Al Lewis acid-catalyzed regiodivergent 1,2-rearrangement of α-siloxy aldehydes: scope and mechanism

Article abstract of DOI:10.1016/j.tet.2009.06.126

Regiodivergent 1,2-rearrangement of α-siloxy aldehydes bearing α-aryl and α-alkyl substituents into α-siloxy ketones has been realized by using different Al Lewis acid catalyst/solvent systems. The scope of this unprecedented protocol has been investigate

Full text of DOI:10.1016/j.tet.2009.06.126

Tetrahedron 65 (2009) 7516–7522
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Tetrahedron
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Al Lewis acid-catalyzed regiodivergent 1,2-rearrangement of
aldehydes: scope and mechanism
a-siloxy
,
b,
*
Kohsuke Ohmatsu a, Takayuki Tanaka b, Takashi Ooi a , Keiji Maruoka
*
a Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603, Japan
b Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2009
Received in revised form 30 June 2009
Accepted 30 June 2009
Available online 4 July 2009
Regiodivergent 1,2-rearrangement of
a-siloxy aldehydes bearing a-aryl and a-alkyl substituents into
a-siloxy ketones has been realized by using different Al Lewis acid catalyst/solvent systems. The scope of
this unprecedented protocol has been investigated with various substrates, clearly demonstrating its
utility for the selective synthesis of two structural isomers from one substrate. Controlled experiments
proved that the regiodivergency resulted from the switch of the migrating group.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aluminum
Lewis acids
Rearrangement
Regioselectivity
Synthetic methods
1. Introduction
features that will drive the rearrangement in the desired direction,
and in principle the obtainable product is restricted to only one. In
1,2-Rearrangements, represented by pinacol1 and Wagner–
Meerwein2 rearrangements, are classical yet powerful tools for the
structural reorganization of organic molecules through the con-
secutive or concurrent cleavage and formation of carbon-carbon
bonds,3 often making it feasible to construct otherwise hard-to-
access molecular frameworks with simplicity and high level of
atom economy.4 Inducing regiochemistry in such processes, how-
ever, leads to a formidable problem in that it requires the control of
migrating group (Eq. (1)).
contrast, intentional control of the migratory tendency for the se-
lective synthesis of any isomers from one substrate is attractive yet
challenging objective.
In various 1,2-rearrangement, the relative migratory tendency of
aryl>alkyl is generally accepted. For instance, phenyl group is well
known to have an excellent migrating ability in pinacol and Wag-
ner–Meerwein rearrangement. This large migratory aptitude of aryl
group is usually accounted for by participation of
p-orbitals
delocalizing the developing charge of the carbonium ion into the
aromatic ring.5d,e,7 The stability of the transition states in 1,2-
rearrangement, however, depends not only on the activity of the
migrating group but also on the steric and/or electronic effects of
the non-migrating group.7 Therefore, the ability of aryl group to
conjugatively stabilize a neighboring cation could sometimes cause
inverse aptitude to prevail.8 Indeed, in our previous research on the
ð1Þ
enantioselective 1,2-rearrangement of differently
a
a,a-disubstituted
A common approach to this problem is the design of substrates
based on the relative migratory aptitude of substituents,5 and/or
conformational effect,6 which often establishes selective trans-
formation leading to the most favorable isomers. Nevertheless, this
strategy requires the preparatory installation of all the structural
-siloxy aldehydes,9 the reaction of 1a predominantly afforded
siloxy ketone 2a (Scheme 1), which was interpretable as the result
of selective migration of benzyl group over phenyl despite higher
migrating ability of phenyl group. In consideration of such a con-
tradiction, we have been interested in the possibility of developing
the regiodivergent 1,2-rearrangement via intentional control of
migrating group, i.e., switch of migratory tendency.10,11 Reported
herein are the study on the realization of regiodivergency in 1,2-
* Corresponding authors. Tel.: þ81 52 789 4501; fax: þ81 52 789 3338 (T.O.);
tel./fax: þ81 75 753 4041 (K.M.).
rearrangement of
investigations.
a-siloxy aldehydes and the detailed mechanistic
E-mail addresses: tooi@apchem.nagoya-u.ac.jp (T. Ooi), maruoka@kuchem.
kyoto-u.ac.jp (K. Maruoka).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.126

K. Ohmatsu et al. / Tetrahedron 65 (2009) 7516–7522
7517
similar, but less Lewis acidic methylaluminum bis(2,6-di-tert-butyl-
4-methylphenoxide) (MAD)15,16 (entries 5 and 6). Subsequently, we
tuned the reaction parameters for enhancing the preference toward
the formation of 3a. To our delight, use of dichloromethane as a sol-
vent instead of toluene led to improvement of the selectivity (entry 7
vs 4) and 3a was eventually isolated as a sole product by lowering the
reaction temperature to –20 ꢀC (entry 8).
2.2. Substrate scope
With the protocol for switching the regioselectivity in hand,
subsequent experiments were conducted to probe the substrate
scope of this unprecedented regiodivergent 1,2-rearrangement
Scheme 1. Kinetic resolution of differently a,a-disubstituted a-siloxy aldehyde.
(Table 2). In the reactions of
a-triethylsiloxy aldehydes bearing
2. Results and discussion
Table 2
Substrate scope
2.1. Development of regiodivergent 1,2-rearrangement
of -siloxy aldehydes
a
Toexaminewhetherthedegreeofregioselectivitywasdependent
only on the structural features of substrate, we initiated our in-
vestigation by performing the reaction of -siloxy aldehydes 1a with
a
various Al catalysts. Although one of the most conventional Al Lewis
acids, Me2AlCl, promoted the predominant transformation of 1a to
2a in toluene at 0 ꢀC, the use of biphenyl-based Al catalyst 412 was
found to provide a mixture of two regioisomers, 2a and 3a, in a ratio
of 5:1 (entries 1 and 2, Table 1). Encouraged by this interesting result,
we conducted further examination by using other Al Lewis acids.
