Heterogeneous enantioselective catalyzed carbonyl- and imino-ene reactions using copper bis(oxazoline) zeolite Y

Article abstract of DOI:10.1002/anie.200352534

A recovery discovery: A simple pathway for the synthesis of α-hydroxy and α-amino carbonyl compounds with good yields and high enantioselection is provided by the first heterogeneously catalyzed enantioselective carbonyl-ene and imino-ene reactions. The c

Full text of DOI:10.1002/anie.200352534

Angewandte
Chemie
the reaction was widened to the use of 1,1-disubstituted
alkenes with titanium–binol (binol = 2,2'-dihydroxy-1,1'-
[
3]
binaphthyl) homogeneous catalysts. Recently, interest has
focused on the use of soluble copper(ii) bis(oxazoline)
complexes as catalysts for the reaction of a range of glyoxylate
and pyruvate esters and substituted alkenes to generate a-
hydroxy carbonyl compounds in high yields and with high
[
4a]
ee values. In contrast, there is only a single example of a
homogeneously catalyzed imino-ene reaction involving
copper binap (binap = [1,1’-binaphthalene]-2,2’-diylbis(di-
[
5]
phenylphospane)) complexes. These catalysts and processes
remain, however, limited in their economic efficiency because
of the inability to recover the catalysts from the reaction
medium. Previously, bis(oxazoline) bound to soluble poly-
(ethylene glycol) has been used to generate a recyclable catalyst
which is recovered by precipitation at the end of each reaction
[6]
cycle, but the enantioselection decreased with each reuse.
Herein, we present the first heterogeneously catalyzed,
efficient enantioselective carbonyl- and imino-ene reactions
using a readily recyclable catalyst. Our approach to designing
highly enantioselective heterogeneous catalysts uses electro-
static immobilization of cations within zeolites and mesopo-
rous materials. Previously, we have shown that heterogeneous
catalysts for the enantioselective aziridination of alkenes, with
[
7]
ee ꢀ 95%, can be designed on this basis. In addition, we
have shown that the copper bis(oxazoline) complex, when
[
8]
constrained within the zeolite structure, gives substantially
[
7,9]
higher enantioselection than the homogeneous catalysts.
Similar effects have been noted for other immobilized
Immobilized Catalysts
[
10]
catalysts. We have now found that bis(oxazoline)-modified
CuH zeolite Y catalysts are extremely effective catalysts for
asymmetric carbonyl- and imino-ene reactions and, further-
more, these catalysts can be readily recovered and reused
without loss of catalyst performance.
Heterogeneous Enantioselective Catalyzed
Carbonyl- and Imino-Ene Reactions using
Copper Bis(Oxazoline) Zeolite Y**
The reaction of ethyl glyoxylate with a range of alkenes
has been investigated using the immobilized copper–zeolite Y
Neil A. Caplan, Frederick E. Hancock,
Philip C. Bulman Page, and Graham J. Hutchings*
(Cu-HY) bis(oxazoline) catalyst and the results are shown in
Table 1. In the absence of the bis(oxazoline), negligible
reaction was observed. The results show that the reactions
proceed with good yields and, in many cases, high enantio-
selection. Interestingly, the use of (S,S)-2 as the ligand with a-
methylstyrene leads to significantly higher ee value (93%)
than the use of (S,S)-1 (77%). Even removal of the methyl
groups on the bridging carbon atom, that is, using (S,S)-3 gives
a higher ee value under the same conditions. This result shows
that, by further fine tuning of the ligand, improved enantio-
selection can be expected. Of particular note is the reaction of
The current high demand in the pharmaceuticals industry for
efficient and economical routes to enantiomerically pure a-
hydroxy and a-amino carbonyl compounds has focused
interest on carbonyl-ene and imino-ene reactions as a
[
1]
potential source of these compounds. Homogeneously
catalyzed carbonyl-ene reactions have been reported using a
[2]
chiral methyl–aluminum–binaphthol complex, but the scope
of this catalyst was very limited. Subsequently, the scope of
2
-methylhept-2-ene using (R,R)-1 which gave a major and
[
*] Prof. Dr. G. J. Hutchings
minor product in a molar ratio of 3.2:1 (ca. 76:24) The anti:syn
diastereoselectivity of the major product was 5:1 (i.e. ca.
