Organocatalytic asymmetric Michael-type reaction between β,γ-unsaturated α-keto ester and α-nitro ketone

Article abstract of DOI:10.1039/c1ob06191g

A Michael-type reaction of β,γ-unsaturated α-keto ester and α-nitro ketone was established. With a thiourea catalyst derived from cinchona alkaloid, the reactions afford products in 47-94% yields with 68-96% ee. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06191g

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Organocatalytic asymmetric Michael-type reaction between b,c-unsaturated
a-keto ester and a-nitro ketone†
Pengfei Li,a,b Sau Hing Chan,b Albert S. C. Chan*a and Fuk Yee Kwong*b
Received 18th July 2011, Accepted 15th September 2011
DOI: 10.1039/c1ob06191g
A Michael-type reaction of b,c-unsaturated a-keto ester and a-
nitro ketone was established. With a thiourea catalyst derived
from cinchona alkaloid, the reactions afford products in 47–
94% yields with 68–96% ee.
reaction of b,g-unsaturated a-keto esters. To examine this idea,
a a-nitro ketone was chosen as the nucleophile and the model
reactions of this ketone with a b,g-unsaturated a-keto ester were
then investigated.
Very recently, Wang9a and Yan9b reported the asymmetric
organocatalytic Michael/hemiketalization/retro-Henry reaction
between a b,g-unsaturated a-keto ester and a a-nitro ketone,
giving more than 90% ee and yield in the presence of the
bifunctional Brønsted-base thiourea catalyst.10 However, the
reactions of aliphatic a-nitro ketones afforded relatively poor
enantioselectivities (no more than 79% ee). Herein, we present
this transformation in good yield with 68–96% ee using a thiourea
catalyst derived from cinchona alkaloid. Notably up to 96% ee
was obtained from the reaction of an aliphatic a-nitro ketone and
a b,g-unsaturated a-keto ester.
At the outset of our initial investigation, we focused on the
reaction between methyl 2-oxo-4-phenylbut-3-enoate (1a) and 2-
nitro-1-phenylethanone (2a). Interestingly, the 1H NMR spectrum
of the product showed that a Michael-type reaction occurred
(Scheme 1). There were two groups of doublet peaks for two
hydrogens of the C C double bond conjugated with the aromatic
ring at the range from 6.00 ppm to 7.00 ppm (J = 16.0 Hz) in the 1H
NMR spectrum of the aldol adduct. In contrast, only one group
of doublet peaks near 6.8 ppm was found for the Michael-type
product and the coupling constant had changed to 9.6 Hz. This
Organocatalysis has been an alternative and/or complementary
approach to currently developed organometallic and enzymatic
catalysis. Indeed, the emerging of an organocatalytic proto-
col has displayed great success in modular organic molecule
assembly/transformations in the last decade.1 In particular,
organocatalytic asymmetric Michael addition reactions have re-
ceived widespread attention for accessing a variety of optically
active adducts which are synthetically useful building blocks in
versatile organic synthesis.2 Notably, the Michael-type domino
reactions efficiently furnish complex chiral natural molecules and
diverse intermediates in a one-pot process.3
b,g-Unsaturated a-keto esters represent a resourceful moiety
in synthetically useful components. For instance, the asymmetric
aldol reactions of b,g-unsaturated a-keto esters furnish b-hydroxy
carbonyl compounds bearing a tertiary alcohol motif.4 Enan-
tioselective Diels–Alder reactions provide a beneficial route for
assembling cyclic products.5 Asymmetric Michael additions6 and
Michael-type tandem reactions7 result in g-functional carbonyl
compounds, which can generally be further transformed to obtain
the stereospecific molecules.
Recently, we successfully developed an organocatalytic asym-
metric aldol reaction of a b,g-unsaturated a-keto ester with a
ketone.8 We found that the aldol reaction, rather than Michael
addition or Diels–Alder reaction, was occurred preferentially
between the ketone and b,g-unsaturated a-keto ester. Moreover,
the size of the ketone substrate affected the product yield and
stereo-induction greatly. These outcomes underlined the fact that
a sterically more congested ketone could efficiently prevent the
aldol reaction of b,g-unsaturated a-ketoesters. Based on the
aforementioned findings, we proposed a more active nucleophile
with proper steric hindrance that might lead to a Michael-type
information indicates that the conjugate system between the C
double bond and the aromatic ring is broken.
C
aDepartment of Chemistry, Faculty of Science, Hong Kong Baptist Univer-
sity, Hong Kong, China. E-mail: ascchan@hkbu.edu.hk
bState Key Laboratory for Chirosciences and Department of Applied Biology
and Chemical Technology, The Hong Kong Polytechnic University, Hong
Kong, China. E-mail: bcfyk@inet.polyu.edu.hk; Fax: (+852)-2364-9932;
Tel: (+852)-3400-8682
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06191g
Scheme 1 1H NMR spectra of products from 2-oxo-4-phenylbut-3-
enoate.
Having confirmed the reaction type, we next carried out the
screening of organocatalysts (Table 1). Catalyst I and II have
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Table 1 Screening of organocatalystsa
Table 2 Optimization of reaction conditionsa
Entry
Solvent
T/◦C
t/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8d
CH2Cl2
EtOAc
Toluene
THF
1,4-dioxane
t-BuOMe
Et2O
20
20
20
20
20
20
20
20
24
24
24
24
24
24
24
12
69
70
62
71