Switching the catalyst from 4 to comparatively strong Lewisacid5a13
resulted in reducing the proportion of 2a (entry 3). Moreover, the
productdistributionwas reversed in thereaction under theinfluence
of 5b with ever higher Lewis acidity (entry 4), which implied that
stronger Lewis acid might lead to increase in the ratio of 3a in the
present rearrangement. Although it was assumed that the selectivity
was influenced mainly by the steric size of the catalyst rather than its
Lewis acidity, this possibility was ruled out by the distinct difference
of the regioselectivity between the reactions with methylaluminum
bis(2,6-di-tert-butyl-4-bromophenoxide) (MABR)14 and structurally
Entrya
Substrate
Method
Temp.
Yieldb
2/3c
1
2
A
B-1
0 ꢀ
C
91
99
10:1
1:>20
ꢁ20 ꢀC
3
4
5
A
B-1
B-2
0 ꢀ
C
93
64
98
>20:1
1:5
1:>20
ꢁ20 ꢀC
ꢁ40 ꢀC
Table 1
0 ꢀ
C
61
71
>20:1
1:>20
1,2-Rearrangement of a-siloxy aldehydes 1a with several Lewis acids
6
7
A
B-1
ꢁ20 ꢀC
8
9
10
A
B-1
B-2
0 ꢀ
C
99
99
63
>20:1
1:3
1:>20
ꢁ20 ꢀC
ꢁ50 ꢀC
11
A
B-1
rt.
60
76
>20:1
1:>20
12d
ꢁ20 ꢀ
C
C
13
14
A
B-1
0 ꢀ
ꢁ20 ꢀ
C
97
99
11:1
1:>20
Entrya
Lewis acid
Conditions (solvent, ꢀC)
Yieldb (%)
2a/3ac
1
2
3
4
5
6
7
8
Me2AlCl
4
5a
Toluene, 0
Toluene, 0
Toluene, 0
Toluene, 0
Toluene, 0
Toluene, 0
CH2Cl2, 0
91
71
99
99
45
35
99
99
>20:1
5:1
3:1
1:1.5
1:1
5:1
1:4
1:>20
15
16
A
B-1
rt.
81
73
3:1
1:>20
ꢁ20 ꢀC
5b
MABR
MAD
5b
a
The reaction was carried out with 10 mol % of Lewis acid under the given
reaction conditions.
5b
CH2Cl2, ꢁ20
a
b
The reaction was carried out with 10 mol % of Lewis acid under the given
reaction conditions.
Isolated as a mixture of 2 and 3.
c
Determined by 1H NMR analysis.
b
d
Isolated as a mixture of 2a and 3a.
The rearranged product 3f immediately isomerized to the corresponding allenyl
Determined by 1H NMR analysis.
c
ketone.

7518
K. Ohmatsu et al. / Tetrahedron 65 (2009) 7516–7522
benzyl and various aryl substitutents 1b–d, the catalytic Me2AlCl
system in toluene (method A) was uniformly effective, and
migration, two mechanistic rationales are conceivable for
quenching the remaining cation; one is intra- or intermolecular
transfer of the silyl group (path a, Scheme 2) and the other is a 1,2-
hydride migration (path b).
a
-siloxy ketones 2 were obtained with good to excellent selec-
tivities (entries 1, 3 and 6). In contrast, the reactions with Al
catalyst 5b in CH2Cl2 (method B-1) proceeded with opposite sense
of regioselectivities, leading to the preferential formation of siloxy
ketones 3 (entries 2, 4 and 7). Whereas the rearrangement of 1c
with an electron-deficient aryl group exhibited only moderate
selectivity under the influence of 5b, complete selectivity for 3
was achieved with 5c in CH2Cl2 (method B-2) at lower tempera-
ture (entry 4 vs 5). By the appropriate choice of the method (i.e.,
method A: with Me2AlCl in toluene, method B-1: with 5b in
CH2Cl2 and method B-2: with 5c in CH2Cl2), the reversals of
regioselectivity were also observed in the reactions of phenyl- and
In order to clarify whether silyl group transfer or 1,2-hydride
migration is involved in quenching the zwitterionic intermediate,
the reactions were performed using 13C (C
[
*
) labeled substrate
13C]-1a (Scheme 3). When aldehyde [13C]-1a was treated with
10 mol % of Me2AlCl in toluene at 0 ꢀC (method A), siloxy ketone
[2-13C]-2a was obtained as a sole product, and the isomer [1-13C]-
2a was not detected by either 1H or 13C NMR spectroscopy. Further,
upon treatment with 5b in CH2Cl2 at –20 ꢀC (method B-1), [13C]-1a
underwent selective transformation to a product [1-13C]-3a, in
which 13C was incorporated at the carbon bearing ethereal oxygen.
If the 1,2-hydride shift had occurred, the isomers [1-13C]-2a and
[2-13C]-3a incorporating 13C at the carbonyl carbon would have
been produced. Thus, these results unequivocally confirmed that
the rearrangement exclusively proceeded via silyl transfer process,
and the realization of the regiodivergent synthesis of siloxy ke-
tones 2 and 3 essentially stemmed from the switch of the mi-
grating group.
various alkyl-substituted a-siloxy aldehydes 1e–h (entries 8–16).
These substrates were also tolerated to afford siloxy ketones 2
with moderate to high selectivities by using method A (entries 8,
11, 13 and 15). Although method B-2 proved to be superior for the
selective formation of siloxy ketones 3, the complicated procedure
for the preparation of 5c led us to employ it only when
unsatisfactory results were obtained with 5b. For instance, the
selectivity in the transformation of 1e having phenyl and allylic
substituents to the corresponding siloxy ketone 3 was greatly
improved by changing the method from B-1 to B-2 (entry 9 vs 10).
