Asymmetric conjugate addition of organozinc compounds to α,β-unsaturated aldehydes and ketones with [2.2] paracyclophaneketimine ligands without added copper salts

Article abstract of DOI:10.1002/anie.200501732

(Chemical Equation Presented) The ligand makes it possible: The asymmetric conjugate addition of diethylzinc to α,β-unsaturated aldehydes and ketones occurs with catalytic amounts of the paracyclophaneketimine ligand 1 without further additives.

Full text of DOI:10.1002/anie.200501732

Angewandte
Chemie
Synthetic Methods
(Table 1, entries 1–7). Unlike all previously described
ligands,[10] the ketimines 1 also transformed a,b-unsaturated
aldehydes 2 into the respective 1,4-addition products 3 in a
highly enantioselective manner. This even takes place with a
relatively small amount of catalyst, 2 mol%, without the
addition[11] of compounds having a soft metal center (copper,
nickel, or indium[12]). The 1,2-addition products 4 were also
formed in most cases, but with only moderate enantioselec-
tivity. The reason is that with a,b-unsaturated aldehydes,
unlike, for example, benzaldehyde,[13] the uncatalyzed reac-
tion also takes place. Other ligands (dimethylaminoethanol,
3-exo-(dimethylamino)isoborneol (DAIB)) gave, as de-
scribed in the literature,[10] only 1,2-addition products 4.
The ratio between 1,2- and 1,4-addition was temperature
dependent: low temperatures increased the proportion of the
more thermodynamically favorable 1,4 products. However,
the reaction rate dropped to such an extent that a compromise
between acceptable reaction rate and selectivity had to be
found.
DOI: 10.1002/anie.200501732
Asymmetric Conjugate Addition of Organozinc
Compounds to a,b-Unsaturated Aldehydes and
Ketones with [2.2]Paracyclophaneketimine
Ligands without Added Copper Salts**
Stefan Bräse* and Sebastian Höfener
Dedicated to Professor Henri B. Kagan
on the occasion of his 75th birthday
Asymmetric catalysis has established itself as a versatile
method in modern synthetic chemistry. In particular, many
transformations with almost complete enantioselectivity are
possible today through the use of chiral ligands. One example
is the conjugate addition of organometallic reagents to a,b-
unsaturated carbonyl compounds, especially to ketones.[1] In
the presence of copper additives different ligand systems give
almost complete stereocontrol. The copper ions influence the
electronic properties of the carbonyl group, they determine
which alkyl or aryl residues are transferred, and they act as
bridging units in the transition state.[2,3] As an extension of the
non-enantioselective copper-free 1,4-addition to a,b-unsatu-
rated aldehydes described previously by Knochel et al.,[4] we
present here for the first time a highly enantioselective
copper-free variant.
In the addition of diethylzinc to cinnamaldehyde (2a,
entries 1–3 in Table 1) or its derivatives o-methoxycinnamal-
dehyde (2b, entry 5) and p-chlorocinnamaldehyde (2c,
entry 6) and also 3-thiophen-3-yl-propenal (2d, entry 7) the
yield of the 1,4 product was as high as 52% with enantiomeric
excesses of between 96 and 98% ee. Better regioselectivity
was obtained with 6-methoxy-2,2-dimethyl-2H-chromene-3-
carbaldehyde (2e) after 62 h at 08C. Here both (Sp,S)-1a
(Table 1, entry 9) and (Rp,S)-1a (entry 8) gave the 1,4 product
in 78–80% yield and 97 and 96% ee, respectively. In both
cases the syn diastereomers were formed preferentially
(74% de with (Sp,S)-1a, 77% de with (Rp,S)-1a), which was
confirmed by NOE experiments. The addition of diisopro-
pylzinc to cinnamaldehyde (2a) was also successful; the 1,4
product was formed with a yield of 39% at 91% ee (entry 4).
