Bidentate Organoaluminum Lewis Acids
A R T I C L E S
phenoxy group to 2,6-xylenoxy (11), 2,6-diisopropylphenoxy
(14b), and 2,6-di-tert-butylphenoxy (14c) groups, the Z-selectiv-
ity decreased from 80:20 to 70:30, 67:33, and 33:67, respec-
tively. Based on the results, the stereochemical outcome of the
present organoaluminum-promoted Michael addition should be
discussed. The Z-selectivity observed with sterically less
hindered 14a or 11 is interpreted by the preferrable formation
of complex S. The aluminum phenoxide 14b or 14c possessing
more hindered 2,6-substituents would tend to coordinate to the
carbonyl lone pair anti to the methyl group (complex T), which
would be in equilibrium shifted to the conformationally more
stable complex U due to the steric repulsion between the
phenoxy ligand and ketone substituent, thereby increasing the
formation of E-isomeric Michael adduct 16. In the ultimate case,
bidentate 2a can be utilized to obtain E-isomeric 16 as a major
product via the formation of complex V with s-trans conforma-
tion (Scheme 6).38
Figure 8.
one pair of interaction orbitals in the monodentate complex R
(Figure 8). Actually, the electronic charge shifted from the
formaldehyde to Lewis acid was calculated to be 0.171 for the
complex Q and 0.134 for the complex R, respectively,36
suggesting that the carbonyl group is more strongly activated
in Q toward an attack of a nucleophile.
Next, we evaluated numerically the extent of the activation
of the formaldehyde moiety by the Lewis acids. Because the
SCF calculations for each complex system show that the
carbonyl π* orbital is obtained as one of the canonical
unoccupied orbitals and is almost 100% localized on the
carbonyl group as in the formaldehyde molecule in an isolated
state, the energy level of this π* MO (LUMO) orbital can be a
good index for the reactivity of the carbonyl moiety. It has been
calculated to be 0.052 au in Q and 0.068 au in R, 0.086 and
0.070 au lower than the value of formaldehyde itself, respec-
tively. This, together with the result obtained above, directly
support the double electrophilic activation of the carbonyl group
by the bidentate Lewis acid 2a.13a,22f,23b,c
Chemoselectivity. In addition to the stereoselectivity, the
chemoselectivity of the bidentate Lewis acids was investigated
in conjunction with our interest in the molecular recognition
ability of bis(organoaluminum) 2a. The chemoselective func-
tionalization between carbonyls and their masked acetals is a
synthetically useful operation. Most of the ordinary Lewis acid
promoters activate both carbonyl and acetal functions.39 The
discrimination of acetals over carbonyls is commonly achievable
using TiCl4 and Me3SiOTf; these, for instance, induce selective
aldolization of acetal functionality with enol silyl ethers in the
presence of carbonyl groups by taking advantage of the inherent
inertness of ketones and aldehydes toward enol silyl ethers under
the influence of them.40 However, the opposite selectivity, that
is, chemoselective functionalization of carbonyls, seems quite
difficult to attain in view of the high reactivity of acetal
counterparts for Lewis acids, and hence it has not yet been fully
realized in electrophilic reactions despite long-standing concern.
In this situation, chemoselective preference for carbonyl com-
pounds in the aldol reactions with ketene silyl acetals has been
achieved by use of organotin Lewis acids,41 utilizing the fact
that ketene silyl acetals intrinsically react with aldehydes more
readily than with acetals, whereas enol sily ethers are compatible
with acetals. Actually, reaction of a mixture of 1 equiv each of
benzaldehyde and its dimethyl acetal with 1-(trimethylsiloxy)-
1-cyclohexene under the influence of catalytic Me3SiOTf (5 mol
%) in CH2Cl2 at -78 °C for 3 h afforded aldol products 12 (R
) H) and 18 (86% combined yield) in a ratio of 9:91 (Scheme
7).40a,b,42 Switching a Lewis acid from Me3SiOTf to TiCl4
resulted in the loss of selectivity (ratio of 12:18 ) 59:41), and
both SnCl4 and BF3‚OEt2 exhibited moderate and opposite
chemoselectivity (73:27 and 74:26, respectively). In contrast,
however, bis(organoaluminum) 2a as a bidentate Lewis acid,
on treatment with an equimolar mixture of benzaldehyde and
Evaluation of the Selectivity of Bidentate Organoalumi-
num Lewis Acids: Stereoselectivity. We then focused our
attention on examining the selectivity of bidentate Lewis acids
in organic synthesis and first applied bis(organoaluminum) 2a
to the regio- and stereocontrolled Michael addition of silyl
ketene acetals to R,â-unsaturated ketones as acceptors.37 Reac-
tion of benzalacetone and silyl ketene acetal 13 with dimethyl-
aluminum aryloxides of type 14 gave rise to a mixture of
Michael adducts 15 and 16 almost exclusively, where the
stereoselectivity was found to be profoundly influenced by the
steric size of a phenoxy ligand. Initial treatment of benzalacetone
with dimethylaluminum phenoxide 14a and subsequent reaction
with 13 in CH2Cl2 at -78 °C instantaneously produced 15 and
16 in 74% combined yield, and the 15/16 (Z/E) ratio was
1
determined to be 80:20 by H NMR analysis. Switching the
(38) The E-isomer 16 is a thermodynamically less stable product, and standing
of 16 resulted in gradual conversion to a thermodynamically more stable
Z-isomer 15.
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