Planar and central chiral [2.2]paracyclophane-based N,O-ligands as highly active catalysts in the diethylzinc addition to aldehydes

Article abstract of DOI:10.1039/b108347c

The application of planar and central chiral [2.2]paracyclophane-based N,O-ligands in asymmetric diethylzinc additions to various aldehydes is described revealing an unusual substrate spectrum for the catalysts and their remarkably high activity.

Full text of DOI:10.1039/b108347c

Planar and central chiral [2.2]paracyclophane-based N,O-ligands as
highly active catalysts in the diethylzinc addition to aldehydes†
Stefan Dahmena and Stefan Bräse*b
a Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule Aachen,
Professor-Pirlet-Strasse 1, D-52074, Aachen, Germany
b Kekulé-Institut für Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universität
Bonn, Gerhard-Domagk-Strasse 1, D-53121, Bonn, Germany. E-mail: braese@uni-bonn.de;
Fax: +49 228 739608; Tel: +49 228 732653
Received (in Cambridge, UK) 17th September 2001, Accepted 11th November 2001
First published as an Advance Article on the web 29th November 2001
The application of planar and central chiral [2.2]para-
cyclophane-based N,O-ligands in asymmetric diethylzinc
additions to various aldehydes is described revealing an
unusual substrate spectrum for the catalysts and their
remarkably high activity.
on the unusual substrate spectrum and the high activity of these
ligands.
The diethylzinc addition to aldehydes is one of the most
extensively studied enantioselective catalytic reactions, partic-
ularly because of features like autoinduction and nonlinear
effects.‡ However, of the approximately 600 ligands recently
reviewed by Pu and Yu,7 only a small number (10 to 15) is
currently capable of efficiently catalysing the diethylzinc
addition to aliphatic and especially a-branched aliphatic
aldehydes.
Initially, all four ligands were tested with benzaldehyde as
standard substrate (Table 1, entries 1–4). The diastereomers 1
showed cooperative effects of the two chiratopic elements of the
ligand structure with (Sp,S)-1 giving 85% ee (R) and the (Rp,S)-1
giving 65% ee (S). In contrast to that, the diastereomers 2
catalysed the addition with quasi equal selectivity for both
enantiomers (82 vs. 83% ee, entries 3 and 4). The configuration
of the chiral centre in the sidechain of the ligands 2 obviously
does not influence the selectivity of the reaction. However, in
The element of planar chirality plays an important role in many
modern ligand systems.1–3 The combination of different
individual chirotopic elements within the ligand molecule can
lead to highly selective catalysts as for instance observed in
various ferrocene derivatives2 and arene transition metal
complexes.3 However, limited attention has been paid to planar
chiral ligands derived from [2.2]paracyclophane4 and even
fewer reports focus on planar and central chiral [2.2]para-
cyclophane-ligands and their application in asymmetric catal-
ysis.5
During ligand screening employing various hydroxy imine,
hydroxy ketimine and amino alcohol ligands based on the
[2.2]paracyclophane backbone, we discovered that ketimines
like 1 and 2 (Fig. 1) showed superior selectivity and activity in
the diethylzinc addition to benzaldehyde and revealed cooper-
ative effects arising from the combination of the different
chirotopic elements of the ligands (chiral cooperativity).
However, the ketimines 1 and 2 were first synthesised by
Rozenberg and Belokon who used them for the resolution of the
corresponding racemic hydroxy ketones.6 Here, we will report
Table 1 Enantioselective addition of diethylzinc to aldehydes catalysed by
in situ formed zinc-complexes of ligands 1 and 2a
Yield
[%]b
Entry
Aldehyde
Ligand
ee [%]c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
2-Methoxybenzaldehyde
2-Methoxybenzaldehyde
1-Naphthaldehyde
1-Naphthaldehyde
3,5-Dimethoxybenzaldehyde
3,5-Dimethoxybenzaldehyde
(Rp,S)-1
(Sp,S)-1
(Rp,S)-2
(Sp,S)-2
(Sp,S)-1
(Rp,S)-1
(Sp,S)-1
(Sp,S)-1
(Rp,S)-2
(Sp,S)-1
(Rp,S)-2
(Sp,S)-1
(Rp,S)-1
36
100
94
100
100
0
60 (S)
85 (R)
82 (S)
83 (R)
88 (R)
d
—
98
86 (R)
55 (R)
41 (S)
86 (R)
77 (S)
84 (R)
—
100
100
80
66
98
0
95
0
100
100
100
92
97
97
3,5-Dibenzyloxybenzaldehyde (Sp,S)-1
3,5-Dibenzyloxybenzaldehyde (Rp,S)-1
81 (R)
-
a-Methylcinnamaldehyde
Cyclohexanecarbaldehyde
Cyclohexanecarbaldehyde
Cyclohexanecarbaldehyde
Cyclohexanecarbaldehyde
Pivalaldehyde
(Sp,S)-1
(Rp,S)-1
(Sp,S)-1
(Rp,S)-2
(Sp,S)-2
(Sp,S)-1
(Sp,S)-2
86 (R)
96d (S)
95d (R)
99d (S)
86d (R)
98d (R)
98d (R)
Pivalaldehyde
100
Fig. 1 Diastereomeric [2.2]paracyclophane-based ketimine ligands em-
ployed in the diethylzinc addition.
a 0.5 mmol Aldehyde, 1.0 mmol diethylzinc (1 molar in hexane), 1 ml of
toluene, 1% ligand, 0 °C, 12 h.b Determined by GC.c Determined by GC
(Lipodex G: entries 1–4, 17–20; Chirasil-Dex: entries 5–13), by HPLC
((S,S)-Whelk-O 1: entries 14–16), or by GC of (1S)-camphanic ester (entries
21,22).d No toluene was used as co-solvent.
† Electronic supplementary information (ESI) available: synthesis, NMR
data, optical rotation and chiral analysis. See http://www.rsc.org/suppdata/
cc/b1/b108347c/
26
CHEM. COMMUN., 2002, 26–27
This journal is © The Royal Society of Chemistry 2002