79
44
48
56
77
79
85
82
80
93
93
94
Et2O
a Unless noted, the following reaction conditions were used: 1a (0.13
mmol), 2a (0.1 mmol), IIIb (10 mol%) in solvent (0.3 mL) at temperature
indicated for the time given in Table 2. b Isolated yield. c ee was determined
by chiral HPLC. d IIIb (15 mol %) and Et2O (0.5 mL) were used.
Entry
Cat.
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
Ia
53
60
30
77
69
73
77
41
4
11
74
77
-64
-72
Table 3 Substrate scopea
Ib
II
IIIa
IIIb
IVa
IVb
a Reaction conditions: 1a ◦(0.13 mmol), 2a (0.1 mmol), catalyst (10 mol%)
in CH2Cl2 (0.3 mL) at 20 C for 24 h. b Isolated yield. c ee was determined
by chiral HPLC.
Entry R1
R2
R3
Product Yield (%)b ee (%)c
1
2
Ph
Ph
Me Ph
Et Ph
i-Pr Ph
Et
Et
Et
Et
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
56
50
61
50
71
62
58
56
49
50
47
56
47
70
58
56
63
94
51
50
45
43
61
63
69
55
50
54
94
84
72
82
86
84
91
86
90
82
86
88
88
92
84
82
73
68
96
83
89
90
82
73
84
88
94
78
3
4
5
6
7
8
9
Ph
2-ClPh
2-BrPh
3-ClPh
3-BrPh
3-NO2Ph
3-NO2Ph
3-MePh
3-MeOPh
4-FPh
4-ClPh
4-BrPh
4-NO2Ph
4-MePh
4-MeOPh
Ph
Ph
Ph
Ph
been successfully employed in the asymmetric aldol reactions of
b,g-unsaturated a-keto esters with nitromethane4b and ketone,8
respectively. However, unsatisfactory results were obtained from
both I- and II-catalyzed reactions (Table 1, entries 1–3). When
thiourea catalysts III and IV were used, remarkable enhancements
of both yield and enantioselectivity were achieved. The best
enantioselectivity was obtained with the aid of IIIb catalyst
(77%, Table 1, entry 5). Particularly noteworthy was that this
methodology could constitute an access to both enantiomers
of 3aa, taking advantage of the pseudoenantiomeric effect of
thiourea catalyst derived from cinchona alkaloid.
Further optimization of reaction conditions was investigated
and representative results are listed in Table 2. Commonly used
organic solvents were examined and Et2O was found to be more
suitable for this transformation (Table 2, entries 1–7). Systematic
screening studies including the effect of mixed solvents, reaction
temperature, the molar ratio of reactants, various added additives
and catalyst loading revealed that IIIb enabled the formation of
3aa in 56% yield with 92% ee at 20 ◦C in 12 h (Table 2, entry 8, see
ESI for more details†).
Under the optimized reaction conditions, IIIb-catalyzed
Michael-type reactions between a series of b,g-unsaturated a-keto
esters 1 and 2a were surveyed (Table 3). In the presence of IIIb,
Michael-type products 3aa–ra were isolated in 47–74% yield with
72–94% ee. The ester functionality of the b,g-unsaturated a-keto
ester had a large influence on the enantioselectivity: increasing the
size of ester group resulted in lowering product ee (Table 3, entries
1–3). Various substituents, either electron-withdrawing (Table 3,
entries 4–9, 12–15) or electron-donating groups (Table 3, entries
10–11, 16–17), could be introduced into the aromatic ring of b,g-
Me Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
5-Me-2-thienyl Et
Ph
Ph
Me n-Pr 3ab
Et
Et
Et
Et
Et
Et
Et
Et
Et
n-Pr 3bb
n-Pr 3fb
n-Pr 3gb
n-Pr 3ib
n-Pr 3kb
n-Pr 3lb
n-Pr 3mb
n-Pr 3nb
n-Pr 3pb
3-ClPh
3-BrPh
3-NO2Ph
3-MeOPh
4-FPh
4-ClPh
4-BrPh
4-MePh
a Unless noted, the following reaction conditions wer◦e used: 1 (0.13 mmol),
2 (0.1 mmol), IIIb (15 mol%) in Et2O (0.5 mL) at 20 C for 12 h. b Isolated
yield. c ee was determined by chiral HPLC.
unsaturated a-keto ester. No significant electronic effect on the
aromatic moiety was observed. A heteroaromatic b,g-unsaturated
a-keto ester afforded 3ra in up to 94% yield with 68% ee (Table 3,
entry 18).
The reaction of challenging aliphatic a-nitro ketone with 1 was
also probed. 1-Nitropentan-2-one (2b) reacted with 1a to afford
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3ab in moderate yield with up to 96% ee (Table 3, entry 19). Product
3bb was formed in similar yield with 83% ee from ethyl 2-oxo-4-
phenylbut-3-enoate (Table 3, entry 20). The substituted aromatic
b,g-unsaturated a-keto ester could also be employed to afford3ab–
3pb in medium yields with good to excellent enantioselectivities
(Table 3, entries 21–28). It should be noted that more than 90% ee
were obtained not only from the aromatic a-nitro ketone but also
from the aliphatic a-nitro ketone.
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The absolute configuration of the products was R, which was
determined by comparison of optical rotations with those in the
literature.9
In conclusion, we have developed a new Michael-type reaction
of b,g-unsaturated a-keto ester with both aromatic and aliphatic
a-nitro ketone to afford products in 47–94% yields with 68–96%
ee. Compared with Wang’s and Yan’s reports,9 higher ee values
were obtained from aliphatic a-nitro ketone. It should be noted
that this methodology offered an enantioselective pathway for the
synthesis of chiral 5-nitro-pent-2-enoates, a precursor to chiral a-
ketolactam. Development of new type organocatalysts and further
applications of these reactions are currently under investigation.
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We gratefully thank the European Commission FP7-201431
(CATAFLU.OR) and PolyU Internal Grant DA (A-PD0X) for
financial support.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 7997–7999 | 7999
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