Asymmetric Michael addition of malonates to enones catalyzed by nanocrystalline MgO

Article abstract of DOI:10.1016/j.tetlet.2007.08.108

Highly enantioselective Michael addition of malonates to cyclic and acyclic enones has been achieved by using nanocrystalline magnesium oxide at -20 °C.

Full text of DOI:10.1016/j.tetlet.2007.08.108

Tetrahedron Letters 48 (2007) 7646–7649
Asymmetric Michael addition of malonates to enones
catalyzed by nanocrystalline MgO
M. Lakshmi Kantam,a,* Kalluri V. S. Ranganath,a Koosam Mahendar,a
Lakkoju Chakrapania and B. M. Choudaryb
aInorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bOgene Systems(I) Pvt. Ltd, 11-6-56, GSR Estates, Moosapet, Hyderabad, India
Received 23 May 2007; revised 18 August 2007; accepted 30 August 2007
Available online 4 September 2007
Abstract—Highly enantioselective Michael addition of malonates to cyclic and acyclic enones has been achieved by using nanocrys-
talline magnesium oxide at ꢀ20 °C.
Ó 2007 Elsevier Ltd. All rights reserved.
Michael addition is one of the most important C–C
bond-forming reactions in organic chemistry.1 The cata-
lytic asymmetric Michael (AM) reaction of malonates to
enones, in which asymmetric induction occurs at the
b-position of the enone, is an important organic trans-
formation and the resultant compounds have been used
in the synthesis of several natural products and drug
molecules.2,3 These reactions are reported in homo-
geneous media using in situ prepared heterobimetallic
complexes,4 ruthenium, copper, cobalt, rhodium and
palladium derived catalysts5 and phase transfer or
organocatalysts6,7 with moderate to excellent ees.
Proline and its rubidium salts were successfully used in
asymmetric Michael addition reactions between enones
and various nucleophiles.8 Chiral polymers were pre-
pared and applied successfully in asymmetric Michael
addition reactions.9 Although impressive results have
been achieved in many asymmetric reactions, reports
on enantioselective Michael addition reactions with
excellent ees have been limited mostly to cyclic sub-
strates or the yields of the products are very low.9a,10
considered to be suitable candidates for proper align-
ment with prochiral substrates for unidirectional intro-
duction of reacting species to induce asymmetry.
Recently, we have reported asymmetric Henry, Michael,
and epoxidation reactions using heterogeneous nano-
crystalline MgO.12a,b The asymmetric Michael addition
of acyclic enones with various nitroalkanes in the pres-
ence of (1R,2R)-(ꢀ)-1,2-diaminocyclohexane using
heterogeneous nanocrystalline MgO has been carried
out.12b
Herein, we report the AM addition of malonates to cyc-
lic and acyclic enones to afford Michael adducts in good
to excellent yields and ees using nanocrystalline MgO as
catalyst in the presence of the chiral auxiliary (1R,2R)-
(+)-1,2-diphenyl-1,2-ethylenediamine (DPED) (Scheme
1). This method provides an easy synthetic route to opti-
cally active keto esters.
The applications of simple MgO (CM-MgO) as a basic
catalyst in liquid phase reactions have been very
Nanocrystalline metal oxides find excellent applications
as active adsorbents for gases, for the destruction of haz-
ardous chemicals, and as catalysts for various organic
transformations.11,12 Nanomaterials with their three-
dimensional structure and defined size and shape are
RO2C
CO2R
R=CH3, C2H5,
Bn
O
O
O
Ph
Ph
*
Ph
Ph
H2C(COOR)2, NAP-MgO
Chiral auxiliary, THF, -20 ºC
R=CH3, C2H5
O
( )n
*
( )
CO2R
n
RO2C
Keywords: Asymmetric Michael; Malonates; Nanocrystalline MgO.
*
Scheme 1. AM addition between malonates and enones catalyzed by
Corresponding author. Tel.: +91 40 27193510; fax: +91 40
NAP-MgO in the presence of Chiral auxiliary.
27160921; e-mail: mlakshmi@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.108