Whereas in the 1,4-addition to aldehydes temperatures of
À208C (or 08C) are of advantage for selectivity reasons, 1,4-
additions to ketones such as benzylideneacetone (2 f) and 3-
octen-2-one (2g) can be carried out at room temperature
(Table 1, entries 10–12). The 1,2-addition products were
never formed as by-products, only the corresponding aldol
addition products. However, in the case of benzylideneace-
tone their fraction could be reduced from 15 to 5% by
increasing the amount of ligand from 2 to 4 mol% (Table 1,
entries 10 and 11). The enantioselectivities varied between 73
and 90% ee for the ketones. Ketones were also successfully
reacted with diisopropylzinc (see the Supporting Informa-
tion).
Over the last few years we have been
able to demonstrate that readily acces-
sible, configurationally stable, planar
and centrochiral ketimines 1 with a
[2.2]paracyclophane framework[5] are
highly suitable for the asymmetric addi-
tion of alkyl[6] and alkenyl residues[7] to
aliphatic aldehydes. In addition, these
ligands have proved to be useful in the
addition of alkyl[8] and aryl residues[9] to
N-acylimines.
Since the addition to N-acylimines is
comparable to a conjugate addition, we postulated that a,b-
unsaturated aldehydes and ketones could also be suitable as
substrates. Therefore different a,b-unsaturated aldehydes
were tested under standard reaction conditions (2 mol%
ligand 1, 4 equiv ZnEt2 or 2 equiv diisopropylzinc, À208C)
The diastereomeric ketimine ligands (Sp,S)-1a and (Rp,S)-
1a led in each case to the complementary main enantiomers
of the 1,4- and 1,2-addition products. This pivotal influence of
the planar chirality on product configuration confirms
previous investigations on 1,2-additions to saturated alde-
hydes, which also indicated the strongly
[*] Prof. Dr. S. Bräse, Dr. S. Höfener
Institut für Organische Chemie
Universität Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+49)721-608-8581
E-mail: braese@ioc.uka.de
dominating effect of the planar chirality
as opposed to the centrochirality of the
[**] This research was supported by the Fonds der Chemischen
Industrie. We thank Alexander Tung-Qiang Wong and Jens Adler for
their contributions to the experimental work.
ligands.[14]
The nonplanar analogue 5 of the
paracyclophaneketimine ligand 1 also
catalyzed conjugate addition, albeit
Supporting information for this article is available on the web under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2005, 44, 7879 –7881
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Communications
pressure, and the regioisomers were
separated by column chromatography
on silica 60 (eluent: cyclohexane/ethyl
acetate).
Table 1: Asymmetric conjugate addition of diethylzinc and diisopropylzinc to aldehydes and ketones.
Variant B: The same as variant A
but the twice the quantities were used.
Variant C: The same as variant A,
but the reaction was carried out at 08C
(62 h) and not warmed to room temper-
ature.
Variant D: The ligand (SP,S)-1a
(0.01mmol)
and
cinnamaldehyde
(0.5 mmol) were mixed. The reaction
vessel was purged with argon and cooled
to À208C before a solution of diisopro-
pylzinc (1m in toluene; 1mL, 1mmol)
was added. The reaction mixture was
then stirred for 62 h at À208C before the
reaction was quenched by the addition
of semisaturated ammonium chloride
solution (3 mL) and worked up as in
variant A.
Variant E: (SP,S)-1a (0.01mmol)
and the ketone (0.5 mmol) were placed
in a 10-mL flask. The reaction vessel was
purged with argon before diethylzinc or
diisopropylzinc solution was added (1m
in hexane or toluene; 1mL, 1mmol).
After 62 h stirring at room temperature
the reaction was quenched by the addi-
tion of semisaturated ammonium chlo-
ride solution (3 mL) and worked up as in
variant A.