8
substrate, albeit with a low yield, shows the advantages of
using the heterogeneous catalysts, since previous studies
have shown that enantioselective reactions with 1,2-disubsti-
tuted alkenes are not catalytic with the homogeneous copper
bis(oxazoline) complex catalysts.
Department of Chemistry, Cardiff University
P.O. Box 912, Cardiff, CF10 3TB (UK)
Fax : (+44)292-087-4075
3:17). However, the observation of reaction with this
E-mail: hutch@cf.ac.uk
[
4b]
Dr. N. A. Caplan, F. E. Hancock
Johnson Matthey Catalysts
Cambridge Science Park, Cambridge CB4 0FP (UK)
Prof. Dr. P. C. Bulman Page
Department of Chemistry
Loughborough University, Loughborough, LE11 3TU (UK)
The scope of the reactions using the immobilized catalyst
was extended and the reaction of a-methylstyrene with
methyl pyruvate was investigated (Scheme 1). These results,
[
**] This work was sponsored by Synetix Chiral Technologies.
Angew. Chem. Int. Ed. 2004, 43, 1685 –1688
DOI: 10.1002/anie.200352534
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Communications
Table 1: Enantioselective carbonyl-ene reactions catalyzed by bis(oxazoline) Cu-HY.
Bis(oxazoline)
Alkene
Enophile
Product
T
Yield
[%]
ee config.
[%]
[h]
(
S,S)-1
S,S)-1
a-methylstyrene
20
85
65
77 S
94 S
(
methylene cyclohexane
100
(
S,S)-1
R,R)-1
methylene cyclopentane
2-methylheptene
100
150
71
69
93 S
72 R
(
(R,R)-1
2-methylhept-2-ene
150
23
77 R
(S,S)-2
(S,S)-3
(R,R)-1
a-methylstyrene
a-methylstyrene
a-methylstyrene
12
12
20
87
91
66
93 R
85 R
80 R
(
S,S)-1
S,S)-2
a-methylstyrene
a-methylstyrene
10
5
87
83
90 R
92 R
(
along with those in Table 1, show that the heterogeneous
copper catalysts are active for the carbonyl-ene reactions
across a range of alkene substrates and carbonyl compounds.
The scope was further extended to imino-ene reactions
the immobilized copper catalyst. Previous studies involving
[
5]
homogeneous catalysts have used imine compounds that
have an electron-withdrawing substituent, usually a carbonyl
or carboxyl group, adjacent to the imine carbon atom to
enhance its reactivity. Our preliminary study using N-benzyl
isovalerimine shows that these groups are not necessary with
the immobilized heterogeneous catalyst.
(
Table 1). The results demonstrate that both a-carboxyl
imine (ethyl-N-benzhydryliminoethanoate) and alkylimine
N-benzyl isovalerimine) compounds readily react with a-
(
methylstyrene giving high yields and enantioselectivity with
The reaction of the immobilized copper–bis(oxazoline)
zeolite Y catalyst was compared with a homogeneous copper
catalyst, Cu(OTf)2 in the presence of the bis(oxazoline),
under comparable conditions (Table 2). Although the homo-
geneous catalyst gave a higher yield, the ee values observed
for a-methyl styrene and methylene cyclohexane were com-
parable for the two catalysts. However, the ee values observed
with the heterogeneous catalyst for methylene cyclopentane
Scheme 1. Cu-HY=Immobilized copper–zeolite Y catalyst.