M. L. Kantam et al. / Tetrahedron Letters 48 (2007) 7646–7649
7647
limited.13 Various forms of MgO crystals, NAP-MgO
(NanoActive Plus MgO, aerogel prepared MgO, SA:
600 m2/g), NA-MgO (NanoActive MgO, conventionally
prepared MgO, SA: 250 m2/g), and CM-MgO (Com-
mercial MgO, SA: 25 m2/g), were initially evaluated
for the AM reaction between chalcone and dimethyl
malonate (DMM). None of these showed any activity.
When we used various chiral amine ligands to induce
the reaction and enantioselectivity, the Michael product
was obtained in good yields and ees because of their
high nucleophilicity. We also tested the reaction with
(S)-Binol and (+)-DET ligands, and there was no reac-
tion, but they gave the best ee in the asymmetric Henry
and epoxidation reactions.12a,b
Table 2. AM reaction between chalcone and malonates catalyzed by
NAP-MgO in the presence of the chiral auxiliary DPED at ꢀ20 °C21
RO2C
CO2R
H2C(COOR)2, NAP-MgO
DPED, THF, -20 ºC
O
O
Ph
Ph
Ph
Ph
*
R=CH3, C2H5,
Bn
Entry
R
Time (h)
Yielda (%)
eeb (%)
1
2
3
CH3
C2H5
Bn
12, 12c, 12d
15
18
93, 90,c 0d
95
92
82, 70,c 0d
76
85
Reaction conditions: chalcone (1.0 mmol), malonate (5.0 mmol), NAP-
MgO (0.125 g), dry THF (5 mL). In all cases 25 mol % of ligand was
used.
a Isolated yields.
b Ee was determined by HPLC analysis using a Chiralcel AS column
(2-propanol–hexane (1:9), 1.2 mL/min, kmax = 254 nm for entry 1
and Chiralcel AD column for entries 2 and 3).
c At 0 °C.
The reaction with various primary, secondary, cyclic
and acylic amines is described in Table 1. Among them
(1R,2R)-(+)-1,2-diphenyl-1,2-ethylenediamine (DPED)
proved to be the best ligand. The AM reaction between
chalcone and dimethyl malonate was studied initially.
Among the MgO samples screened in the AM reaction
of chalcone and dimethyl malonate using DPED as chi-
ral auxiliary at 25 °C, NAP-MgO was found to be supe-
rior to NA-MgO and CM-MgO in terms of yields and
ees. Whereas the AM reaction between chalcone and
dimethyl malonate in the presence of either NAP-MgO
or chiral auxiliary alone showed no catalytic activity
individually (Tables 1 and 2, entry 1). In an attempt to
optimize the AM reaction, the effect of temperature
was studied. NAP-MgO, using DPED as chiral auxiliary
in THF at ꢀ20 °C, was found to be the best system.
With NAP-MgO, the rate of the reaction was faster in
the presence of a chiral auxiliary. These results are in
consonance with the earlier reported ligand acceleration
effects which include metal-diamine accelerated Michael
reactions.14 In general, chiral bidentate systems compos-
ing of primary and secondary amines afforded better ees,
while chelation with COOH or OH displayed no ees
(Table 1). The nature of the ester group of the malonate
affected the ee of the product. As the bulkiness of the
ester group increased, the rate of reaction decreased with
an increase in ee (Table 2).
d Without DPED.
nates. The rate of the reaction was slower with cyclic
enones than with acyclic enones. As the ring size
increased, the rate of reaction decreased but with an
increase in ee (Table 3). The ee was found to be higher
with cyclic enones than with acyclic enones. This may
be due to the rigidity of the cyclic systems (Tables 2
and 3).
To understand the relationship between structure and
reactivity in the AM reaction, it is important to know
the structure and nature of the reactive sites of NAP-
MgO. The rationale for the selection of nanocrystalline
MgO is NAP-MgO has a three-dimensional polyhedral
structure, which has high surface concentrations of
edge/corner and various exposed crystal planes (such
as 002, 001, 111), leading to inherently high surface reac-
tivity per unit area. Thus, NAP-MgO displayed the
highest activity compared to NA-MgO and CM-MgO.
Besides this, NAP-MgO has a Lewis acid site, Mg2+
,
Lewis basic sites, O2ꢀ and Oꢀ, lattice bound and iso-
lated Bronsted hydroxyls, and anionic and cationic
vacancies.15 The Michael reaction is known to be driven
by basic catalysts,16 and accordingly, the surface OH
and O2ꢀ of these oxide crystals are expected to trigger
Encouraged by these results, the AM reaction was also
extended to various cyclic enones with different malo-
Table 1. Effect of ligand on the AM reaction between chalcone and dimethyl malonate catalyzed by NAP-MgO at 25 °C
Entry
Ligand
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
(1R,2R)-(+)-1,2-Diphenylethylene diamine
(1R,2R)-(ꢀ)-1,2-Diaminocyclohexane
(1S,2R)-(+)-2-Amino-1,2-diphenylethanol
(1R,2S)-(ꢀ)-N-Methyl ephedrine
(S)-(ꢀ)-1,10-Binaphthyl-2,20-diamine
(L)-Proline
8, 14,c 24,d 12,e 8,f 12g
8
12
12
12
15
12
91, 64,c 30,d 60,e 89,f 0g
95
89
88
60, 42,c 10,d 60e, 60,f 0g
52
50
51
60
—
72
90
No reaction
30
(L)-Proline methyl ester
Reaction conditions: chalcone (1.0 mmol), malonate (5.0 mmol), NAP-MgO (0.125 g), dry THF (5 mL). In all cases 25 mol % of ligand was used.
a Isolated yields.
b Ee was determined by HPLC analysis using a Chiralcel AS column (2-propanol–hexane (1:9), 1.2 mL/min, kmax = 254 nm).
c With NA-MgO.
d With CM-MgO.
e With silylated NAP-MgO.
f Fifth cycle.
g Without NAP-MgO.