On the other hand, the use of method B-1 was sufficient for ex-
clusive production of 3 in the rearrangement of phenyl- and
propargyl-, phenyl- and cyclopropylmethyl-, or phenyl- and
cyclohexyl-substituted substrates 1f–h (entries 12, 14 and 16).
2.3. Mechanistic investigation
2.3.1. Interrogating the 1,2-hydride shift
The catalytic cycle of 1,2-rearrangement of
-siloxy ketones 2 or 3 would be initiated by the activation of
aldehyde via the coordination of Lewis acid, which promotes the
nucleophilic migration of -substituent. Following this initial
a-siloxy aldehyde 1
to
a
Scheme 3. 1,2-Rearrangement of the 13C-labeled substrate [13C]-2a.
a
2.3.2. Silyl group transfer pathway
To gain insight into the silyl group transfer, we performed
crossover experiments with two siloxy aldehydes, 1a and [TBS]-1i,
which were differentiated in the identity of both silyl groups and a-
alkyl substituents (Scheme 4). When an equimolar mixture of 1a
and [TBS]-1i was treated with 10 mol % of Me2AlCl in toluene, 2a
and [TBS]-2i were obtained in a ratio of 1:1, and neither [TBS]-2a
nor 2i was detected by 1H NMR spectroscopy, revealing that the
silyl transfer process takes place intramolecularly. On the other
hand, the distribution of silyl groups was observed under the in-
fluence of 5c in dichloromethane,17 affording a mixture of 3a, [TBS]-
Scheme 2. The two possible reaction pathways.
Scheme 4. Test for the silyl transfer pathway.

K. Ohmatsu et al. / Tetrahedron 65 (2009) 7516–7522
7519
3a, [TBS]-3i and 3i. Additional control experiments showed that
neither the silyl group of siloxy aldehydes 1a and [TBS]-1i nor that
of siloxy ketones 3a and [TBS]-3i was exchanged under similar
conditions. These experimental results suggested the involvement
of the intermolecular silyl group transfer process. One of the two
possible pathways is the intermolecular silyl shift between the
zwitterionic intermediates, and the other is the siloxocarbenium
ion-promoted 1,2-rearrangement. In the reaction with method B-2,
the strong coordination of oxygen anion to the highly Lewis acidic
Al of 5c in the intermediate might diminish the nucleophilicity of
the alkoxy moiety, and hence both the intra- and intermolecular
silyl shift would be suppressed, allowing the generation of highly
active siloxocarbenium ion. This cationic silyl species could pro-
mote the subsequent rearrangement as a Lewis acid (Fig. 1),18 from
which the distribution of silyl groups might result.
Figure 2. Plausible transition state of 1,2-benzyl migration.
Scheme 6. 1,2-Rearrangement of optically active substrate with 5b.
group would generate the intermediary zwitterions as shown in
Figure 3, in which the alkoxy functionality is aligned at anti position
to the siloxy group. From this disposition, the intramolecular silyl
shift is apparently unfavorable, leading to either the intermolecular
silyl shift or the generation of siloxocarbenium ion intermediate.
Figure 1. 1,2-Rerarrangement promoted by the siloxocarbenium ion.
2.3.3. Conformation in transition states
Finally, to elucidate the preferred conformation of transition
states, stereospecific 1,2-rearrangement of optically active a-siloxy
aldehyde was tested. Thus, (R)-1a (97% ee) was treated with
10 mol % of Me2AlCl in toluene at 0 ꢀC for 24 h, and the rearranged
2a was isolated in 90% yield with 94% ee (Scheme 5). Its absolute
configuration was established as R by comparison of the optical
rotation with a reported value after desilylation,9,19 which sug-
gested that the benzyl group migration via ‘siloxy-eclipsed confor-
mation’ is operative almost exclusively (Fig. 2). As a result of the
selective benzyl shift in such a manner, the zwitterionic in-
termediate with the alkoxy moiety disposed at syn position to the
siloxy group would be generated, thereby undergoing the facile
intramolecular silyl shift.
Figure 3. Plausible transition state of 1,2-phenyl migration.
In summary, a complete switch of migratory aptitude in 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 demonstrated that the methods to rigorously
control the group migration could be applied to various substrates.
The reaction pathways of the 1,2-rearrangements were proposed
based on the detailed mechanistic studies. These investigations
should pave the way for the development of a new protocol for the
selective preparation of any structural isomers from one substrate
by switching the migratory tendency in the skeletal rearrangement.
Scheme 5. 1,2-Rearrangement of optically active substrate.
Next, we examined the rearrangement of (R)-1a with method B-
1 and found that the 1,2-migration of phenyl group was concomi-
tant with a significant decrease in ee, resulting in a maximum value
of 75% (Scheme 6).
The absolute configuration of the resulting 3a was determined
to be R by comparison of the optical rotation with a known litera-
ture value20 after derivatization. This result indicated that, in con-
trast to the case with method A, phenyl migration preferably
proceeds via ‘benzyl-eclipsed’ conformation. Such 1,2-shift of phenyl
3. Experimental procedures
3.1. General
Infrared (IR) Spectra were recorded on a Shimadzu FT-IR. 1H and
13C NMR spectra were measured on JEOL JNM-FX400 (400 MHz)
and JEOL AL-400 (400 MHz) spectrometers. Chemical shifts of 1H
NMR spectra were reported in ppm relative to tetramethylsilane
(d
0). Chemical shifts of 13C NMR spectra were reported in ppm

7520
K. Ohmatsu et al. / Tetrahedron 65 (2009) 7516–7522
relative to the residual solvent (chloroform,
d
77.07). Analytical high
chromatography on silica gel (CH2Cl2/hexane¼1:4 as eluant) to give
the title compound (2.8 g, 8.2 mmol, 82% yield for three steps) as
colorless oil. 1H NMR (400 MHz, CDCl3)
9.77 (1H, s, CHO), 7.26–
performance liquid chromatography (HPLC) was performed on
a Shimadzu LC-10AT instrument equipped with a column of Daicel
Chiralcel OD-H and OJ-H. Optical rotations were measured on
a JASCO DIP-1000 digital polarimeter. The high-resolution mass
spectra (HRMS) were measured on an BRUKER DALTONICS micro-
TOF focus-KR spectrometer. Analytical thin layer chromatography
(TLC) was performed on Merck precoated TLC plates (silica gel 60
GF254, 0.25 mm) throughout this work. Flash column chromato-
graphy was performed on silica gel 60 (Merck 1.09386.9025, 230–
400 mesh). EYELA PSL-1400 and EYELA PSL-1800 constant tem-
perature baths were used for low temperature 1,2-rearrangement
reactions.
