Novel heterobimetallic catalysts for asymmetric Michael reactions

Article abstract of DOI:10.1016/S0957-4166(02)00737-1

The newly developed chiral catalysts 1 and 2 show opposite enantioselectivity in Michael addition reactions of cyclic enones and malonates resulting in the production of both enantiomers of products in good chemical yield and enantiomeric excess. ^27<

Full text of DOI:10.1016/S0957-4166(02)00737-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 113–117
Novel heterobimetallic catalysts for asymmetric Michael
reactions
S. Velmathi,a S. Swarnalakshmib and S. Narasimhana,*
aT.R. Govindachari Centre for Natural Products, SPIC Science Foundation, 88, Mount Road, Guindy, Chennai 600 032, India
bDepartment of Chemistry, Guru Nanak College, Velachery, Chennai 600 042, India
Received 16 October 2002; accepted 31 October 2002
Abstract—The newly developed chiral catalysts 1 and 2 show opposite enantioselectivity in Michael addition reactions of cyclic
enones and malonates resulting in the production of both enantiomers of products in good chemical yield and enantiomeric
excess. 27Al NMR studies showed the formation of different types of complexes for catalysts 1 and 2 and the enantioselectivity
was found to be dependent on the nature of the aluminium complex formed. Scope of the reaction was extended to other Michael
donors such as nitro alkanes and thiols. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
amino acid esters by the previously reported proce-
dure.11a–c
Enantioselective 1,4-addition of active methylene com-
pounds to a,b-unsaturated compounds is one of the
fundamental reactions in organic synthesis for the for-
mation of optically active compounds.1a,b Hence, the
design of efficient chiral promoters for these processes
is of current interest. Catalytic asymmetric Michael
reactions have been extensively examined with chiral
amines,2a–c alkaloids,3a,b polymer bound alkaloids,4a–e
chiral crown ethers and bases,5 optically active Co(II)
complexes,6 natural proteins7 and amino alcohols8 act-
ing as catalysts. A breakthrough in catalytic asymmet-
ric Michael addition reaction was achieved with the
introduction of heterobimetallic catalysts. In a series of
reports Shibasaki et al.9a–e elaborated the utility of such
heterobimetallic catalysts of BINOL-La (Al)-alkali
metals which induced high enantioselectivities.
2. Results and discussion
Chiral ligands 1 and 2 reacted readily with LiAlH4 in
THF with the evolution of H2 resulting in the forma-
tion of heterobimetallic complexes with Al as the cen-
tral metal ion. Typically, reaction of cyclohexenone
with diethyl malonate was studied with the newly devel-
oped heterobimetallic complexes under different reac-
tion conditions and the results are presented in Table 1.
In the initial attempts the Michael reaction of 3 and 4
was performed with heterobimetallic catalysts 1a–d at
room temperature (entries 2, 5, 8 and 9). In all cases the
(S)-enantiomer was obtained in excellent yield with low
to satisfactory enantiomeric excess. The highest enan-
tioselectivity was observed for the complex prepared
from the ligand 1a and LiAlH4 in the ratio 1:1. How-
ever, the Al complex prepared from 1a and LiAlH4 in
the ratio 2:1 resulted in 55% ee (entry 1). Therefore,
other reaction parameters such as catalyst concentra-
tion and temperature were also studied to optimize the
reaction conditions. The influence of the amount of
catalyst on enantiomeric excess of the product was
tested (entries 2–7) and it was found that 20 mol% of 1a
was optimum. Also the reaction yields high ee only at
room temperature (entries 2 and 10) (Scheme 2).
We have already reported the syntheses of new chiral
ligands, which show novel enantiomer—switching
properties in asymmetric reductions of prochiral
ketones10 (Scheme 1). We report here our findings on
the asymmetric Michael addition reactions promoted
by the aluminate of amino ester and amino diol ligands.
The chiral ligands 1a–d and 2a–d were easily syn-
thesized from readily available salicylaldehyde and
Interestingly, when the Al complex, prepared from 2
and LiAlH4, was used the (R)-isomer was obtained
with 60% ee (entry 11) (Scheme 3).
* Corresponding author. Tel.: 91-044-235 1903; fax: 91-044-230 0586;
e-mail: narasim3 @hotmail.com, narasimhan s@yahoo.com
–
–
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00737-1

