Recyclable organocatalysis: Highly enantioselective Michael addition of 1,3-diaryl-1,3-propanedione to nitroolefins

Article abstract of DOI:10.1039/b813915f

The first Michael addition of 1,3-diaryl-1,3-propanedione to nitroolefins was demonstrated using a simple organocatalyst, which afforded excellent yields (81-97%) and enantioselectivities (90 to >99% ee); the catalyst and excess reactant can be reused sev

Full text of DOI:10.1039/b813915f

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Chemical Communications
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Number 7 | 21 February 2009 | Pages 713–844
ISSN 1359-7345
FEATURE ARTICLE
COMMUNICATION
Takashi Kato et al.
Guofu Zhong et al.
Self-assembly of functional columnar
liquid crystals
Recyclable organocatalysis
1359-7345(2008)7;1-0

COMMUNICATION
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Recyclable organocatalysis: highly enantioselective Michael addition
of 1,3-diaryl-1,3-propanedione to nitroolefinsw
Bin Tan, Xuan Zhang, Pei Juan Chua and Guofu Zhong*
Received (in Cambridge, UK) 12th August 2008, Accepted 31st October 2008
First published as an Advance Article on the web 20th November 2008
DOI: 10.1039/b813915f
The first Michael addition of 1,3-diaryl-1,3-propanedione to
nitroolefins was demonstrated using a simple organocatalyst,
which afforded excellent yields (81–97%) and enantioselectivities
(90 to 499% ee); the catalyst and excess reactant can be reused
seven times through a simple filtration operation.
The development of a highly enantioselective recyclable
strategy11 for organocatalysis remains a challenging task. To
the best of our knowledge, only a few recyclable processes
have been designed by attaching the catalyst to polymers,12
using recyclable fluorous catalysts13 and ionic liquids.14
However, only moderate results have been achieved so far.
Herein, we present the first asymmetric Michael addition
reaction of 1,3-diaryl-1,3-propanedione to nitroolefins using
a more readily accessible organocatalyst involving a recyclable
homogenous organocatalysis strategy.
Recent years have witnessed a dramatic upsurge in awareness
among chemists of the potential utility of asymmetric organo-
catalysis as a tool for the synthesis of enantiopure molecules
under mild and environmentally benign conditions.1 The
Michael addition of 1,3-dicarbonyl nucleophiles to nitro-
olefins2 provides a particularly attractive target for organoca-
talyst design, largely due to the ready availability and high
reactivity of nitroalkenes and the ability of the nitro function-
ality to accept hydrogen bonds from suitably designed catalyst
systems, especially for the synthesis of important nitrogen
containing bioactive agrochemical and pharmaceutical com-
pounds.3 Thus, reactions of this nature have been reported to
proceed in high yield and with good enantioselectivity by the
use of various asymmetric catalysts.4 In contrast, organo-
catalytic conjugated additions using aromatic ketones as the
Michael donor are rarely studied. 1,3-Diphenyl-1,3-propanedione
(1a) is normally not considered as a good Michael donor due
to the steric hindrance of the two aryl groups and usually
requires harsh reaction conditions and long reaction times.
Bifunctional catalysts containing a thiourea group and a
tertiary amine in the molecule usually lead to high yields and
enantioselectivities.5 Takemoto et al. assumed that a thiourea
moiety and a tertiary amino group in the catalyst activated a
nitro group and a 1,3-dicarbonyl compound respectively to
afford the Michael adduct with high enantio- and diastereo-
selectivity.6 Recently, 9-epi-amino Cinchona alkaloid deriva-
tives and diaminocyclohexane derivatives have proved to be
efficient organocatalysts to catalyze Michael reactions,7 aldol
reactions8 and aminations.9 Based on our recent research10
and comprehension of this type of reaction, we reasoned that
more readily available primary amines of Cinchona alkaloid
derivatives can activate 1a through H-bond activation and
thus promote the Michael addition reaction to nitroolefins.
Fig. 1 Structures of the Cinchona alkaloid catalysts.
In the initial studies, six Cinchona alkaloid catalysts (Fig. 1)
were screened for their catalytic ability to promote the Michael
addition reaction of 1a and trans-b-nitrostyrene (2a) (Table 1).
A survey of solvents revealed that all the reactions proceeded
smoothly and completed within 17 h at room temperature.
Reactions conducted in THF, toluene and diethyl ether all
offered good yields and enantioselectivities (up to 98% ee).
Remarkably, the Michael adduct precipitated in solid form in
diethyl ether gave the highest ee value. This suggested a route
to develop a recyclable and practical methodology to reuse the
catalyst and excess reactant.
As shown in Table 1, reaction promoted by catalyst VI
gave the highest enantioselectivity and catalyst V (with the
double bond reduced) gave a slightly lower ee value. Lowering
the reaction temperature to 4 1C or reducing the catalyst loading
to 10 mol% prolonged the reaction time and decreased the yield,
though the ee value remained the same. Examination of the
structures of catalysts I–IV revealed that both the primary amine
and the methoxy groups played significant roles in controlling
enantioselectivity. The reactions promoted by quinine and
cinchonidine which do not contain the primary amine group
resulted in very low ee values. Almost racemic adducts were
observed for the processes catalyzed by cinchonidine derivatives
III and IV, both of which do not contain a methoxy group.
Having established the optimum reaction conditions for the
enantioselective Michael addition of 1a to nitroolefins, we next
screened a series of analogues bearing various substituents on
the aromatic ring (Table 2). All the reactions proceeded
smoothly at room temperature (23 1C) in the presence of
15 mol% of catalyst VI and completed within 8–30 h regardless
of the electronic properties. The desired adducts were obtained
Division of Chemistry and Biological Chemistry, School of Physical &
Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371, Singapore.
E-mail: guofu@ntu.edu.sg; Fax: (+65) 6791 1961;
Tel: (+65) 6316 8761
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization, spectra and chiral HPLC conditions.
CCDC 658642. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b813915f
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 779–781 | 779