d
7.33 (5H, m, Ph-H), 7.12–7.14 (3H, m, Ph-H), 6.95–6.98 (2H, m, Ph-
H), 3.32 (1H, d, J¼14.2 Hz, PhCH2), 3.25 (1H, d, J¼14.2 Hz, PhCH2),
0.89 (9H, t, J¼8.0 Hz, CH3CH2Si), 0.58 (6H, q, J¼8.0 Hz, CH3CH2Si);
13C NMR (100 MHz, CDCl3)
d 199.8, 139.4, 135.4, 130.7, 128.2, 127.6,
127.5, 126.3, 126.0, 85.1, 44.9, 7.0, 6.8; IR (neat) 2954, 2937, 2910,
2875, 2808, 1734, 1496, 1454, 1242, 1143, 1076, 1008, 956, 761, 729,
698 cmꢁ1; HRMS (ESI-TOF) Calcd for C21H28NaO2Si ([MþNa]þ):
363.1751. Found: 363.1762.
a
-Siloxy aldehydes 1b,11 1c,9 1d,11 1e,9 and 1f–h11 showed the
identical spectra according to the literature.
All air- and moisture-sensitive reactions were performed under
an atmosphere of argon in flame-dried, round bottom flasks fitted
with rubber septa. The manipulations for Al-catalyzed 1,2-rear-
rangements were carried out with standard Schlenk techniques
under nitrogen. In experiments requiring dry solvent, toluene and
CH2Cl2 were purified by both A2 alumina and Q5 reactant using
a GlassContour solvent dispensing system. Tetrahydrofuran (THF)
was purchased from Kanto Chemical Co., Ltd. as ‘dehydrated’. Me3Al
and Me2AlCl were kindly supplied from Tosoh-Finechem Co., Ltd.,
Japan. Other simple chemicals were purchased and used as such.
3.3. General procedure for 1,2-rearrangement of a,a-
disubstituted a-siloxy aldehydes
3.3.1. With dimethylaluminum chloride
To a solution of 1a (170.3 mg, 0.5 mmol) in toluene (5.0 mL) was
added a 1 M toluene solution of Me2AlCl (50
L, 0.05 mmol) at 0 ꢀC
under nitrogen. After stirring for 24 h, sodium fluoride (8.4 mg,
0.2 mmol) and water (2.7 L, 0.15 mmol) were added and the whole
m
m
mixture was stirred for 30 min at room temperature. To remove
precipitates, filtration through Celite with EtOAc was carried out.
Concentration of the filtrate and purification by column chroma-
tography on silica gel (CH2Cl2/hexane¼1:4 as eluant) afforded
a mixture of 2a and 3a (154.9 mg, 0.455 mmol, 91% yield, 2/
3.2. Preparation of a-siloxy aldehyde 1a
3.2.1. 2-Phenyl-2-(triethylsiloxy)acetonitrile
To a solution of benzaldehyde (1.0 mL, 10 mmol) and tri-
ethylsilylcyanide (1.4 g, 10 mmol) in CH2Cl2 (30 mL) was added
iodine (253.8 mg, 1.0 mmol) at 0 ꢀC under argon. After stirring for
1 h, the reaction mixture was quenched with satd Na2SO3 and ex-
tractive workup was conducted with EtOAc. The combined extracts
were washed with brine and dried over anhydrous Na2SO4. After
filtration and concentration, the resulting liquid was used for next
step without any purification. 1NMR of the title compound
3¼>20:1) as colorless oil. 2a: 1H NMR (400 MHz, CDCl3)
d 8.05–
8.07 (2H, m, Ph-H), 7.56 (1H, t, J¼7.6 Hz, Ph-H), 7.45 (2H, t, J¼7.6 Hz,
Ph-H), 7.21–7.29 (5H, m, Ph-H), 4.95 (1H, dd, J¼9.0, 4.0 Hz, SiOCH),
3.10 (1H, dd, J¼13.6, 4.0 Hz, PhCH2), 3.00 (1H, dd, J¼13.6, 9.0 Hz,
PhCH2), 0.75 (9H, t, J¼8.0 Hz, CH3CH2Si), 0.39 (6H, q, J¼8.0 Hz,
CH3CH2Si); 13C NMR (100 MHz, CDCl3)
d 200.7, 137.5, 134.9, 133.0,
129.6, 129.1, 128.3, 128.1, 126.5, 78.6, 42.2, 6.4, 4.4; IR (neat) 2954,
2910, 2875, 1697, 1680, 1454, 1278, 1240, 1109, 1004, 771, 744, 731,
698 cmꢁ1; HRMS (ESI-TOF) Calcd for C21H28NaO2Si ([MþNa]þ):
363.1751. Found: 363.1749.
(400 MHz, CDCl3)
d 7.47–7.49 (2H, m, Ph-H), 7.38–7.44 (3H, m, Ph-
H), 5.51 (1H, s, CHCN), 0.98 (9H, t, J¼8.0 Hz, CH3CH2Si), 0.67–0.74
(6H, m CH3CH2Si).
