 1-naphthyl
H2N
1f
, Ar = 2-thienyl
VII
VIII
Entry
1
Time (h)
Yielda (%)
eeb (%)
O
O
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
2
2.5
2
2
2
2.5
2.2
2.3
2
4a, 98
4b, 96
4c, 95
4d, 97
4e, 95
4f, 96
4g, 97
4h, 94
4i, 93
93
83
81
65
77
73
89
83
85
N
2c
3c
4
N
H2N
H2N
5c
6
N
H
IX
X
7
8
9
Figure 1. Structure of chiral primary amine catalysts.
a
Isolated yield.
b
picolinic acid, and aliphatic carboxylic acids as additives (entries 4
and 11–17). Among the additives probed, the best results (98%
yield and 93% ee) were achieved when the reaction was conducted
in benzoic acid (entry 4).
Enantiomeric excess was determined by HPLC analysis using chiral columns
(Chiralpak AS for 4a, AS–H for 4g, IC for 4h, AD–H for 4b–d, 4f, 4i, and Chiralcel OD–
H for 4e).
c
m-CN–C6H4CO2H was used as acid additive.
Table 1
Optimization of the reaction conditions
With optimal reaction conditions in hand, we then carried on
evaluating the generality of this protocol. The results of a represen-
O2N
Ph
CO2Et
tative selection of
tion reaction are summarized in Table 2. As demonstrated,
organocatalyst IV-catalyzed Michael addition of -nitroacetate
(2) to ,b-unsaturated ketones 1 proved to be a general approach
for the synthesis of versatile chiral d-keto- -nitroacetates 3 with
a,b-unsaturated ketones for the conjugate addi-
O2N
Ph
O2N
Ph
CO2Et
O
H2O, EtOH
Et3N
cat. (20 mol%)
acid (40 mol%)
2
O
5 h, 50 o
C
a
+
O
H2O, rt
Me
Me
a
Me
4a
3a
a
1a
diastereomeric ratios of 1:1–1:1.2. The conjugate addition adducts
3 can be readily converted into the corresponding d-keto nitroalk-
anes 4 by decarboxylation.7,14 Notably, good to high enantiomeric
excess was obtained (up to 93% ee). The
a,b-unsaturated ketones
Entry
Cat.
Acid
Time (h)
Yielda (%)
eeb (%)
bearing substituted aryl, naphthyl, heteroaromatic, and methyl
groups in b-position could effectively participate in the process
(entries 1–8). Furthermore, cyclic system was also effective sub-
strate for the process (entry 9). Absolute configuration was deter-
mined by comparison of the optical rotation and chiral HPLC data
of the corresponding d-keto nitroalkanes 4.6,12 The conjugate addi-
tion adduct 3j can be readily converted into the corresponding d-
keto ester 5a by denitration without racemization (Scheme 1).5a,13
In conclusion, we have developed organocatalytic enantioselec-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
I
II
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
3
4
2
2
3
2
10
13
3
3
5
4
5
7
7
12
2 d
95
93
92
98
97
92
90
71
90
98
93
94
93
90
87
89
28
77
90
83
93
77
92
37
59
15
39
93
75
65
87
89
61
65
III
IV
V
VI
VII
VIII
IX
X
IV
IV
IV
IV
IV
IV
IV
m-CN-C6H4CO2H
tive conjugate addition reaction of
a-nitroacetate (2) to
a,b-unsat-
2-Cl-4,5-F2-C6H2CO2H
p-NO2–C6H4CO2H
o-SH-C6H4CO2H
Picolinic acid
BrCH2(CH2)4CO2H
CH3COCO2H
urated ketones 1 to afford synthetically useful chiral
c-nitro
ketones in water. The process is efficiently catalyzed by a simple
cinchona alkaloid derivative containing chiral primary amine. The
significance of the approach is highlighted by its capability to intro-
duce d-keto nitroalkanes and d-keto ester with high enantioselec-
tivity and yields under aqueous reaction conditions. Further
details and application of this asymmetric Michael addition of nit-
roalkane nucleophiles will be presented in due course.
a
Isolated yield of 4a.
Enantiomeric excess was determined by HPLC analysis using a Chiralpak AS
column.
b

2908
H. W. Moon, D. Y. Kim / Tetrahedron Letters 51 (2010) 2906–2908
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O2N
Ph
CO2Me
2b
O2N
CO2Me
O
IV
cat. (20 mol%)
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PhCO2H (40 mol%)
Ph
Me
+
O
H2O, rt
3j
Bu3SnH C6H6
AIBN
MeO2C
Ph
Me
1a
reflux, 5 h
O
Me
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5a
81 % yield, 89% ee
Scheme 1. Denitration of 1,4-addition adduct 3j into d-keto ester 5a.
References and notes
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deoxyepiquinine (IV, 17.6 mg, 0.06 mmol), and benzoic acid (14.6 mg,
0.12 mmol) in 0.9 mL of H2O were stirred at room temperature for 5 min.
Ethyl 2-nitroacetate (2, 79.8 mg, 0.6 mmol) was added and the reaction
mixture was stirred at room temperature for a specified reaction time period.
EtOH (1.2 mL), H2O (1.2 mL), and triethylamine (0.4 mL) were added into the
reaction mixture and the resulting mixture was stirred at 50 °C. After being
stirred for 5 h, the reaction mixture was extracted with ethyl acetate. The
organic phase was dried over anhydrous MgSO4 and concentrated in vacuo.
The crude product was purified by column chromatography on silica gel, eluted
by hexane/EtOAc = 5:1 to give the desired product 4.