Table 1 Organocatalytic asymmetric Michael addition of 1a and
trans-b-nitrostyrenea
Entry
Catalyst
Solvent
t/h
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
I
II
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
MeOH
THF
Toluene
Et2O
Et2O
8
8
8
8
8
8
8
15
8
17
12
95
95
97
98
94
96
93
82
97
94
85
À21
À2
3
III
IV
V
VI
VI
VI
VI
VI
VI
7
93
98
65
98
95
98
98
Scheme 1 Diversities of Michael donors and acceptors.
selectivity of this method (eqn (2), Scheme 1). Further inves-
tigation of the diversity of the Michael donor revealed that
different substituents in the 1,3-dione have limited influence on
the reactivities and enantioselectivities (eqn (3), Scheme 1).
According to the dual activation model,6 the two substrates
involved in the reaction are activated simultaneously by the
catalyst as shown in Fig. 2 (left). In this model, we predicted
the configuration of 3g to be S. The absolute configuration of
3g, which was determined by X-ray analysis, (Fig. 2, right, the
X-ray crystallographic data deposition number: CCDC
658642w) is in accordance with our prediction and the relative
structure anticipated from the catalytic mechanism.
9
10d
11e
a
Unless otherwise specified, the reaction was carried out with dione 1a
(3 eq.) and nitrostyrene 2a (0.1 mmol, 1 eq.) dissolved in solvent
(0.3 mL) in the presence of 15 mol% of catalyst at room temperature.
b
c
Isolated yields. Enantiomeric excess (ee) determined by chiral
d
e
HPLC analysis (Chiralpak AS-H). Reaction at 4 1C. 10 mol%
catalyst used.
Table 2 Michael addition of 1a and trans-nitroolefins catalyzed by
catalyst VIa
To examine the validity of recyclable homogenous organo-
catalysis, the reactions of 1a and nitroolefins (2a and 2g) in
diethyl ether were further studied as typical examples using
15 mol% catalyst VI (Fig. S4, in ESIw). Interestingly, the
Michael adducts’ very poor solubility in diethyl ether could be
used to separate organocatalyst VI from the product 3a or 3g
by simple filtration since it was precipitated from the reaction
solution. The recyclability of the catalyst was tested seven
times and amazingly, the catalyst kept its high efficiency,
giving almost quantitative yields (average 96%) and excellent
enantioselectivities in each cycle (Table 3) (also, see ESIw).
Based on this operationally simple product (precipitate)–
catalyst (soluble) separation, the pure product is isolated by
filtration from the reaction mixture when the reaction is complete
and the catalyst, which is kept in the filtrate, could be reused
directly for the next cycle. Hence, the strategy for recyclable
homogeneous organocatalysis was developed (Fig. S4w).
Entry
R
Product
t/h
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
8
12
16
16
12
8
96
92
91
94
93
96
97
92
91
91
88
92
86
98
97
93
99
4-OMe-Ph
3-OMe-Ph
2-OMe-Ph
4-Me-Ph
4-Br-Ph
98
499
499
97
98
97
96
94
94
4-Cl-Ph
8
2-Thienyl
2-Furyl
3-Furyl
1-Naphthyl
2-NO2-Ph
4-NO2-Ph
12
16
12
16
12
24
9
10
11
12
13
3j
3k
3l
3m
In summary, we have demonstrated the first example of a
highly enantioselective Michael addition reaction with a
simple organocatalyst VI. 9-Amino-9-deoxyepiquinine (VI)
has been successfully employed as a catalyst in the Michael
additions of 1,3-diaryl-1,3-propanedione to various nitro-
olefins, where the diketone is usually not a good donor. The
a
Unless otherwise specified, the reaction was carried out with dione 1a
(3 eq.) and nitrostyrene 2 (0.1 mmol, 1 eq.) dissolved in solvent
(0.3 mL) in the presence of 15 mol% of catalyst at room temperature.
b
c
Isolated yields. Enantiomeric excess (ee) determined by chiral
HPLC analysis.
exclusively in yields of 86–97% and excellent enantioselectivity
(up to 499%). The nitroolefins bearing either neutral
(Entries 1, 11), electron-donating (Entries 2–5), electron-
withdrawing (Entries 6–7, 12–13) or heterocyclics (Entries 8–10)
and containing a variety of substitution (para, meta and ortho)
patterns all participated in this reaction efficiently. It is
noteworthy that different functional groups on the benzene
ring did not affect the results (eqn (1), Scheme 1), and
substrate 2o displayed the great regioselectivity and enantio-
Fig. 2 Left: proposed action of catalyst; right: X-ray structure of 3g.
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This journal is The Royal Society of Chemistry 2009
780 | Chem. Commun., 2009, 779–781