3.3.2. With Al catalyst 5b
3.2.2. 2,3-Diphenyl-2-(triethylsiloxy)propanenitrile
To a solution of 2,20-bis(trifluoromethanesulfonylamino)-1,10-
biphenyl (24.6 mg, 0.055 mmol) in CH2Cl2 (5.0 mL) was added
a 1 M toluene solution of Me2AlCl (50 mL, 0.05 mmol) was added at
room temperature under positive nitrogen pressure and the
resulting mixture was kept for 30 min with stirring. Then, this
solution was cooled to ꢁ20 ꢀC, and 1a (170.3 mg, 0.5 mmol) was
introduced into it. After stirring for 12 h at the same temperature,
To a solution of diisopropylamine (1.7 mL, 12 mmol) in THF
(10 mL) was added a 1.5 M hexane solution of n-BuLi (8.0 mL,
12 mmol) at ꢁ78 ꢀC under argon, and the mixture was stirred for
15 min. A solution of crude 2-phenyl-2-(triethylsiloxy)acetonitrile
in THF (10 mL) was transferred into this mixture at the same
temperature and the resulting mixture was kept for 30 min. After
addition of benzyl bromide (1.4 mL, 12 mmol), the whole reaction
mixture was stirred for additional 1 h at ꢁ78 ꢀC. Then, the solution
was poured into water and extracted with EtOAc. The organic ex-
tracts were washed with brine and dried over anhydrous Na2SO4.
After evaporation of solvents and drying under vacuum, the
resulting crude oil was used for next step without any purification.
sodium fluoride (8.4 mg, 0.2 mmol) and water (2.7 mL, 0.15 mmol)
were added and the whole mixture was stirred for 30 min at room
temperature. To remove precipitates, filtration through Celite with
EtOAc was carried out. Concentration of the filtrate and purification
by column chromatography on silica gel (Et2O/hexane¼1:10 as
eluant) afforded a mixture of 2a and 3a (169.9 mg, 0.5 mmol, 99%
yield, 2/3¼1:>20) as colorless oil. 3a: 1H NMR (400 MHz, CDCl3)
1NMR of the title compound (400 MHz, CDCl3)
d 7.44–7.47 (2H, m,
Ph-H), 7.33–7.37 (3H, m, Ph-H), 7.23–7.25 (3H, m, Ph-H), 7.09–7.11
(2H, m, Ph-H), 3.24 (1H, d, J¼13.6 Hz, PhCH2), 3.12 (1H, d, J¼13.6 Hz,
PhCH2), 0.81 (9H, t, J¼8.0 Hz, CH3CH2Si), 0.45–0.62 (6H, m,
CH3CH2Si).
d
7.44 (2H, d, J¼7.0 Hz, Ph-H), 7.18–7.36 (6H, m, Ph-H), 7.01 (2H, d,
J¼7.0 Hz, Ph-H), 5.18 (1H, s, SiOCH), 3.90 (1H, d, J¼16.6 Hz, PhCH2),
3.72 (1H, d, J¼16.6 Hz, PhCH2), 0.91 (9H, t, J¼8.0 Hz, CH3CH2Si),
0.59 (6H, q, J¼8.0 Hz, CH3CH2Si); 13C NMR (100 MHz, CDCl3)
d
207.3, 138.4, 134.1, 129.6, 128.4, 128.2, 128.0, 126.6, 125.9, 80.7,
3.2.3. 2,3-Diphenyl-2-(triethylsiloxy)propanal 1a
42.6, 6.6, 4.6; IR (neat) 2954, 2937, 2910, 2875, 1726, 1494, 1452,
1413, 1240, 1188, 1130, 1095, 1068, 1004, 864, 727, 698 cmꢁ1; HRMS
(ESI-TOF) Calcd for C21H28NaO2Si ([MþNa]þ): 363.1750. Found:
363.1755.
To a solution of crude 2,3-diphenyl-2-(triethylsiloxy)propanenitrile
in CH2Cl2 (20 mL) under argon was introduced a 1 M toluene so-
lution of DIBAH (20 mL, 20 mmol) at ꢁ78 ꢀC, and the reaction
mixture was stirred for 1 h at the same temperature. Then, the
mixture was quenched with 1 N HCl and extracted with ether. The
organic extracts were washed with brine and dried over anhydrous
Na2SO4, and concentrated. The residual oil was purified by column
3.3.3. With Al catalyst 5c
An oven-dried Schlenk tube equipped with direct light excluded
was charged with AgNTf2 (19.4 mg, 0.05 mmol) and CH2Cl2

K. Ohmatsu et al. / Tetrahedron 65 (2009) 7516–7522
7521
(3.0 mL). A 1 M toluene solution of Me2AlCl (50
m
L, 0.05 mmol) was
through Celite with EtOAc was carried out. Concentration of the
filtrate and purification by column chromatography on silica gel
(CH2Cl2/hexane¼1:4, then Et2O/hexane¼1:10 as eluant) afforded
separated products, 2a (77.4 mg, 0.23 mmol, 91% yield, [TBS]-2a
was not detected) and [TBS]-2i (87.0 mg, 0.24 mmol, 94% yield, 2i
was not detected). 2a TLC (EtOAc/hexane¼1:10): Rf 0.5, [TBS]-2i:
Rf 0.3.
added under nitrogen and the resulting mixture was stirred at
room temperature for 12 h. To this mixture was added a solution of
2,20-bis(trifluoromethanesulfonylamino)-1,10-biphenyl (24.6 mg,
0.055 mmol) in CH2Cl2 (1.0 mL) and stirred for another 1 h. After
being cooled to ꢁ40 ꢀC, a solution of 1c (179.3 mg, 0.5 mmol) in
CH2Cl2 (1.0 mL) was transferred into this mixture and the stirring
was maintained at ꢁ40 ꢀC for 24 h. Then, the reaction mixture was
quenched with 1 N HCl and extracted with EtOAc. The organic ex-
tracts were washed with brine and dried over anhydrous Na2SO4.