114
S. Velmathi et al. / Tetrahedron: Asymmetry 14 (2003) 113–117
Scheme 1.
Table 1. Enantioselective Michael addition of cyclohexenone and diethylmalonate catalysed by heterobimetallic complexesa
S. no
Ligand
L:LiAlH4 ratio
Reactants
Mol% Temp. (°C)
Time (h)
Yield (%)b
eec (%)
Abs. config.d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1c
1d
1a
2a
2:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
3 and 4
20
20
10
50
10
20
50
20
20
20
20
30
30
30
30
30
30
30
30
30
0
4
4
4
4
4
4
4
4
4
4
4
85
90
70
90
65
75
80
80
80
70
79
55.5
95e
65
S
S
S
S
S
S
S
S
–
81
13.5
22.5
25
17
0
9
10
11
47
60
S
R
30
a All reactions were performed in THF solvent.
b Isolated yield.
c Based on specific rotation values available in the literature Ref. 9.
d Determined by comparison of the sign of optical rotation values with those in the literature Ref. 9.
e Based on HPLC analysis using Chiralcel OD (see Section 4).
The results indicate that chiral switching is occurring
with cyclic enones and malonates, with 1a producing
the (S)- and 2a yielding the (R)-enantiomer. This
prompted us to study if there could be any change in
the nature of the Al complex produced under the
reaction conditions.
detailed 27Al NMR studies were carried out using
AlCl3·6H2O as external reference (l 0 ppm). Shibasaki
et al.9d have already utilised 27Al NMR to study the
interaction between enone and aluminium. They have
reported one broad signal at l 75 ppm for the BINOL-
Al–Li complex and upon addition of 3 equiv. of cyclo-
hexenone two additional signals were obtained at l 40
and l 23 ppm. The latter signal became stronger and
was a major peak under the conditions of the Michael
reaction. Similar studies were made with ligands 7 and
8 and the chemical shift values are given in Table 2.
Ligand 1 when used in a stoichiometric amount reacted
instantaneously with LiAlH4 liberating 2 equiv. of
hydrogen and the balance utilized for the reduction of
the ester group presumably resulting in 7. However,
when ligand 2 was used in the ratio of 2:1, 4 equiv. of
H2 was liberated instantaneously without participation
from the -NH group producing the conventional com-
plex 8 (Scheme 4).
2.1. 27Al NMR studies on Michael reaction
In order to explore the unique behavior of ‘enantiomer-
switching’ achieved with the two catalysts, 1a and 2a,
Scheme 2.

S. Velmathi et al. / Tetrahedron: Asymmetry 14 (2003) 113–117
115
Scheme 3.
Scheme 4.
Table 2. 27Al NMR values—a comparison with the other reported aluminium complexes
Ligand
Al complex (l ppm)
Al complex+enone (l ppm)
Al complex+enone+DEM* (l ppm)
7
0–5
+23
0–5
8
+36
+18
+36 and +18
–
BINOL-Al–Li
+759d
+40 and +23a
* Diethyl malonate.
a With 3 equiv. of enone.
In the case of ligand 8 the 27Al NMR value is similar to
BINOL based ligands, indicating the formation of a C2
symmetric complex, which is expected to produce the
(R)-enantiomer in asymmetric Michael addition
reactions.
a,b-unsaturated enones and enals (Scheme 5). The
results obtained are listed in Table 3.
The lower rigidity of acyclic a,b-unsaturated carbonyl
compounds accounts for the nucleophilic attack of the
enolate from both the faces (Re and Si ) thus resulting
in the racemic product. Even though Michael reactions
carried out with nitro alkanes gave racemic product,
the Michael adducts were formed in moderate yield of
60–75% in a short period of 10 h, when compared to
the existing catalysts which require 43–62 h for the
completion of the reaction.12 Similar to nitro alkanes,
even thiols gave racemic products when subjected to the
Michael reaction. In most cases the Michael adducts
were obtained in good yield in less than 2 min. How-
ever no enantioselectivity was achieved in these reac-
tions. The lower probability of sulfur coordinating to
However, the value for complex 7 shows an upfield
shift indicating considerable shielding of the Al atom.
This could be due to the p-stacking interaction between
the phenyl ring of the catalyst and the p-system of the
enone. Presumably this provides a stereochemically bet-
ter locking of the reactants resulting in higher ee.
Encouraged by the high enantioselectivity obtained in
the Michael addition of malonic esters to cyclic enones
the study was extended to Michael addition of malonic
esters, nitro alkanes and thiols to cyclic and acyclic
Scheme 5.

