Complete switch of migratory aptitude in aluminum-catalyzed 1,2-rearrangement of differently α,α-disubstituted a-siloxy aldehydes

Article abstract of DOI:10.1002/anie.200800801

(Chemical Equation Presented) Control of the migration tendency: The regiodivergent 1,2-rearrangement of asiloxy aldehydes bearing α-aryl and α-alkyl substituents into α-siloxy ketones has been realized by using different aluminum Lewis acid catalyst/solvent systems (see scheme). The scope of this unprecedented protocol has been investigated with various substrates and clearly demonstrates its utility for the selective synthesis of two structural isomers from one substrate.

Full text of DOI:10.1002/anie.200800801

Angewandte
Chemie
DOI: 10.1002/anie.200800801
Skeletal Rearrangement
Complete Switch of Migratory Aptitude in Aluminum-Catalyzed 1,2-
Rearrangement of Differently a,a-Disubstituted a-Siloxy Aldehydes**
Kohsuke Ohmatsu, Takayuki Tanaka, Takashi Ooi, and Keiji Maruoka*
Skeletal rearrangements involving 1,2-carbon-to-carbon
migration are powerful methods for the structural reorgan-
ization of organic molecules,[1] and they often make it feasible
to construct otherwise hard-to-access molecular frameworks.
Unsymmetrical substrates, however, generally give a mixture
of structural isomers, which constitutes a major drawback of
the 1,2-rearrangement and debases its synthetic utility. Thus,
research into the regioselective 1,2-rearrangement to afford a
single product is of practical importance.
A common
approach to this subject is the design of substrates based on
the relative migratory aptitudes of the substituents[2] and/or
conformational effects,[3] which often establishes selective
transformation leading to the most favorable isomers. Never-
theless, this strategy requires the preparatory installation of
all structural features that will drive the rearrangement in the
desired direction, and, in principle, the obtainable products
are restricted to just one. In contrast, intentional control of
the migratory tendency for the selective synthesis of any
isomer from one substrate by switching the migrating group is
challenging and attractive. Even now, successful examples to
address this issue are very limited.[4]
As part of our research on aluminum-mediated selective
1,2-migrations, we recently developed an enantioselective 1,2-
rearrangement of a,a-disubstituted a-siloxy aldehydes by
using the chiral aluminum Lewis acid 1,[5] in which a kinetic
resolution of racemic, differently a,a-disubstituted a-siloxy
aldehydes was also achieved. When a-siloxy aldehyde 2a was
treated with 1 in toluene at À208C for 12 h, siloxy ketone 3a
was obtained almost exclusively in 49% yield with 86% ee,
along with recovered 2a (51%, 84% ee; Scheme 1). Although
the observed predominant formation of 3a is explicable by
assuming selective migration of the benzyl group over the
Scheme 1. 1,2-Rearrangement of the differently a,a-disubstituted
a-siloxy aldehyde 2a.
phenyl group (with subsequent transfer of the silyl group),
such an interpretation is inconsistent with common under-
standing because the prominent migratory ability of the
phenyl group has been well-documented in pinacol and
Wagner–Meerwein rearrangements. This contradiction
prompted us to pursue further research in a new direction
in order to figure out the crucial element governing the
unique regioselectivity of this reaction, which would enable
the selective preparation of any isomer at will. Herein, we
detail our discovery of an unprecedented regiodivergent 1,2-
rearrangement of differently a,a-disubstituted a-siloxy alde-
hydes.
Our initial investigation was focused on verification of the
effect of the Lewis acid catalyst on the regioselectivity in the
reaction of 2a. Since the previously reported aluminum Lewis
acid 1 has the two characteristic features of steric hindrance
and relatively weak Lewis acidity, we first examined the
impact of the bulkiness of catalyst, and the rearrangement of
2a was thus conducted with a series of sterically hindered
aluminum Lewis acids[6] (Table 1). Interestingly, the use of
ATPH[7] as a catalyst was found to provide an equimolar
mixture of the two isomers, 3a and 4a (Table 1, entry 1).
Whereas a similar product distribution was retained in the
reaction with MABR,[8] 3a was obtained preferentially, with a
3a/4a ratio of 5:1, when the structurally similar but less Lewis
acidic MAD[9,10] was employed (Table 1, entries 2 and 3).
These results, particularly the distinct difference in the
regioselectivity between the reactions with MABR and
MAD, imply that the selectivity is influenced by the Lewis
acidity of the catalyst rather than its steric size. Enhancement
of the Lewis acidity might thus lead to an increase in the
proportion of 4a in the rearranged products.
[*] K. Ohmatsu, T. Tanaka, Prof. T. Ooi,[+] Prof. K. Maruoka
Department of Chemistry
Graduate School of Science
Kyoto University, Sakyo, Kyoto, 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[+] Current address:
Department of Applied Chemistry
Graduate School of Engineering
Nagoya University, Chikusa, Nagoya, 464-8603 (Japan)
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformation of
Carbon Resources” from the Ministry of Education, Culture, Sports,
Science, and Technology (Japan). K.O. is grateful to the Japan
Society for the Promotion of Science for Young Scientists for a
Research Fellowship.