After evaporation, the residual oil was purified by column chro-
matography on silica gel (CH2Cl2/hexane¼1:4 as eluant) to afford
a mixture of 2c and 3c (175.9 mg, 0.49 mmol, 98% yield, 2/
3.5.2. With catalyst 5c
To a mixture of AgNTf2 (19.4 mg, 0.05 mmol) in CH2Cl2 (3.0 mL)
was added 1 M toluene solution of Me2AlCl (50 mL, 0.05 mmol)
under nitrogen and the resulting mixture was stirred at room
temperature for 12 h. To this mixture was added a solution of 2,20-
bis(trifluoromethanesulfonylamino)-1,10-biphenyl (24.6 mg, 0.055
mmol) in CH2Cl2 (1.0 mL) and stirred for another 1 h. After being
cooled to ꢁ40 ꢀC, a solution of 1a (85.1 mg, 0.25 mmol) and [TBS]-
1i (92.6 mg, 0.25 mmol) in CH2Cl2 (1.0 mL) was transferred into this
mixture and the stirring was maintained at ꢁ40 ꢀC for 48 h. Then,
the reaction mixture was quenched with 1 N HCl and extracted
with EtOAc. The organic extracts were washed with brine and dried
over anhydrous Na2SO4. After evaporation, the residual oil was
purified by column chromatography on silica gel (CH2Cl2/
hexane¼1:4, then Et2O/hexane¼1:10 as eluant) to give products,
a mixture of 3a and [TBS]-3i (84.8 mg, 0.25 mmol, 99% yield, 3a/
3¼1:>20) as colorless oil. 3c: 1H NMR (400 MHz, CDCl3)
d 7.38–7.41
(2H, m, Ar-H), 7.19–7.26 (3H, m, Ar-H), 7.00–7.05 (4H, m, Ar-H), 5.15
(1H, s, SiOCH), 3.88 (1H, d, J¼16.2 Hz, PhCH2), 3.74 (1H, d, J¼16.2 Hz,
PhCH2), 0.91 (9H, t, J¼8.0 Hz, CH3CH2Si), 0.59 (6H, q, J¼8.0 Hz,
CH3CH2Si); 13C NMR (100 MHz, CDCl3)
d
207.3, 162.6 (d, JC–F
¼
¼
247 Hz), 134.3 (d, JC–F¼2.5 Hz), 133.9, 129.5, 128.3, 127.6 (d, JC–F
8.2 Hz), 126.6, 115.4 (d, JC–F¼22.2 Hz), 80.0, 42.7, 6.6, 4.6; IR (neat)
2956, 2877, 1726, 1506, 1222, 1085, 1014, 862, 819, 731, 698 cmꢁ1
;
HRMS (ESI-TOF) Calcd for C21H27FNaO2Si ([MþNa]þ): 381.1656.
Found: 381.1653.
Compounds 2b,11 2c,9 2d,11 2e,9 2f–2h,11 3b11 and 3d–3h11
showed the identical spectra according to the literature.
[TBS]-3a¼2:1), and
a mixture of [TBS]-3i and 3i (92.0 mg,
0.25 mmol, 99% yield, [TBS]-3i/3i¼2:1). A mixture of 3a and [TBS]-
3a TLC (EtOAc/hexane¼1:10): Rf 0.5, [TBS]-3i and 3i: Rf 0.3.
3.4. Synthesis of 13C labeled substrate
Benzaldehyde (510
mL, 5.0 mmol) was slowly added to a stirred
3.5.3. 2-(tert-Butyldimethylsiloxy)-3-(4-methoxyphenyl)-2-
solution of sodium hydrogensulfite (58% assay, mixture of NaHSO3
and Na2S2O5, 1.8 g, 10 mmol) in distilled water (3.0 mL) at room
temperature to afford a white precipitate. The mixture was allowed
to stir for 2 h once addition was complete, at which point the
mixture was cooled to 0 ꢀC and a solution of potassium cyanide-13C
(>99.5 atom % 13C, 650 mg, 10 mmol) in water (2.0 mL) was added.
After being warmed up to room temperature, this mixture was
stirred for additional 2 h, and the precipitate gradually disappeared.
The reaction mixture was extracted with ether and the ethereal
extracts were washed with brine and then dried over Na2SO4. After
filtration and evaporation, further drying of residue in vacuo was
conducted. To a solution of this crude compound and N,N-diiso-
propylethylamine (1.0 mL, 6.0 mmol) in CH2Cl2 (15 mL) was added
triethylsilyl chloride (1.0 mL, 6.0 mmol) at 0 ꢀC under argon. The
reaction mixture was warmed up to room temperature and main-
tained for 2 h with stirring. Then, this mixture was poured into
water and extracted with EtOAc. The combined organics were
washed with brine and dried over anhydrous Na2SO4. Filtration,
removal of solvents and further drying under vacuum afforded al-
most pure 2-phenyl-2-(triethylsiloxy)acetonitrile in which 13C was
incorporated in cyano position. Further, the same manipulations for
the preparation of 1a gave the 13C labeled substrate [13C]-1a. 1H
phenylpropanal [TBS]-1i
1H NMR (400 MHz, CDCl3)
d 9.71 (1H, s, CHO), 7.26–7.33 (5H, m,
Ph-H), 6.91 (2H, d, J¼9.2 Hz, Ar-H), 6.68 (2H, d, J¼9.2 Hz, Ar-H), 3.73
(3H, s, MeOC6H4), 3.35 (1H, d, J¼14.6 Hz, ArCH2), 3.22 (1H, d,
J¼14.0 Hz, ArCH2), 0.94 (9H, s, t-BuSi), 0.04 (3H, s, MeSi), ꢁ0.05 (3H,
s, MeSi); 13C NMR (100 MHz, CDCl3)
d 199.9, 158.1, 139.3, 131.7,
128.3,127.7,127.5,126.3,113.1, 85.2, 55.1, 43.5, 26.2,18.9, ꢁ2.2, ꢁ2.4;
IR (neat) 2954, 2929, 2856, 1734, 1514, 1253, 1141, 1037, 958, 912,
831, 777, 700 cmꢁ1; HRMS (ESI-TOF) Calcd for C22H30NaO3Si
([MþNa]þ): 393.1856. Found: 393.1865.