Table 3 Recycling in the organocatalytic Michael addition of 1,3-
diphenyl-1,3-propanedione and trans-b-nitrostyrene with catalyst VIa
Tetrahedron Lett., 2004, 45, 9185; (d) H. Li, Y. Wang, L. Tang,
F. Wu, X. Liu, C. Guo, B. M. Foxman and L. Deng, Angew.
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A. Ikagawa, H. Wang, K. Murata and T. Ikariya, J. Am. Chem.
Soc., 2004, 126, 11148; (g) D. A. Evans and D. Seidel, J. Am.
Chem. Soc., 2005, 127, 9958; (h) J. M. Betancort and C. F. Barbas
III, Org. Lett., 2001, 3, 3737; (i) N. Mase, K. Watanabe, H. Yoda,
K. Takabe, F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc.,
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and A. Cordova, Adv. Synth. Catal., 2006, 348, 418;
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T. Constantieux and J. Rodriguez, Chem. Commun., 2008, 4207;
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Commun., 2008, 2923.
R = Ph (3a)
R = 4-Cl-Ph (3g)
t/h Yield (%)b Ee (%)c t/h Yield (%)b ee (%)c
Cycle
1
2
3
4
5
6
7
8
9
74
83
110
95
109
94
101
98
97
97
96
96
95
94
8
10
11
13
16
19
23
76
82
108
96
114
97
97
499
99
98
97
96
96
95
10
12
15
19
30
5 (a) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005,
44, 6367; (b) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun.,
2005, 4481; (c) B. Vakulya, S. Varga, A. Csampai and T. Soos,
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Org. Lett., 2005, 7, 1967; (d) B. Li, L. Jiang, M. Liu, Y. Chen,
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a
The reaction was carried out using 2a or 2g (0.1 mmol, 1 eq.) and
dione 1a (0.3 mmol, 3 eq.) with 15 mol % of VI in cycle 1 and in cycles
b
2–7 only 2a or 2g (0.1 mmol) and 1 (0.1 mmol) were added. Average
c
yield 96%. Determined by chiral HPLC analysis.
reactions proceeded smoothly at room temperature, giving
high to excellent yields (81–97%) and excellent enantio-
selectivities (90 to 499% ee). Exploiting the use of the
insolubility of the adduct, product (precipitate)–catalyst (soluble)
separation significantly simplified the separation and purifica-
tion process, and allowed the reaction to be recyclable. Such
reactions may be applicable to large scale industrial produc-
tion and thus greatly reduce the cost of catalyst preparation.
Research support from the Ministry of Education in
Singapore (ARC12/07, no. T206B3225) and Nanyang Techno-
logical University (URC, RG53/07 and SEP, RG140/06) is
gratefully acknowledged. We thank Dr Yongxin Li of
Nanyang Technological University for the X-ray crystallo-
graphic analysis.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 779–781 | 781