1
686
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Table 2: Comparison of the immobilized catalyst (Cu-HY) with the homogeneous catalyst for the reaction (Entry 1, Table 3) which
carbonyl-ene reaction.
was then washed out into the reac-
Bis-oxazoline Alkene
Enophile
Catalyst Product
Cu-HY
T
[
Yield ee config. tion mixture during the subsequent
h] [%] [%]
reaction. For this reason, subse-
quent experiments on catalyst
reuse involved a washing procedure
(R,R)-1
a-methyl-
20 66
80 R
styrene
(
Entries 3–5, Table 3) to ensure
(
R,R)-1
S,S)-1
Cu(OTf)2
Cu-HY
20 94
66 R
94 S
product was not retained in the
reused catalyst. The results show
that, following washing, even with-
out the further addition of bis(ox-
azoline), the washed, reused cata-
lysts give comparable yields and
ee values to those expected from a
fresh catalyst (Entries 3–5, Table 3).
In addition, it is possible to use the
(
methylene
cyclohexane
100 65
(
S,S)-1
S,S)-1
Cu(OTf)2
Cu-HY
100 92
100 71
99 S
93 S
(
methylene
cyclopentane
(S,S)-1
Cu(OTf)2
100 94
57 S
was significantly higher than that observed with the homoge-
neous catalyst. This is considered to be due to the confine-
ment of the heterogeneous catalyst within the zeolite pores,
and we have also observed this in our previous studies on
catalyst for different reactions in successive experiments
(Entries 1, 3–5, Table 3), which fully demonstrates the
flexibility of the heterogeneous catalyst. If the reused catalyst
is retreated with bis(oxazoline) prior to use, then improved
enantioselection is observed (experiment 6, Table 3), but such
a retreatment is not considered essential.
[
7]
aziridination.
Following the reaction of methyl pyruvate and a-methyl-
styrene (Scheme 1), the catalyst was recovered, dried, and
reused giving the same results. The aqueous phase from the
crude-product washing step was analyzed, and it was deter-
mined that only approximately 1% of the copper added with
the heterogeneous catalyst leached, under the reaction
conditions, into the reaction mixture. Further experiments
showed that this level of copper was not an active homoge-
neous catalyst for the carbonyl- and imino-ene reactions.
Hence, the copper–bis(oxazoline) zeolite Y catalyst is acting
as a heterogeneous catalyst. A further series of experiments
were carried out to demonstrate the facile reuse of this
immobilized catalyst (Table 3). A large scale reaction of ethyl
glyoxylate with a-methylstyrene was carried out (Entry 1,
Table 3). Following the reaction, the catalyst was isolated by
filtration and pretreated according to three different methods
We have previously shown, using detailed EPR spectros-
[
8]
copy, that the bis(oxazoline) chelates to the copper within
the supercages of the zeolite to form a square-planar complex.
In the present study, we consider this is the active site for the
catalyzed reaction, since the experiments reported clearly
demonstrate the material is acting as a heterogeneous catalyst.
In conclusion, we have demonstrated the first heteroge-
neously catalyzed, enantioselective carbonyl-ene and imino-
ene reactions, which provide a simple pathway for the
synthesis of a-hydroxy and a-amino carbonyl compounds
with good yields and high enantioselection.
Experimental Section
Cu-exchanged zeolite Y was prepared by ion-exchange of zeolite HY
(
Table 3). The pretreated, used catalyst was then used for
(50 g) with a solution of copper(ii) acetate (7.85 g, 39.3 mmol in
subsequent reactions with either ethyl glyoxylate or methyl
pyruvate. Our initial experiments were based on simply
recovering the catalyst by filtration and vacuum drying before
reusing (Entry 2, Table 3). Although the catalyst could be
reused, the yield increased while the ee value decreased. This
effect was due to product being retained from the initial
deionized water (150 mL)) for 16 h at 208C with periodic adjustment
of the pH value to 7.5. The material was recovered by filtration, dried
(
(
1108C), and calcined (5508C). Using inductively coupled plasma
ICP) analysis, the zeolite was found to contain 3.1 wt% Cu.
Heterogeneous catalyzed carbonyl-ene reactions using ethyl
glyoxylate: The Cu-exchanged zeolite Y (0.360 g, 0.15 mmol Cu)
was dried in a Schlenk flask under high vacuum (1508C, 2h) and then
cooled (208C). CH Cl (5.0 mL) and the bis(oxazoline) (0.025 g,
[
a]
2
2
Table 3: Reuse of the heterogeneous catalyst.
