Heterogeneous J?rgensen–Hayashi catalyst for asymmetric Michael addition of malonates to α,β-enals. Cooperative effect with Ca(OTf)2

Article abstract of DOI:10.1016/j.mencom.2016.11.002

Heterogeneous chiral J?rgensen–Hayashi catalyst promotes enantioselective Michael addition of malonates at cinnamic aldehydes. In combination with Ca(OTf)₂, it provides high yields (up to 78%) and excellent enantiomeric excesses (up to 99%) of

Full text of DOI:10.1016/j.mencom.2016.11.002

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 469–470
Heterogeneous Jørgensen–Hayashi catalyst for asymmetric Michael
addition of malonates to a,b-enals. Cooperative effect with Ca(OTf)2
Anton A. Guryev, Maksim V. Anokhin, Alexei D. Averin and Irina P. Beletskaya*
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 1139; e-mail: beletska@org.chem.msu.ru
DOI: 10.1016/j.mencom.2016.11.002
O
N
N
CF3
N
Heterogeneous chiral Jørgensen–Hayashi catalyst promotes
enantioselective Michael addition of malonates at cinnamic
aldehydes. In combination with Ca(OTf)2, it provides high
yields (up to 78%) and excellent enantiomeric excesses (up to
99%) of the adducts.
O
O
PS
CF3
N
H
OTMS
CF3
F3C
O
O
Ar
Ar
20 mol%
+
Ca(OTf)2, 100 mol%
CH2Cl2
HC(CO2R)2
CH2(CO2R)2
Jørgensen-Hayashi catalyst I of diarylprolinol silyl ether chemo-
type1,2 (Figure 1) belongs to privileged organocatalysts which
provide high yields and enantioselectivity via enamine or iminium
ion activation in such fundamental transformations as aldol
condensation, Mannich, Michael and Diels–Alder reactions.3,4
Organocatalytic enantioselective addition of malonates to aromatic
a,b-enals is a key step in the synthesis of vital medicaments
Paroxetin and Femoxetin.5 However, to achieve high yields and
excellent enantiomeric purity of these products, catalysts are
used in substoichiometric amounts (ca. 20 mol%). Application of
immobilized analogues of these catalysts simplifies the product
separation from catalysts by simple filtration and enables repeated
use of the catalyst, which significantly improves efficiency of the
process (TON). Immobilization of a,a-diarylprolinol trimethyl-
silyl ethers was described by a number of authors and was
studied in aldol condensation and Michael addition reactions.6–14
However, often enantiomeric excess was poor and recyclization
was problematic. Previously we synthesized an easily recoverable
heterogeneous bis[3,5-bis(trifluoromethyl)phenyl]prolinolsilyl
ether immobilized onto polystyrene and demonstrated its satis-
factory catalytic activity in the a-amination of aliphatic aldehydes
via enamine substrate activation in 5 cycles.15 In this work we
extended its application for the reactions proceeding via iminium
ion activation using an exemplary malonate addition to a,b-enals.
The model reaction of dimethyl malonate (R = Me) with
cinnamic aldehyde (Ar = Ph)5,16–25 (Scheme 1) was carried out
in the presence of 20 mol% a,a-bis[3,5-bis(trifluoromethyl)
phenyl]prolinol trimethylsilyl ether immobilized onto polystyrene
(catalyst II, Figure 1).
O
CO2R
Ar
O
Ar
+
CO2R
RO2C
CO2R
Scheme 1
This reaction is known to proceed in EtOH in the presence of
the homogeneous catalyst I to give the product in 85% yield with
95% ee (Table 1, entry 1).5 Under analogous conditions in the
presence of the heterogeneous catalyst II, the same reaction did
not occur at all (Table 1, entry 2). We have chosen CH2Cl2 among
the solvents promoting the swelling of the polymeric support,
but the reaction did not occur as well (Table 1, entry 3). It is
known that the addition of malonates to aldehydes is accelerated
in the presence of lithium salts26 without loss of enantioselectivity,
however, in our case the addition of lithium acetate was inefficient
(Table 2, entry 4).
CF3
CF3
N
H
OTMS
CF3
F3C
Jørgensen–Hayashi organocatalyst I
O
Table 1 Optimization of addition of dimethyl malonate CH2(CO2Me)2 at
cinnamic aldehyde PhCH=CHCHO (catalyst, 20 mol%, 36 h).
N
N
CF3
N
Isolated
yield (%)
eea (%)
O
O
Entry Catalyst
Additive (mol%) Solvent
PS
CF3
1
2
3
4
5
6
Catalyst I
Catalyst II
Catalyst II
–
–
–
EtOH
855
95
–
N
H
OTMS
b
EtOH
–
b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
–
b
Catalyst II LiOAc (20)
Catalyst II Ca(OTf)2 (20)
Catalyst II Ca(OTf)2 (100)
–
–
CF3
F3C
56
62
85
86
Heterogeneous Jørgensen–Hayashi organocatalyst II
a By chiral HPLC. b Conversion 0% by 1H NMR.
Figure 1
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 469–470
Table 2 Addition of malonates at cinnamic aldehydes [see Scheme 1;
catalyst II (20 mol%), Ca(OTf)2 (100 mol%), CH2Cl2, 72 h].
malonates to a,b-enals in good yields and with good to high
(up to 99% ee) enantioselectivity. Heterogeneous catalyst can be
easily removed by filtration.
Entry
Ar
R
Isolated yield (%)
eea (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Me
Et
62
44
78
10
51
61
68
74
76
65
59
86
86
92
28
77
77
89
85
99
53
90
This work was supported by the Russian Science Foundation
(grant no. 14-23-00186).
Bn
Me
Bn
Me
Et
Bn
Bn
Bn
Me
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-O2NC6H4
2-O2NC6H4
2-O2NC6H4
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†
Addition of malonates to a,b-enals. A mixture of appropriate aldehyde
(0.6 mmol), malonate (0.3 mmol), additive (see Tables 1 and 2), catalyst II
(obtained according to described procedure,15 80 mg, 0.06 mmol) in
CH2Cl2 (1 ml) was stirred at room temperature for 72 h. After terminating
the reaction, the mixture was filtered to separate the catalyst. The catalyst
was washed with THF (5 ml), MeOH (5 ml) and THF (5 ml). The com-
bined organic extracts were concentrated and the residue was chromato-
graphed on silica gel using EtOAc in light petroleum.All analytical data of
prepared Michael adducts (see Table 2) are consistent with those described
in literature.16,18,19,28
Received: 14th June 2016; Com. 16/4956
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