Enantioselective addition of diethyl malonate to ω-nitrostyrenes in the presence of cobalt and manganese complexes with N,N′-dibenzyl-(1S,2S)- cyclohexane-1,2-diamine

Article abstract of DOI:10.1134/S1070363212110163

Enantioselective addition of diethyl malonate to nitrostyrene and para-chloronitrostyrene is catalyzed by cobalt and manganese complexes with N,N′-dibenzyl-(1S,2S)-cyclohexane-1,2-diamine generated in situ. Enantiomeric excess of the (R)-isomers in the re

Full text of DOI:10.1134/S1070363212110163

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 11, pp. 1827–1829. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.N. Reznikov, E.V. Golovin, Yu.N. Klimochkin, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 11, pp. 1837–
1
839.
Enantioselective Addition of Diethyl Malonate
to ω-Nitrostyrenes in the Presence of Cobalt
and Manganese Complexes
with N,N'-Dibenzyl-(1S,2S)-cyclohexane-1,2-diamine
A. N. Reznikov, E. V. Golovin, and Yu. N. Klimochkin
Samara State Technical University, ul. Molodogvardeiskaya 244, Samara, 443100 Russia
e-mail: orgphosphorus@yandex.ru
Received October 20, 2011
Abstract—Enantioselective addition of diethyl malonate to nitrostyrene and para-chloronitrostyrene is
catalyzed by cobalt and manganese complexes with N,N'-dibenzyl-(1S,2S)-cyclohexane-1,2-diamine generated
in situ. Enantiomeric excess of the (R)-isomers in the reaction products is 66–87%.
DOI: 10.1134/S1070363212110163
Enantioselective addition of diethyl malonate to ω-
high enantiomeric excesses in adducts [9]. However,
the requirement of high concentrations of catalyst (5–
20 mol %) and their synthetic inaccessibility limit the
possibility of practical application of this method. It
was shown [10] that the Ni(II) complexes with chiral
ligands based on trans-(1R,2R)-cyclohexane-1,2-
diamine are effective catalysts for the addition of some
1,3-dicarbonyl derivatives to nitroalkenes. The assumed
mechanism involved the formation of the Ni(II)
complex of acetylacetonate type, followed by intra-
coordination nucleophilic attack of the acetylacetonate
ligand on the multiple bond of the nitroalkene. Evans
et al. examined the effect of the nature of the 1,3-
dicarbonyl compound and unsaturated substrate on the
reaction rate and enantioselectivity. However, the
scope of catalysts reviewed in [10] is limited to
complexes of Ni(II) and there is no information on the
impact of the metal nature on the catalytic properties
of the metal complexes. The central role of the
transition metal in the catalytic activation of 1,3-
dicarbonyl compounds determines the interest in the
study of its effect on the catalytic properties in the
reactions of nitrostyrene with diethylmalonate.
nitrostyrene is a convenient approach to the synthesis
of key intermediates in producing neurotrophic agents
(
R)-phenotropil, (R)-phenibut, (R)-baclofen, and (R)-
rolipram [1, 2]. Although at present these
pharmaceuticals are produced in racemic form, it was
found that the neurotropic activity is exhibited by the
(
R)-enantiomers, whereas the (S)-enantiomers are
inactive [3].
The methods of synthesis of individual enan-
tiomers described in the literature are based mainly on
the separation of racemic mixtures of proper pharma-
ceutical substances or of their synthetic precursors [4–
6
]. A number of chemoenzymatic [7] and enantio-
selective syntheses of the (R)-phenibut and (R)-
baclofen [8] preparations has been developed. Ho-
wever, these methods have several major drawbacks:
low overall yields of desired products, the need for
separation of the diastereomeric intermediates, the use
of an expensive chiral auxiliary reagent in stoi-
chiometric amount. Therefore it is still relevant to
develop more cost-effective approaches to the synt-
hesis of enantiomerically pure derivatives of γ-amino-
butyric acid.
We found that cobalt and manganese complexes
with N,N'-dibenzyl-(1S,2S)-cyclohexane-1,2-diamine
(I), generated in situ from the corresponding metal
halide hydrates and the chiral diamine are enantio-
selective catalysts in the reaction of nitrostyrene IIa
Since recently the methods became widespread of
enantioselective organocatalysis for the enantioselec-
tive addition of various Michael donors to α,β-
unsaturated nitro derivatives, which allowed obtaining
1
827