Entry Substr. Variant[a]
R
T [8C]
Ligand
1,4 Product
1,2 Product
Yield [%][b] ee [%][c] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2b
2c
2d
2e
2e
2 f
2 f
2g
B[f]
B[f]
B[f]
D[f]
B[f]
A[f]
A[f]
C
Et
Et
Et
iPr
Et
Et
Et
Et
Et
Et
Et
Et
À20 (Rp,S)-1a
À20 (Sp,S)-1a
À20 (Sp,S)-1b
À20 (Sp,S)-1a
À20 (Sp,S)-1a
À20 (Sp,S)-1a
À20 (Rp,S)-1a
43
36
46
39
52
42
45
80
78
85
95
88
98(S)
99(R)
97(R)
91
97
96
99
96
97
23
37
38
22
13
34
31
4
69
58
53
n.d.[d]
n.s.[e]
57
50
0
0
(Rp,S)-1a
(Sp,S)-1a
n.d.[d]
n.d.[d]
–
9
C
12
–
10
11
12
E[g]
E[g,h]
E[g]
RT (Sp,S)-1a
RT (Sp,S)-1a
RT (Sp,S)-1a
87(R)
90(R)
73
–
–
–
–
[a] See Experimental Section for details. [b] Determination by GC on an achiral stationary phase (HP1).
[c] Determination by GC on a chiral stationary phase (CP-Chirasil-Dex for entries 1–8 and 11; Lipodex E
for entries 9 and 10). [d] n.d.=not determined. [e] n.s.=no separation of enantiomers on chiral
stationary phase. [f] The condensation product of the 1,2 product was also identified by GC-MS. [g] The
aldol products were formed as by-products. [h] Amount of catalyst used: 4 mol%.
Received: May 19, 2005
Revised: August 17, 2005
Published online: November 17, 2005
with a poorer ratio of 1,2- to 1,4-addition products and lower
enantioselectivities. The reaction of cinnamaldehyde (2a) at
À208C gave the 1,2 and 1,4 products in a ratio 2.3:1 (with
17%ee for the 1,4 product and 4% ee for the 1,2 product).
Here the first copper-free[11] asymmetric 1,4-addition of
diethylzinc or diisopropylzinc to a,b-unsaturated aldehydes
and ketones has been described. This methodology supple-
ments the spectrum of synthetic methods for b-chiral
aldehydes and ketones.[15] The application to the synthesis
of biologically active compounds and the extension of the
substrate spectrum represents further objectives of our
investigations.
Keywords: aldehydes · asymmetric catalysis ·
conjugate additions · cyclophanes · zinc
.
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Experimental section
Variant A: The ligand (0.01mmol) and the aldehyde (0.5 mmol) were
placed in a 10-mL flask. The reaction vessel was purged with argon
and cooled to À208C before a solution of diethylzinc (1min toluene or
hexane; 1mL, 1mmol) was added. The reaction mixture was stirred
for 24 h at this temperature before more diethylzinc solution (1mL)
was added. The reaction mixture was then stirred at À208C for 38 h,
warmed to room temperature, and stirred for a further 24 h. The
reaction was quenched by the addition of semisaturated ammonium
chloride solution (3 mL). The reaction mixture was treated with
diethyl ether, filtered, and separated in a separating funnel. The
organic phase was washed three times with deionized water and dried
over magnesium sulfate. GC chromatograms were recorded for these
solutions. The solution was then concentrated under reduced
[4] a) P. Knochel, Sci. Synth. 2004, 3, 5 – 90; b) P. Jones, C. K. Reddy,
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7880 www.angewandte.org
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[8] S. Dahmen, S. Bräse, J. Am. Chem. Soc. 2002, 124, 5941– 5942.
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[11] According to ICPMS measurements the copper content of the
commercial diethylzinc solutions used is (50 Æ 5)mm or less. This
gives a ligand/copper ratio of at least 100:1 and a zinc/copper
ratio of at least 20000:1. We assume that these copper ions do
not play any role in the catalyst cycle since other catalysts show
no cuprate-like behavior. We thank Dr. Zsolt Berner, Institut fꢀr
Mineralogie und Geochemie der Universität Karlsruhe (TH),
for carrying out these measurements.
[12] B. G. Kelly, D. G. Gilheany, Tetrahedron Lett. 2002, 43, 887 – 890.
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[14] S. Höfener, F. Lauterwasser, S. Bräse, Adv. Synth. Catal. 2004,
346, 755 – 759.
[15] a) Diastereoselective addition: P. Mangeney, A. Alexakis, J. F.
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