116
S. Velmathi et al. / Tetrahedron: Asymmetry 14 (2003) 113–117
Table 3. Michael additions of malonic esters, nitro alkanes and thiols to acyclic a,b-unsaturated enones and enals using
catalyst 7 or 8*
S. no
Enone
Malonate (R)
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
R%=R¦=Ph
R%=R¦=Ph
R%=R¦=Ph
R%=Ph, R¦=H
R%=Ph, R¦=H
R%=Ph, R¦=H
R%=CH3, R¦=H
R%=CH3, R¦=H
R%=CH3, R¦=H
Ethyl
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
6
7
5
7
8
7
4
5
3
70
65
75
75
70
72
80
70
75
Isopropyl
Benzyl
Ethyl
Isopropyl
Benzyl
Ethyl
Isopropyl
Benzyl
Nitro alkane
CH3NO2
CH3CH2NO2
CH3NO2
10
11
12
13
R%=R¦=Ph
R%=R¦=Ph
Cyclohexenone
Cyclohexenone
7 or 8
7 or 8
7 or 8
7 or 8
8
9
9
75
70
65
60
CH3CH2NO2
10
Thiols
14
15
16
17
18
19
20
21
22
R%=R¦=Ph
R%=R¦=Ph
R%=R¦=Ph
R%=Ph, R¦=H
R%=Ph, R¦=H
R%=CH3, R¦=H
R%=CH3, R¦=H
Cyclohexenone
Cyclohexenone
C6H5SH
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
7 or 8
2
2
30
5
5
3
3
1
2
90
88
95
770
65
80
75
92
90
CH3-C6H4SH
CH3COSH
C6H5SH
CH3-C6H4SH
C6H5SH
CH3-C6H4SH
C6H5SH
CH3-C6H4SH
* All the products were characterized through 1H and 13C NMR spectroscopy.
lithium (hard and soft acid base principle) allows only
weak coordination between them, leaving a very reac-
tive sulfur anion to attack the stacked enone from both
the faces, resulting in racemic product. This also
accounts for the much less reaction time (30 s–5 min/
rt).
mg, 5 mmol) and diethyl malonate (800 mg, 5 mmol)
were added. The mixture was stirred for 4 h. The
reaction was quenched with 1N HCl and the mixture
was extracted with ethyl acetate (3×10 mL). The
organic layer was washed successively with saturated
NaHCO3 solution and water and dried over anhydrous
Na2SO4. Removal of the solvent under reduced pres-
sure gave a syrupy mass which on flash column chro-
matography gave the product as a colourless oil (1.1 g,
90% yield [h]D −2.86 (c=5 in CHCl3).
3. Conclusion
In conclusion, we have developed new heterobimetallic
complexes, which show novel enantiomer switching
behavior in the asymmetric Michael addition reactions
of cyclic enones with dialkyl malonates resulting in the
production of both enantiomers with excellent enan-
tioselectivity. The ligands also promote 1,4-Michael
additions of nitro alkanes and thio phenols to acyclic
enones and enals but resulted in no enantioselectivity.
Thus, complexes 7 and 8 are excellent chiral catalysts
for asymmetric Michael addition reactions of malonate
derivatives.
HPLC analyses were carried out using a Chiralcel OD
column with hexane/isopropanol (99:1) as eluent (flow
rate 0.5 ml/min, UV detection u 230 nm: retention time
for the (R)-enantiomer 14.9 min and retention time for
the (S)-enantiomer 15.9 min).
Acknowledgements
One of the authors S.V. thanks CSIR for financial
assistance and S.S. thanks Department of Chemistry,
Guru Nanak College for their support.
4. Experimental
4.1. General experimental procedure for Michael addi-
tion reaction
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