1
828
REZNIKOV et al.
and para-chlornitrostyrene IIb with diethylmalonate
III.
plexes obtained with the ratio of metal/ligand = 1/1
proved to be inactive in the reaction.
The acido ligand nature affects significantly the
catalytic properties of complexes. The manganese acetate
complexes showed no catalytic activity. The catalytic
activities and enantioselectivities of the cobalt chloride
and bromide complexes in this reaction are similar.
NH
NH
Thus, the highest enantioselectivity in the addition
reactions of diethylmalonate to nitrostyrene and p-
chloronitrostyrene is achieved at the catalysis with the
cobalt complexes; the use of the diamine (S,S)-isomer
as a ligand leads to a product of (R)-configuration both
in the case of complexes of cobalt and manganese.
I
EtOOC
R
COOEt
NO2
COOEt
kt
R
+
NO2
EXPERIMENTAL
COOEt
III
IIa, IIb
IVa, IVb
General procedure for the study of the reaction
of α,β-unsaturated nitro derivatives (IIa, IIb) with
diethylmalonate. All operations were performed in an
argon atmosphere. To 0.432 mmol of N,N'-dibenzyl-
(1S,2S)-cyclohexane-1,2-diamine I and 0.144 mmol of
cobalt(II) chloride hexahydrate or manganese(II)
chloride tetrahydrate was added 1.44 ml of diethyl
malonate III, and the mixture was stirred until the
formation of a homogeneous solution. The resulting
II, IVa: R = Ph; II, IVb: R = p-Cl-Ph.
The results of these studies are summarized in the
table.
With the cobalt complex the enantiomeric excess of
target (R)-nitroesters IVa, IVb reaches 87.0%,
whereas the catalysis with manganese complex leads
to (R)-(IVa, IVb) with the enantiomeric excess up to
0
.1 M of the catalyst solution in diethylmalonate
(
0.20 ml, 1.30 mmol of diethylmalonate) was added to
7
9.0%.
a solution of 1 mmol of compound IIa or IIb in 3.75 ml
of toluene. The reaction mixture was kept at a
temperature of 20◦C. The conversion (with respect to
The investigation of the effect of metal/ligand ratio
on the catalytic properties of metal complexes obtained
in situ (see the table) showed that among the cobalt
complexes the maximum activity is reached at a ratio
of 1/2, while further addition of ligand does not
significantly change the catalyst properties. The com-
1
the nitro derivative IIa, IIb) was determined from H
NMR data. Compounds IVa, IVb were isolated by
chromatography on silica gel Kieselgel 60 (0.063–
0.100 mm, Merck), eluent chloroform.
Catalytic properties of the generated in situ cobalt and manganese complexes in the reaction of nitroalkenes IIa, IIb with
diethyl malonate
Concentration of
catalyst, mol %
Reaction time,
h
Conversion of
nitroalkene,%
(R)-IVа, IVb,
% ее
Catalyst
[M]:L
Substrate
CoCl
CoCl
CoCl
CoCl
CoCl
2
2
2
2
2
·6H
·6H
·6H
·6H
·6H
2
2
2
2
2
O + I
O + I
O + I
O + I
O + I
1:2
1:2
1:1
1:2
1:3
1:2
1:3
1:3
1:3
2
IIa
IIb
IIa
IIa
IIa
IIa
IIa
IIb
IIb
41
96
91.0
100
0
86.2
87.0
–
2
0.2
0.2
0.2
0.2
2
108
108
108
108
16
32.0
35.0
34.3
99.7
85.7
0
86.0
81.3
86.7
66.0
79.0
–
CoBr
2
+ I
·4H
·4H
MnCl
MnCl
2
2
2
O + I
O + I
+ I
2
2
96
Mn(OAc)
2
2
16
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

ENANTIOSELECTIVE ADDITION OF DIETHYL MALONATE
1829
Diethyl (R)-(2-nitro-1-phenylethyl)malonate (IVa).
Determination of the specific rotation angles was
carried out on a Rudolph Research Analytical polarimeter.
3
0
–1
Yield 90.3%, [α] –6.62° (c 0.015 g ml , CHCl ),
D
3
3
0
(
[α] –6.00°, c 1.0, CHCl , for a product with ee 93%
D
3
1
13
ACKNOWLEDGMENTS
according to [1]). The H and C NMR spectra
correspond to the published data [1]. Mass spectrum,
+
This work was financially supported by the Federal
Program “Research and development of priority
directions of scientific-technological complex of
Russia for 2007–2013 years,” a government contract of
February 18, 2011, no. 16.512.11.2011. We used
scientific instruments of the Center for collective use
of Samara Technical University “Investigation of
physical and chemical properties of substances and
materials.”
m/z (I ): 309 [M] , 263 (12), 218 (12), 190 (13), 189
rel.
(
(
9
100), 171 (58), 161 (56), 145 (30) , 133 (22), 131
20), 117 (28), 115 (70), 105 (15), 104 (55), 103 (34),
1 (26), 78 (15), 77 (20) .
Diethyl (R)-[2-nitro-1-(4-chlorophenyl)ethyl]malo-
2
0
–1
nate (IVb). Yield 87.2%, [α] –7.45° (с 0.015 g ml ,
D
2
5
CHCl ) ([α] –8.56°, CHCl for the product with ee >
3
D
3
1
13
9
9% according to [1]). The H, C NMR spectra of the
product correspond to the published data [1]. Mass
+
spectrum, m/z (I ): 343 [M] , 297 (10), 252 (7), 225
REFERENCES
rel.
(
(
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22), 138 (58), 115 (75), 103 (24), 89 (7), 77 (15).
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012