3.5.4. 2-(tert-Butyldimethylsiloxy)-3-(4-methoxyphenyl)-1-
phenylpropan-1-one [TBS]-2i
1H NMR (400 MHz, CDCl3)
d 8.05–8.07 (2H, m, Ph-H), 7.53–7.57
(1H, m, Ph-H), 7.43–7.47 (2H, m, Ph-H), 7.13–7.16 (2H, m, Ar-H),
6.80–6.84 (2H, m, Ar-H), 4.86 (1H, dd, J¼9.2, 4.0 Hz, SiOCH), 3.78
(3H, s, MeOC6H4), 3.05 (1H, dd, J¼14.0, 4.0 Hz, ArCH2), 2.95 (1H, dd,
J¼14.0, 9.2 Hz, ArCH2), 0.76 (9H, s, t-BuSi), ꢁ0.20 (3H, s, MeSi),
ꢁ0.22 (3H, s, MeSi); 13C NMR (100 MHz, CDCl3)
d 201.0, 158.4, 134.9,
133.0, 130.7, 129.6, 129.2, 128.3, 113.6, 79.5, 55.2, 41.4, 25.6, 18.1,
ꢁ5.2, ꢁ5.5; IR (neat) 2953, 2929, 2856, 1724, 1512, 1300, 1247, 1178,
1132, 1095, 1068, 1037, 877, 837, 779, 746, 700 cmꢁ1; HRMS (ESI-
TOF) Calcd for C22H30NaO3Si ([MþNa]þ): 393.1856. Found:
393.1857.
NMR (400 MHz, CDCl3)
d
9.76 (1H, d, JC–H¼178.4 Hz, 13CHO), 7.26–
7.32 (5H, m, Ph-H), 7.12–7.13 (3H, m, Ph-H), 6.95–6.97 (2H, m, Ph-
H), 3.31 (1H, dd, J¼14.4, JC–H¼3.6 Hz, PhCH2), 3.25 (1H, dd, J¼14.4,
JC–H¼2.4 Hz, PhCH2), 0.89 (9H, t, J¼8.0 Hz, CH3CH2Si), 0.58 (6H, q,
J¼8.0 Hz, CH3CH2Si).
3.5.5. 1-(tert-Butyldimethylsiloxy)-3-(4-methoxyphenyl)-1-
phenylpropan-2-one [TBS]-3i
1H NMR (400 MHz, CDCl3)
d 7.42–7.44 (2H, m, Ar-H), 7.29–7.36
3.5. Test for silyl group transfer pathway
(3H, m, Ar-H), 6.90 (2H, d, J¼8.4 Hz, Ar-H), 6.77 (2H, d, J¼8.4 Hz, Ar-
H), 5.17 (1H, s, SiOCH), 3.81 (1H, d, J¼17.8 Hz, ArCH2), 3.75 (3H, s,
MeOC6H4), 3.69 (1H, d, J¼17.8 Hz, ArCH2), 0.95 (9H, s, t-BuSi), 0.08
3.5.1. Experimental procedure for the reaction with Me2AlCl
To a solution of 1a (85.1 mg, 0.25 mmol) and [TBS]-1i (92.6 mg,
0.25 mmol) in toluene (5.0 mL) was added a 1 M toluene solution
(3H, s, MeSi), 0.01 (3H, s, MeSi); 13C NMR (100 MHz, CDCl3)
d 207.6,
158.3, 138.4, 130.5, 128.4, 128.0, 126.0, 125.9, 113.7, 80.9, 55.1, 41.6,
of Me2AlCl (50
ring for 24 h, sodium fluoride (8.4 mg, 0.2 mmol) and water
(2.7 L, 0.15 mmol) were added and the whole mixture was stirred
for 30 min at room temperature. To remove precipitates, filtration
m
L, 0.05 mmol) at 0 ꢀC under nitrogen. After stir-
25.7, 18.2, ꢁ4.9, ꢁ5.0; IR (neat) 2953, 2929, 2856, 1724, 1512, 1300,
1247, 1178, 1132, 1095, 1068, 1037, 877, 837, 779, 746, 700 cmꢁ1
;
m
HRMS (ESI-TOF) Calcd for C22H30NaO3Si ([MþNa]þ): 393.1856.
Found: 393.1859.

7522
K. Ohmatsu et al. / Tetrahedron 65 (2009) 7516–7522
3.6. For stereospecific 1,2-rearrangement
Acknowledgements
3.6.1. Preparation of optically active substrate via kinetic
resolution9
To a solution of (S,S)-2-hydroxy-20-[3,5-bis(trifluoromethyl)]
phenyl-3-{2-[3,5-bis(trifluoromethyl)]benzenesulfonylamino}phe-
nyl-1,10-binaphthyl (233.5 mg, 0.275 mmol) in toluene (25 mL)
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformation of
Carbon Resources’ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
was added a 1 M toluene solution of Me3Al (250 mL, 0.25 mmol)
References and notes
at room temperature under nitrogen and stirred for 30 min.
After being cooled to ꢁ20 ꢀC, 2a (1.7 g, 5.0 mmol) was added to
this solution and the stirring was maintained at ꢁ20 ꢀC for 18 h.
1. Fittig, R. Justus Liebigs Ann. Chem. 1860, 114, 54.
2. (a) Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690; (b) Meerwein, H. Justus
Liebigs Ann. Chem. 1914, 405, 129.
3. For review: Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, NY, 1991; Vol. 3, Chapter 3, p 705.
4. For reviews of atom economy, see: (a) Trost, B. M. Science 1991, 254, 1471; (b)
Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259; (c) Trost, B. M. Acc. Chem.