7648
M. L. Kantam et al. / Tetrahedron Letters 48 (2007) 7646–7649
Table 3. AM reaction between various cyclic enones and malonates
catalyzed by NAP-MgO in the presence of the chiral auxiliary DPED
at ꢀ20 °C21
The AM reaction proceeds via dual activation of both
substrates (nucleophiles and electrophiles) by NAP-
MgO. Thus, the Lewis base (O2ꢀ/Oꢀ) of the catalyst
activates the malonates and the Lewis acid moiety
(Mg2+/Mg+) activates the carbonyls of the enones and
the chiral auxiliary. Such dual activation is essential to
promote the reaction with prochiral substrates under
mild conditions with complete stereoselectivity.19 Simi-
larly, the Lewis acid-Bronsted base dichotomy is well
known in enzyme catalyzed enantioselective aldol reac-
tions between dihydroxyacetone phosphate and various
aldehydes.20
O
O
H2C(COOR)2, NAP-MgO
DPED, THF, -20 ºC
( )
( )
*
n
n
CO2R
RO2C
Entry
n
R
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
1
1
2
2
3
3
Me
Et
Me
Et
Me
Et
12
12
16
16
24
24
94
93
95
90
96
90
84
86
90
90
94
96
The NAP-MgO was reused for five cycles with consis-
tent activity. After completion of the reaction, the recov-
ered catalyst was washed properly and activated at
250 °C for 1 h under a nitrogen atmosphere. The crystal
morphology of reused NAP-MgO was unchanged as
indicated by XRD.
Reaction conditions: enone (1.0 mmol), malonate (5.0 mmol), NAP-
MgO (0.125 g), dry THF (5 mL). In all cases 25 mol % of ligand was
used.
a Isolated yields.
b Ee was determined by HPLC analysis using a Chiralcel AS column
(2-propanol–hexane (1:9), 0.5 mL/min, kmax = 210 nm).
To conclude, highly enantioselective Michael addition
of malonates to cyclic and acyclic enones has been
achieved by using nanocrystalline magnesium oxide.
the reaction. To examine the role of OH, Sil- NAP-MgO
devoid of free OH was tested in AM reactions. It was
found that OH groups did not influence the enantio-
selectivity. However, the rate of reaction was slow,
and a longer reaction time was required (Table 1, entry
1). Although both NAP-MgO and NA-MgO possess
defined shapes and the same average concentrations of
surface OH groups, a possible rationale for the display
of a higher rate by NAP-MgO is the presence of more
surface Mg2+(Lewis acid) ions (20%).17 These Mg2+ ions
(Lewis acid) of NAP-MgO and basic chiral auxiliary
have acid-base interactions and these interactions may
be responsible for the induction of enantioselectivity.
Acknowledgments
K.M. and L.C. thank CSIR for providing fellowships.
Nanocrystalline MgO samples were obtained from
Nano Scale Materials Inc., Manhattan, Kansas, USA.
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21. General procedure for the asymmetric Michael addition
between enones and malonates: a mixture of dimethyl
malonate (5.0 mmol, 660.5 mg), ligand (0.25 mmol,
53.0 mg) and NAP-MgO (0.125 g) was introduced into a
50 mL round bottomed flask containing dry THF
(5.0 mL) at ꢀ20 °C and the reaction mixture was stirred
for 1 h under nitrogen. To the reaction mixture, chalcone
(1 mmol, 208 mg) in THF (1.0 mL) was added at the same
temperature. After completion of the reaction (monitored
by TLC), the reaction mixture was centrifuged to separate
the catalyst and the latter was washed several times with
ethyl acetate. The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced
pressure. After purification by flash chromatography on
silica gel (100–200 mesh) using ethyl acetate in hexane
(2:8), the Michael adduct was obtained as a colourless
1
solid. H NMR (CDCl3) d 3.51 (s, 3H), 3.52 (dd, J = 5.3,
7.8 Hz, 1H), 3.71 (d, J = 5.5 Hz, 1H), 3.73 (s, 3H), 3.86 (d,
J = 9.2 Hz, 1H), 4.20 (dt, J = 5.3, 9.4 Hz, 1H), 7.17–7.56
(m, 8H), 7.88–7.91 (d, J = 12 Hz 2H). m/z (ESI-MS) 341
(M+1)+ ee was measured by using HPLC analysis
(DAICEL CHIRAL PAK AS column) i-PrOH–hexane:
1:9, tR: 18.2 min and 26.4 min. The reusability of the
catalyst was assessed as follows using the experimental
conditions described above, the catalyst was washed
several times with ethyl acetate and activated at 250 °C
for 1 h under nitrogen. Then the catalyst was reused for
five cycles with consistent activity.
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