We next performed the reactions of 2a with other
catalysts to elucidate the relationship between the regiose-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: 1,2-Rearrangement of a-siloxy aldehyde 2a with sterically
hindered aluminum Lewis acids.[a]
Lewis acidity (Table 2, entry 4); this result supported the
hypothesis that a stronger Lewis acid might lead to an
increase in the proportion of 4a in this rearrangement.
Encouraged by these interesting results, we subsequently
tuned the reaction parameters to enhance the preference
toward the formation of 4a. To our delight, use of CH2Cl2
instead of toluene as a solvent led to an improvement in the
selectivity (Table 2, entries 5 and 4), and 4a was eventually
isolated as the only product by lowering the reaction temper-
ature to À208C (Table 2, entry 6).
We next evaluated the substrate scope of the regiodiver-
gent 1,2-rearrangement of a-siloxy aldehydes with different
Al catalyst/solvent systems (Table 3). By a judicious choice of
Entry
Lewis acid
Yield [%][b]
3a/4a[c]
Table 3: 1,2-Rearrangement of a-siloxy aldehydes 2 with several alumi-
1
2
3
ATPH
MABR
MAD
29
45
35
1:1
1:1
5:1
num Lewis acid/solvent systems.
[a] The reaction was carried out with 10 mol% of the Lewis acid under
the given reaction conditions. [b] Product isolated as a mixture of 3a and
1
4a. [c] Determined by H NMR analysis.
lectivity and the Lewis acidity (Table 2). Initially, we found
that one of the most conventional aluminum Lewis acids,
Me2AlCl, promoted the rearrangement of 2a to 3a with
complete selectivity (Table 2, entry 1). Biphenyl-based alu-
minum Lewis acids, such as 5[11] and 6,[12] were then chosen for
further examinations because their Lewis acidities could be
readily regulated by an appropriate combination of the
heteroatoms bound to aluminum. The attempted reaction of
2a with 5 preferentially provided 3a (with a 5:1 ratio of 3a/
4a), and switching of the catalyst to the comparatively strong
Lewis acid 6a reduced the regioselectivity (Table 2, entries 2
and 3). Moreover, the product distribution was reversed in the
reaction under the influence of 6b, which has even higher
Entry Substrate Method[a] T [8C] t [h] Yield [%][b] 3/4[c]
1
2
2b
2b
2c
2c
2c
2d
2d
2e
2e
2e
2 f
A
B-1
A
0
À20
0
24
12
24
12
24
24
24
24
24
48
48
48
24
12
24
24
91
99
93
64
98
61
71
99
99
63
60
76
97
99
81
73
10:1
<1:20
>20:1
1:5
3
4
5
6
B-1
B-2
A
À20
À40
0
<1:20
>20:1
<1:20
>20:1
1:3
<1:20
>20:1
<1:20
11:1
7
8
9
10
11
12
13
14[d]
15
16
B-1
A
B-1
B-2
A
B-1
A
B-1
A
À20
0
À20
À50
RT
2 f
À20
Table 2: Reaction of 2a with four Lewis acids.[a]
2g
2g
2h
2h
0
À20
RT
À20
<1:20
3:1
<1:20
B-1
[a] Method A: 10 mol% Me2AlCl in toluene. Method B-1: 10 mol% 6b in
CH2Cl2. Method B-2: 10 mol% 6c in CH2Cl2. [b] Product isolated as a
1
mixture of 3 and 4. [c] Determined by H NMR spectroscopic analysis.
[d] The rearranged product 4 f easily isomerized to the corresponding
allenyl ketone.[14]
.
method, reversals of selectivity were observed in the reactions
of a-triethylsiloxy aldehydes bearing benzyl and various aryl
substituents (Table 3, entries 1–7). For these substrates, the
catalytic Me2AlCl system in toluene (method A) was uni-
formly effective, and a-siloxy ketones 3 were obtained with
good to excellent selectivities (Table 3, entries 1, 3, and 6).
Although the rearrangement of 2c with an electron-deficient
aryl group proceeded sluggishly and exhibited poor regiose-
lectivity under the influence of 6b, almost quantitative yield
and high selectivity were achieved with 6c at a lower
Entry Lewis acid Solvent T [8C] t [h] Yield [%][b] 3a/4a[c]
1
2
3
4
5
6
Me2AlCl
5
6a
6b
6b
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
0
0
0
0
0
24
24
24
24
12
12
91
71
99
99
99
99
>20:1
5:1
3:1
1:1.5
1:4
<1:20
6b
À20
[a] The reaction was carried out with 10 mol% of the Lewis acid under
the given reaction conditions. [b] Product isolated as a mixture of 3a and
1
4a. [c] Determined by H NMR analysis.