0.075 mmol) were added to the dried catalyst by syringe. Filtration at
[
a]
Entry Reuse Pretreatment Carbonyl com-
pound
Yield
[%]
ee config.
[%]
this point yielded an air stable catalyst with the same performance as
that prepared and used in situ, this material was stable when stored in
air at room temperature for up to 6 months. The suspension was
stirred for 3 h at 208C and then alkene (0.149 mmol) and ethyl
glyoxylate solution in toluene (1.02g, 80% solution in toluene,
1
2
–
–
(a)
ethyl glyoxylate
ethyl glyoxylate
66
85
80 R
65 R
2nd
use
2nd
use
3rd
use
4th
use
2nd
use
7.47 mmol) were added by syringe. The reaction mixture was stirred
3
4
5
6
(b)
(b)
(b)
(c)
methyl pyruvate 85
methyl pyruvate 91
83 R
89 R
82 R
80 R
at 208C and the reaction was monitored periodically by thin-layer
chromatography (TLC). After the reaction, the catalyst was sepa-
rated by filtration and the product was purified by flash column
chromatography.
ethyl glyoxylate
89
Homogeneously catalyzed carbonyl-ene reactions: Copper(ii)
triflate (Cu(OTf) , 0.054 g, 0.15 mmol) and bis(oxazoline) (0.056 g,
2
methyl pyruvate 79
0.15 mmol) were added to a dry Schlenk flask under argon and
CH Cl (5 mL) was added by syringe. The solution was stirred for 3 h
2
2
[a] See Experimental Section for method definition.
at 208C and then alkene (1.90 mmol) and ethyl glyoxylate (1.17 g,
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Communications
8
0% solution in toluene, 9.51 mmol) were added by syringe. The
reaction mixture was stirred at 208C and the reaction was monitored
periodically by TLC. After the reaction, the product was purified by
flash chromatography.
Imino-ene reactions: Cu-exchanged zeolite Y (0.423 g, 0.17 mmol
Cu) was dried in a Schlenk flask under high vacuum (1508C, 2h) and
then cooled (208C). CH Cl2 (5.0 mL) and bis(oxazoline) (0.025 g,
2
0
.075 mmol) were added to the dried catalyst by syringe. The
suspension was stirred for 3 h at 208C and then a-methylstyrene
194 mL,149 mmol) and the imino(ethyl-N-benzhydryliminoethan-
(
oate (1.2mmol)), or N-benzyl isovalerimine (2.55 mmol) were
added by syringe. The reaction mixture was stirred at 208C and
monitored periodically by TLC. After complete reaction, the catalyst
was separated by filtration. The crude product was purified by flash
column chromatography.
Large scale reuse experiment: Vacuum-dried Cu-exchanged
zeolite Y (3.1 wt% Cu, 1.44 g, 0.60 mmol Cu) pretreated with
(
(
R,R)-1 (0.10 g, 0.40 mmol) was treated with ethyl glyoxylate
4.08 g, 29.88 mmol) and a-methylstyrene (0.708 g, 5.95 mmol) for
2
0 h at 208C in CH Cl (20 mL). The catalyst was separated by
2 2
filtration and the product recovered and purified by flash column
chromatography. Subsequent reactions of the used catalyst were
carried out at a quarter of this scale. Prior to reuse, the catalyst was
pretreated according to one of the following methods:
a) vacuum drying only (608C, 12h; 150 8C, 3 h);
b) washed with ethylacetate (5 ” 5 mL) before vacuum drying and
repeating the whole procedure twice more;
c) washed and dried as in method (b), calcined (5508C, 6 h), and
retreated with (R,R)-1 (0.025 g, 0.075 mmol).
The ee value was determined using chiral HPLC using a Daicel
Chiralkpak OD column and yields of isolated products are reported.
The IUPAC name for 1,3-oxazoline is 4,5-dihydro-1,3-oxazole
Received: August 1, 2003
Revised: October 31, 2003 [Z52534]
Keywords: CÀC coupling · enantioselectivity · ene reaction ·
.
heterogeneous catalysis · zeolites
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