Res. 2002, 35, 695.
5. Pinacol rearrangement: (a) Winstein, S.; Lindegren, C. R.; Marshall, H.; Ingra-
ham, L. L. J. Am. Chem. Soc. 1953, 75, 147; (b) House, H. O.; Grubbs, E. J. J. Am.
Chem. Soc. 1959, 81, 4733; (c) Wistuba, E.; Ru¨chardt, C. Tetrahedron Lett. 1981, 22,
4069; Wagner–Meerwein rearrangement: (d) Winstein, S.; Morse, B. K.;
Grunwald, E.; Schreiber, K. C.; Corse, J. J. Am. Chem. Soc. 1952, 74, 1113; (e)
Brown, H. C.; Kim, C. J. J. Am. Chem. Soc. 1968, 90, 2082; (f) Phan, T. H.; Dahn, H.
Helv. Chim. Acta 1976, 59, 335.
6. (a) Suzuki, K.; Tomooka, K.; Shimazaki, M.; Tsuchihashi, G. Tetrahedron Lett.
1985, 26, 4781; (b) Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Tet-
rahedron Lett. 2007, 48, 6590.
Then, sodium fluoride (42.0 mg, 1.0 mmol) and water (13.5 mL,
0.75 mmol) were added and the whole mixture was stirred for
30 min at room temperature. To remove precipitates, filtration
through Celite with EtOAc was carried out. Concentration of the
filtrate and purification by column chromatography on silica gel
(CH2Cl2/hexane¼1:4 as eluant) afforded (R)-2a (646.3 mg,
1.9 mmol, 38% recover, 97% ee).
3.6.2. Data for chiral siloxy ketones
25
(R)-2a [
a
]
þ39.1 (c 1.47, CHCl3, 94% ee); HPLC condition:
D
DAICEL Chiralcel OD-H, hexane/i-PrOH¼99:1, flow rate¼0.3 mL/
min,
¼210 nm, retention time: 15.4 min (S), 16.9 min (R).
(R)-3a [
DAICEL Chiralcel OJ-H, hexane/i-PrOH¼99:1, flow rate¼0.3 mL/
min,
¼220 nm, retention time: 18.8 min (S), 20.6 min (R). Absolute
l
28
7. (a) Nakamura, K.; Osamura, Y. Tetrahedron Lett. 1990, 31, 251; (b) Nakamura, K.;
Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112.
8. McKenzie, A.; Dennler, W. S. J. Chem. Soc. 1926, 1596.
a]
–40.9 (c 1.03, CHCl3, 75% ee); HPLC condition:
D
l
9. Ooi, T.; Ohmatsu, K.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 2410.
10. (a) Shine, H. J.; Schoening, C. E. J. Org. Chem. 1972, 37, 2899; (b) Matsuda, T.;
Tanino, K.; Kuwajima, I. Tetrahedron Lett. 1989, 30, 4267; (c) Suda, K.; Kikkawa,
T.; Nakajima, S.-i.; Takanami, T. J. Am. Chem. Soc. 2004, 126, 9554.
11. A part of this work was communicated: Ohmatsu, K.; Tanaka, T.; Ooi, T.; Mar-
uoka, K. Angew. Chem., Int. Ed. 2008, 47, 5203.
12. Ooi, T.; Ichikawa, H.; Maruoka, K. Angew. Chem., Int. Ed. 2001, 40, 3610.
13. Ooi, T.; Ohmatsu, K.; Ishii, H.; Saito, A.; Maruoka, K. Tetrahedron Lett. 2004, 45,
9315.
14. For a report concerning the preparation of MABR, see: Maruoka, K.; Nonoshita,
K.; Banno, H.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 7922.
15. (a) Starowieyski, K. B.; Pasynkiewicz, S.; Skowronska-Ptasinska, M. J. Organo-
met. Chem. 1975, 90, C43; (b) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.;
Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 3588.
16. For a report describing the difference in Lewis acidity of MAD and MABR, see:
Nonoshita, K.; Banno, H.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1990, 112,
316.
17. The reaction under the influence of 5b underwent the non-regioselective mi-
gration of [TBS]-1b, affording 1:6 ratio of alkyl-migrated product 2 and phenyl-
migrated one 3. The distributions of silyl groups were also observed in this case.
18. In Mukaiyama aldol reaction, the silyl enol ether can become the catalyst for
the next catalytic cycle: Hiraiwa, Y.; Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem.
2006, 1837.
configuration was established by comparison of the optical rotation
with a known literature value20 after derivatization as follow.
A solution of 3a (68.1 mg, 0.2 mmol, 75% ee) in THF (2.0 mL) was
treated with 1 N HCl (1.0 mL) with vigorous stirring. After being
kept for 2 h, the reaction mixture was extracted with EtOAc, and the
organic extracts were washed with brine and dried (Na2SO4). Fil-
tration, evaporation and further drying under vacuum were con-
ducted. Then, to a solution of this crude compound and acetic
´
´
anhydride (38
mL, 0.4 mmol) in dichloromethane (1.0 mL) was
added copper(II) trifluoromethanesulfonate (1.8 mg, 5.0
mmol) at
room temperature under argon. After being stirred for 1 h, the
mixture was quenched by the addition of satd NaHCO3. Extractive
workup was performed with EtOAc and the combined organics
were washed with water, brine and dried over anhydrous Na2SO4.
After concentration, resulting crude product was purified by col-
umn chromatography on silica gel (EtOAc/hexane¼1:4 as eluant) to
afford pure 2-oxo-1,3-diphenylpropyl acetate (48.8 mg, 0.18 mmol,
90% yield for two steps).
19. Giordani, A.; Carera, A.; Pinciroli, V.; Cozzi, P. Tetrahedron: Asymmetry 1997, 8, 253.
20. Enders, D.; Bhushan, V. Tetrahedron Lett. 1988, 29, 2437.