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temperature (Table 3, entries 4 and 5). Subsequently, phenyl-
and various alkyl-substituted substrates, 2e–h, were examined
(Table 3, entries 8–16). Although method B-2 proved to be
superior for the selective formation of siloxy ketones 4, the
complicated procedure for the preparation of 6c[13] led us to
employ it only when unsatisfactory results were obtained with
6b. For instance, the selectivity in the transformation of 2e
with phenyl and allylic substituents to the corresponding
siloxy ketone 4 was greatly improved by changing the method
from B-1 to B-2 (Table 3, entries 9 and 10). On the other
hand, excellent regiodivergent rearrangements were feasible
with phenyl- and propargyl- or phenyl- and cyclopropyl-
methyl-substituted substrates (2 f and 2g, respectively), for
which the use of method B-1 was sufficient for the exclusive
production of 4 (Table 3, entries 11–14). Furthermore, the
phenyl- and cyclohexyl-substituted aldehyde 2h was also
tolerated (Table 3, entries 15 and 16).
Scheme 3. The two possible reaction pathways.
The reactions of optically active substrate (R)-2a were
also examined. When (R)-2a (97% ee) was treated with
Me2AlCl (10 mol%) in toluene at 08C for 24 h, the re-
arranged product 3a was isolated in 90% yield with 94% ee
(Scheme 2). By contrast, unfortunately, the reaction with
Scheme 4. 1,2-Rearrangement of the 13C-labeled substrate [13C]-2a.
not detected by either 1H or 13C NMR spectroscopy. Fur-
thermore, upon treatment with 6b in CH2Cl2 at À208C
(method B-1), [13C]-2a underwent selective transformation
into product [1-13C]-4a, in which the 13C label was incorpo-
rated as the carbon atom bearing the ethereal oxygen atom. If
a 1,2-hydride shift had occurred, isomers [1-13C]-3a and [2-
13C]-4a incorporating the 13C label as the carbonyl carbon
atom would have been produced. Thus, these results unequiv-
ocally confirmed that the rearrangement exclusively pro-
ceeded through the silyl-transfer process and that the
regiodivergent synthesis of siloxy ketones 3 and 4 essentially
stemmed from the switch of the migrating group.
In summary, a complete switch of migratory aptitude in
the 1,2-rearrangement of differently a,a-disubstituted a-
siloxy aldehydes has been realized by using different Al
catalysts and conditions, and we have successfully demon-
strated that the methods to rigorously control the group
migration could be applied to various substrates. These
investigations should pave the way for the development of a
new protocol for the selective preparation of any structural
isomer from one substrate by switching the migratory
tendency in the skeletal rearrangement. Further studies are
underway to gain a deep insight into the mechanism of these
unprecedented regiodivergent rearrangements.
Scheme 2. 1,2-Rearrangement of optically active a-siloxy aldehyde
(R)-2a.
catalyst 6b was concomitant with a significant decrease in the
ee value, probably due to the intervention of the two
competing transition states, and this resulted in a maximum
enantioselectivity of 75%.
Next, we turned our attention to the reaction pathway.
1,2-Rearrangement of a-siloxy aldehyde 2 to a-siloxy ketones
3 or 4 would be initiated by activation of the aldehyde through
coordination of the Lewis acid, which promotes the nucleo-
philic migration of the a substituent. After this initial
migration, two mechanistic rationales are conceivable for
quenching the remaining cation; one is intra- or intermolec-
ular transfer of the silyl group (path a) and the other is a 1,2-
hydride migration (path b; Scheme 3).
In order to clarify whether silyl-group transfer or 1,2-
hydride migration is involved in quenching the zwitterionic
intermediate, the reactions were performed with the 13C-
labeled (C*) substrate [13C]-2a (Scheme 4). When aldehyde
[13C]-2a was treated with Me2AlCl (10 mol%) in toluene at
08C (optimized method A), siloxy ketone [2-13C]-3a was
obtained as the only product, and the isomer [1-13C]-3a was
Received: February 19, 2008
Published online: June 4, 2008
Keywords: aluminum · Lewis acids · rearrangement ·
.
regioselectivity · synthetic methods
Angew. Chem. Int. Ed. 2008, 47, 5203 –5206
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Communications
[8] For a report concerning the preparation of MABR, see: K.
Maruoka, K. Nonoshita, H. Banno, H. Yamamoto, J. Am. Chem.
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[1] For a review, see: Comprehensive Organic Synthesis, Vol. 3
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´
´
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[13] 6c was prepared from Me2AlCl, AgNTf2, and 2,2’-bis(trifluoro-
methanesulfonylamino)-1,1’-biphenyl. For details, see the Sup-
porting Information.
[14] While the reaction of 2 f by using method B-1 resulted in the
desired selective rearrangement, the product immediately
tautomerized to the allenyl ketone.
[5] T. Ooi, K. Ohmatsu, K. Maruoka, J. Am. Chem. Soc. 2007, 129,
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[6] For a review, see: N. Miyaura, K. Maruoka in Synthesis of
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Saito, H. Yamamoto, J. Am. Chem. Soc. 1994, 116, 4131.
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