both cases, the planar chirality of the ligand backbone
determines the product configuration.
diethylzinc addition especially to a-branched aliphatic alde-
hydes. Additionally, they reveal remarkably high activity
allowing them to be employed on a 0.5 mol% scale without
decrease of selectivity, which makes them some of the most
efficient ligands for certain substrate classes.
We would like to thank the Deutsche Forschungsge-
meinschaft (SFB 380, BR1750/2) and the Fonds der Chem-
ischen Industrie for financial support.
The ligands were also tested with several other aromatic and
aliphatic substrates (entries 5–22). For nearly all aromatic
substrates, the selectivities obtained with (Sp,S)-1 were in the
range of 81–85% ee. Only ortho-substituted benzaldehydes are
recognised on a lower level (55% ee, entry 8). The mismatched
diastereomer (Rp,S)-1 delivers for all aromatic substrates much
lower yields and selectivities. In some cases, the difference in
substrate recognition between the two diastereomers of 1 is so
high that no product can be found for reactions carried out with
(Rp,S)-1 (Table 1, entries 6,13,15).
Notes and references
However, for aliphatic and especially a-branched aliphatic
aldehydes, which are usually considered as poor substrates for
the majority of catalysts, the selectivities rise into the high 90’s
(Table 1, entries 17–22). In addition, the mismatched diaster-
eomer (Rp,S)-1 now delivers slightly better results than (Sp,S)-1
(Table 1, entry 17). In the case of cyclohexanecarbaldehyde, the
results obtained with ligand 1 are even surpassed by (Rp,S)-2
giving 99% ee (entry 19). For pivalaldehyde, very high
selectivities are obtained also.
Because of their ability to form dimeric complexes, which
results for example in the occurrence of nonlinear effects,
usually ligands for diethylzinc additions have to be employed
on a fairly high loading level (5 to 10%).8 Only very few ligands
have been reported to work effectively on a 1 to 2% level.
The paracyclophane-based ligands, however, can be em-
ployed on a 0.5% level without loss of selectivity. At 0.1%
catalyst loading of ligand (Sp,S)-1, the selectivity towards
benzaldehyde and cyclohexanecarbaldehyde drops only by 2 to
3%. And even at 0.05%, very resonable results are obtained
(91% ee for cyclohexancarbaldehyde and 80% ee for benzalde-
hyde, respectively). Obviously, the decrease in ee value is only
dependent on the catalyst loading and completely independent
of the substrate used (Fig. 2).
‡ General procedure for the addition of diethylzinc to aldehydes: Under a
dry argon atmosphere, the ligand was dissolved in 1.0 mL of dry toluene at
rt and 1.0 mL of a 1 M solution of diethylzinc in hexane was added. After
stirring for 30 min., the resulting yellow solution was cooled to 0 °C, the
aldehyde was added and the solution was kept at this temperature for 12 h.
The solution was quenched with 1 M HCl and filtered over a short plug of
silica to remove the inorganic salts.
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The conversion is at 0.1% catalyst loading virtually complete
after 16 h. Even at 0.05% catalyst loading, 92% (benzaldehyde)
and 75% (cyclohexanecarbadehyde) of product are obtained.
This corresponds to substrate-to-catalyst ratios (s/c) of 1840
(benzaldehyde) and 1500 (cyclohexanecarbaldehyde) respec-
tively. These are, to the best of our knowledge, the highest
activities so far observed in asymmetric diethylzinc additions.
In conclusion, we have demonstrated that [2.2]paracyclo-
phane-based N,O-ligands can be valuable ligands in the
6 V. Rozenberg, T. Danilova, E. Sergeeva, E. Vorontsov, Z. Starikova, K.
Lysenko and Y. Belokon, Eur. J. Chem., 2000, 3295.
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and H.-B. Yu, Chem. Rev., 2001, 101, 757.
8 The formation of dimeric complexes is a phenomenon commonly
observed for amino alcohol ligands in diethylzinc addition reactions.
Formation of hetero-dimeric complexes, which are often more stable than
the homo-dimeric complexes leads to the occurrence of nonlinear effects.
As the catalytically active species is a monomeric zinc alkoxide, often
times high catalyst loadings have to be employed to circumvent catalyst
deactivation by dimer formation. For reviews on nonlinear effects in
asymmetric catalysis, see: C. Girard and H. B. Kagan, Angew. Chem., Int.
Ed., 1998, 37, 2922; M. Avalos, R. Babiano, P. Cintas, J. L. Jiménez and
J. C. Palacios, Tetrahedron: Asymmetry, 1997, 8, 2997.
Fig. 2 Dependency of the ee value of the diethylzinc addition product on
catalyst loading using ligand (Sp,S)-1.
CHEM. COMMUN., 2002, 26–27
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