Dramatic temperature effect in asymmetric catalysis in the enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1039/a808920e

The enantioselectivity of the addition of diethylzinc to aryl aldehydes catalysed by (S)-2-(3-methyl-2-pyridyl)-3,5-di-tert-butylphenol have been found to depend heavily on temperature with the inversion temperatures affected by the para-substituents of a

Full text of DOI:10.1039/a808920e

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Dramatic temperature effect in asymmetric catalysis in the
enantioselective addition of diethylzinc to aldehydes
Huichang Zhang and Kin Shing Chan*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong
Received (in Cambridge) 16th November 1998, Accepted 8th January 1999
The enantioselectivity of the addition of diethylzinc to aryl
aldehydes catalysed by (S)-2-(3-methyl-2-pyridyl)-3,5-di-
tert-butylphenol have been found to depend heavily on
temperature with the inversion temperatures affected by
the para-substituents of aryl aldehydes.
Table 1 Temperature effect on the enantioselectivity of (R)-3a–c (ees
were determined on a Daicel OD column)
3a (X = Cl)
3b (X = H)
3c (X = OMe)
%
(R)
ee
Yield
(%)
% ee
(R)
Yield
(%)
% ee
(R)
Yield
(%)
T/ЊC
Ϫ23
Ϫ15
Ϫ8
Ϫ4
0
Temperature serves as a convenient experimental tool to probe
mechanisms and also provides a practical approach to maxi-
mize selectivity in chemical processes especially in asymmetric
catalysis. Abrupt maxima (or minima) in plots of ln (R/S) vs. 1/T
due to two intercepting linear regions are known as nonlinear
temperature behavior and have generated much recent theor-
52
59
66
75
80
72
48
33
24
64
78
83
85
97
88
89
88
89
35
61
77
84
75
42
17
3
45
67
79
87
90
90
85
86
85
45
66
74
77
66
60
35
30
3
60
74
80
83
96
87
91
90
88
1
etical interest. The temperature at the maximum is the so-
4
8
5
5
called “inversion temperature”. One interpretation of such a
phenomenon is a shift in the rate-determining step of the reac-
tion with the change of temperature. A maximum in such a plot
for the osmium tetroxide asymmetric dihydroxylation of olefins
1
2
1
2
has been interpreted as evidence for a non-concerted pathway.
Practically, the increase of temperature with a resultant faster
reaction rate and more selective chemical conversion would
be most desirable. One recent example is the asymmetric catal-
ytic hydrogenation to yield -Dopa [(Ϫ)--2-amino-3-(3,4-di-
3
hydroxyphenyl)propanoic acid]. In our continuing studies on
3
the enantioselective addition of diethylzinc to aryl aldehydes
catalyzed by (S)-2-(3-methyl-2-pyridyl)-3,5-di-tert-butylphenol
4,5
(
1), we have found a dramatic temperature effect on the enan-
tiomeric excess (ee) of the 1-phenylpropanols formed and that
the inversion temperatures of aryl aldehydes depend on the
para-substituents.
The results of the enantioselective catalytic addition of
diethylzinc to aromatic aldehydes 2a–c [eqn. (1)] catalysed by 5
tBu
tBu
X
(
S)-
N
HO
mol%
1
H
Fig. 1
5
X
CHO
OH (1)
1
Et2Zn, 48 h
Et
temperature effect on ee ever reported. Similar, though less
prominent, effects were observed for p-chlorobenzaldehyde 2a
and p-methoxybenzaldehyde 2c. Neither the catalyst 1 nor the
alcohol 3b underwent any racemization in either acidic (1 M
HCl in MeOH) or in alkaline conditions (1 M NaOH in
MeOH) at room temperature for 24 h. This temperature effect
therefore originated from the asymmetric ethylation.
Toluene, 0 o
C
2
a-c
3a-c
2
a: X = Cl; 2b: H; 2c: X = MeO
6
mol% of 1 (optical purity >99.5%) from Ϫ23 ЊC to 25 ЊC are
summarized in Table 1 and the plots of ln (R/S) of the alcohols
3
a–c vs. 1/T are shown in Fig. 1. The reactions were conducted
The inversion temperature of the more electron-deficient and
more reactive p-chlorobenzaldehyde occurred at 0 ЊC while
5
in toluene under N within 48 h to give high yields of alcohols
2
3
a–c with moderate to high enantioselectivity. The yields were
those of benzaldehyde and p-methoxybenzaldehyde appeared
at Ϫ4 ЊC, which suggests that the more reactive the substrate,
the higher the inversion temperature. The reactivity pattern
suggested that the more reactive substrate gave the more stereo-
selective products as reported earlier.
The origin of this temperature effect remains unclear. The
slightly lower at Ϫ23 ЊC due to slower reactions. The homo-
geneity of the reaction was maintained throughout by visual
judgement. The ee of 3b increased from Ϫ23 ЊC and reached a
maximum at around Ϫ4 ЊC before it sharply dropped to near
zero (Table 1 and Fig. 1). Therefore, an inversion temperature
occurred at Ϫ4 ЊC. Most noticeably, when the temperature of
the reaction with benzaldehyde was raised from 0 to 15 ЊC,
the ee of 75% fell very rapidly to 3%. A 15 degree change in
temperature marks the difference between high or low enantio-
selectivity. To the best of our knowledge, this is the sharpest
5
possible temperature-dependent competing reactions between
7
the monomeric and dimeric zinc species as the active catalyst
might account for the inversion temperature. Alternatively,
the inversion temperature might be caused by the change in
activation energy between the diastereoselective binding of
J. Chem. Soc., Perkin Trans. 1, 1999, 381–382
381

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aldehydes to organozinc species and the alkylation step, which
has been exemplified by Halpern in the olefin binding and
hydrogenation steps with a rhodium complex in the case of
The (S)-(ϩ)-1 was recovered in 80% yield without the loss of
optical purity.
3
asymmetric hydrogenation. Detailed explanations must await
Acknowledgements
further mechanistic and kinetic experiments since exchanges
among the oragnozinc intermediates may be possible and
We thank the Chinese University of Hong Kong for the award
of a postdoctoral fellowship (HCZ) and the Research Grants
Council of Hong Kong (CUHK 4023/98p) for financial
support.
1d
further complicate the mechanistic scheme.
In conclusion, a dramatic temperature effect in the enantio-
selective addition of diethylzinc to aryl aldehydes is observed.
In asymmetric catalysis, careful variations in temperature for
achieving highest ee is encouraged otherwise less satisfactory
results or even the wrong conclusion about a catalyst may be
drawn.
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4
6
and stirred for 48 h under N . Saturated aqueous NH Cl
2
4
0
(
(
5 mL) was added and the mixture was extracted with Et O
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2
thermometer.
7
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over MgSO . Purification by column chromatography on silica
4
gel with a mixture of hexane–EtOAc (4:1) as the eluent
5
afforded 1-phenylpropan-1-ol (3b) (20 mg, 45%) as a colorless
liquid; 35% ee by HPLC analysis (Daicel OD chiral column).
Communication 8/08920E
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J. Chem. Soc., Perkin Trans. 1, 1999, 381–382