Stereoselective 1,5-rearrangement of vinylketene-N,O-acetals: Novel vinylogous Ferrier reaction

Article abstract of DOI:10.1016/j.tetlet.2005.03.050

Vinylketene-N,O-acetals underwent Lewis acid-induced 1,3- or 1,5-rearrangement to afford the corresponding C-alkylated products. 1,5-Rearrangement proceeded predominantly in dichloromethane, and it is quite interesting to achieve an unprecedented high degree of asymmetric induction in such a remote position. Crossover experiments indicated that the reaction proceeded through an ion pair intermediate.

Full text of DOI:10.1016/j.tetlet.2005.03.050

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3245–3248
Stereoselective 1,5-rearrangement of vinylketene-N,O-acetals:
novel vinylogous Ferrier reaction
Masaharu Inui, Seijiro Hosokawa,ꢀ Atsuo Nakazaki and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI), 2641 Yamazaki, Noda, Chiba 278-8510, Japan
Received 28 January 2005; revised 28 February 2005; accepted 4 March 2005
Available online 24 March 2005
Abstract—Vinylketene-N,O-acetals underwent Lewis acid-induced 1,3- or 1,5-rearrangement to afford the corresponding C-alkyl-
ated products. 1,5-Rearrangement proceeded predominantly in dichloromethane, and it is quite interesting to achieve an unprece-
dented high degree of asymmetric induction in such a remote position. Crossover experiments indicated that the reaction proceeded
through an ion pair intermediate.
Ó 2005 Elsevier Ltd. All rights reserved.
We recently reported an unusual MeAlCl2-induced 1,3-
rearrangement of vinylketene-N,O-acetal to C-alkylated
b,c-unsaturated imide.1 For example, when vinylketene-
N,O-acetal 2, prepared from a,b-unsaturated chiral
imide 1, was treated with 2 equiv of MeAlCl2 in toluene
at À78 °C, a-migration product 3 was isolated in 36%
yield with high (20:1) stereoselectivity. A by-product in
this reaction was the 1,5-rearranged product 4 which
was isolated in 25% yield (Scheme 1).
by recombination of the ion pairs at either the a- or
c-position. We were particularly interested in the 1,5-
rearrangement because (1) such a rearrangement of
vinylketene acetal is regarded as an unprecedented vinyl-
ogous Ferrier reaction,2 and (2) 1,5-rearrangement
product could not be easily obtained by the conven-
tional c-alkylation of the corresponding a,b-unsaturated
imide 13 (Scheme 2). These considerations led us to
investigate this rearrangement in detail.
The reaction might proceed through an initial cleavage
of the acetal moiety by the action of MeAlCl2, followed
Since the intermediate of the reaction is an ion pair, it
seemed that the ratio of 1,3- and 1,5-product might be
BnO
N
O
O
O
NaHMDS
BOMCl
MeAlCl
3 36% (20:1)
2
N
O
N
O
toluene
−78°C
THF - HMPA
O
O
BnO
O
O
−78°C
BnO
N
O
1
2
O
4 25%
O
Scheme 1. 1,3-and 1,5-rearrangement of ketene-N,O-acetal.
Keywords: 1,5-Rearrangement; Vinylketene-N,O-acetal; Vinylogous Ferrier reaction; Lewis acid.
*
Corresponding author. Tel./fax: +81 4 7121 3671; e-mail: kobayash@rs.noda.tus.ac.jp
ꢀ Present address: Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.050

3246
M. Inui et al. / Tetrahedron Letters 46 (2005) 3245–3248
BnO
N
O
O
O
LA
3
α-attack
γ-attack
N
O
N
O
BnO CH
BnO
O
O
O
2
O
LA
2
BnO
N
O
O
O
4
Scheme 2. The mechanism of the rearrangement.
strongly affected by the solvent used.4 We then carried
out the reaction of 2 in dichloromethane, and indeed,
the 1,5-rearranged product 4 was isolated as a major
product in 78% yield along with 3 in 15% yield when
10 equiv of MeAlCl2 was used. Among several represen-
tative Lewis acids, aluminum-based Lewis acids afforded
4 in higher yield.5 As shown in Table 1, use of a large
excess of Lewis acid resulted in a slight increase of the
yield of 4.
polar CH2Cl2 resulted in an increase of 1,5-rearranged
product 7. Surprisingly, the 1,5-rearrangement pro-
ceeded in highly stereoselective manner affording 7 in
20:1 ratio.
The stereochemistry of the newly formed chiral center at
the c-position was determined as shown by correlating
to the known monobenzyl ether of 2-methyl-1,3-pro-
panediol 8.6 (Scheme 3) Thus, 7 was treated with ozone
in CH2Cl2–MeOH, followed by reduction with NaBH4
to obtain 8. Measurement of the specific rotation estab-
lished the stereochemistry of 8 and eventually the stereo-
chemistry of 7.
We next prepared c-substituted vinylketene-N,O-acetal
5 from the corresponding unsaturated chiral imide,
and 5 was then subjected to MeAlCl2-induced rear-
rangement (Table 2). Although the ratio of 1,5- and
1,3-rearranged products was not high compared to the
c-unsubstituted substrate 2, the reaction in slightly more
We speculate that the plane of the oxazolidin-2-one moi-
ety might be almost perpendicular to that of the
Table 1. Rearrangement of ketene-N,O-acetal in toluene or CH2Cl2
MeAlCl
2
BnO
N
O
O
N
BnO
N
O
solvent
—78°C
BnO
O
O
O
3
O
4
O
O
2
Entry
Solvent
MeAlCl2 (equiv)
3
4
Yield (%)
d.s.
Yield (%)
1
2
3
Toluene
CH2Cl2
CH2Cl2
2
5
36
13
15
20:1
5:1
25
68
78
10
17:1
Table 2. Rearrangement of c-substituted ketene-N,O-acetal
Me
BnO
Me
MeAlCl
2
BnO
Me
O
N
N
O
O
N
O
solvent
—78°C
BnO
O
O
6
O
O
O
7
5
Entry
Solvent
MeAlCl2 (equiv)
6
7
Yield (%)
d.s.
Yield (%)
d.s.
1
2
Toluene
CH2Cl2
5
4
57
39
42:1
23:1
24
52
20:1
20:1

M. Inui et al. / Tetrahedron Letters 46 (2005) 3245–3248
3247
For the solvent, we think that the intermediary ion pair
exists as a solvent separated ion pair rather than as a
contact ion pair in dichloromethane, and, therefore,
the ion pair might undergo recombination at the more
reactive c-position predominantly.8 In toluene, on the
other hand, initially formed contact ion pair might read-
ily react at the near a-position.
1) O
2) NaBH
3
BnO
Me
BnO
Me
4
O
N
OH
CH Cl , MeOH
2
2
O
O
− 78°C~rt
7
8
57%
d.s. 12:1
24
[α]
-13.9 (c 0.85, CHCl )
D
3
In order to confirm the reaction mechanism, we con-
ducted a crossover experiment. Thus, a mixture of two
vinylketene-N,O-acetal 2 and 9 was treated with
MeAlCl2 in toluene or dichloromethane at À78 °C.
Crossover products are 11 and 12 for 1,3-rearrange-
ment, and 14 and 15 for 1,5-rearrangement, respectively.
Authentic samples of these compounds were prepared
by a rearrangement of the corresponding vinylketene-
N,O-acetals. Results are shown in Table 3. Yields are
6
ent-8 lit. [α] +17.2 (c 3.24, CHCl )
D
3
Scheme 3. Determination of the stereochemistry at the c-position.
dienolate anion, and that the conformation shown in
Figure 1 might be more stable.7 An alternative rota-
tional isomer seems to suffer from steric interaction be-
tween the aluminum group and the sec-butyl group of
the chiral auxiliary. Then, the oxocarbenium ion might
approach from the less hindered upper face to produce
7. The sense of the stereochemical course of the a-alkyl-
ation leading to 3 and 6 could also be explained by con-
sidering the same transition state.1
1
based on the H NMR analysis of the mixture of rear-
ranged products. In toluene (entry 1), the formation of
crossover products was not detected by careful analysis
1
of the H NMR spectra.9 On the other hand, in the
case of dichloromethane (entry 2), a small amount of
1,5-rearranged products, 14 and 15 (5% of each), was
formed in addition to noncrossover products. These re-
sults clearly demonstrate the solvent effect we have spec-
ulated above. In dichloromethane, the solvent separated
ion pair might undergo an intermolecular recombin-
ation. In this case, the alkylation occurs at the more
reactive c-position.
Bn
O
Cl
Al
Cl
In summary, we have observed a novel 1,5-rearrange-
ment of vinylketene-N,O-acetals, which could be re-
O
N
R
garded as
a formal vinylogous Ferrier reaction.
O
Although synthetic applicability of the present rear-
rangement is not significant due to the limitation of sub-
strates, the excellent stereoselectivity is noteworthy
considering that the reaction takes place at a rather
remote site from the chiral center. Therefore, this rear-
rangement would be a unique method for the formal
stereoselective c-alkylation of a,b-unsaturated carbonyl
derivative. Improvements in yield, regioselectivity, and
reaction conditions are now in progress.
Me
O
Al Cl
Cl
Me
Me
Bn
O
Figure 1. Proposed transition state.
Table 3. Crossover experiment using 2 and 9
RO
MeAlCl
2
RO
X
N
X
N
X
N
O
O
2
ROCH O
2
1
2
2
1
1
2
2
1
1
2
(1 equiv.)
(1 equiv.)
3
10
11
4
13
14
R = PhCH
X
= X
= X
= X
= X
R = PhCH
X
= X
= X
= X
= X
2
9
R = PhCH
X
= X
= X
N
N
N
N
N
N
N
N
2
N
N
N
N
N
2
N
N
N
R = p-TolCH
X
X
X
R = p-TolCH
X
N
X
N
X
N
R = p-TolCH
X
2
2
2
N
R = PhCH
R = PhCH
2
2
Ph
12 R = p-TolCH
15 R = p-TolCH
2
2
1
2
X
:
X
N
:
N
O
O
N
N
O
O
Entry
Solvent
MeAlCl2 (equiv)
Yield (%)
a-Alkylation
c-Alkylation
3
10
11
12
4
13
14
15
1
2
Toluene
CH2Cl2
4
8
14
9
10
19
—
—
—
—
23
29
15
24
—
5
—
5

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M. Inui et al. / Tetrahedron Letters 46 (2005) 3245–3248
5. The use of SnCl4 or TiCl4 gave a complex mixture of
References and notes
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AlCl3 were not effective in terms of yield and selectivity.
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4. Reactions in other solvents such as chloroform–dichloro-
methane (1:1) and hexane–dichloromethane (1:1) were also
examined to obtain poor results.