Synthesis of γ-amino alcohols from aldehydes, enamines, and trichlorosilane using Lewis base catalysts

Article abstract of DOI:10.1016/j.tet.2010.10.075

The reaction of aldehydes, enamines, and trichlorosilane in the presence of a Lewis base catalyst, particularly N-methylpyrrolidinone and DMF, affords γ-amino alcohols with a high diastereoselectivity. The method consists of C-C bond formation between an aldehyde and an enamine, and a subsequent intramolecular reduction of the resulting iminium ion intermediate. In most cases, one diastereomer is exclusively generated, and we propose a transition state model for the intramolecular reduction of the iminium ion intermediate. Enamines, prepared beforehand from the corresponding ketone and amine, can be used in the reaction without purification. Furthermore, enantioselective catalysis using a chiral Lewis base catalyst is possible, although the enantioselectivity is modest. The current tandem method offers the first, concise synthetic method of γ-amino alcohols from aldehydes and enamines. Copyright

Full text of DOI:10.1016/j.tet.2010.10.075

Tetrahedron 67 (2011) 531e539
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of
g
-amino alcohols from aldehydes, enamines, and trichlorosilane
using Lewis base catalysts
,
a,
*
Takeru Kashiwagi a, Shunsuke Kotani b, Masaharu Sugiura a , Makoto Nakajima
*
a Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
b Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 October 2010
Received in revised form 22 October 2010
Accepted 26 October 2010
Available online 12 November 2010
The reaction of aldehydes, enamines, and trichlorosilane in the presence of a Lewis base catalyst, par-
ticularly N-methylpyrrolidinone and DMF, affords -amino alcohols with a high diastereoselectivity. The
g
method consists of CeC bond formation between an aldehyde and an enamine, and a subsequent in-
tramolecular reduction of the resulting iminium ion intermediate. In most cases, one diastereomer is
exclusively generated, and we propose a transition state model for the intramolecular reduction of the
iminium ion intermediate. Enamines, prepared beforehand from the corresponding ketone and amine,
can be used in the reaction without purification. Furthermore, enantioselective catalysis using a chiral
Lewis base catalyst is possible, although the enantioselectivity is modest. The current tandem method
Keywords:
Tandem reaction
Lewis base catalysis
Enamine
offers the first, concise synthetic method of
g
-amino alcohols from aldehydes and enamines.
Ó 2010 Elsevier Ltd. All rights reserved.
Trichlorosilane
geAmino alcohol
1. Introduction
enamine 2 affords iminium ion intermediate 4. Subsequently in-
termediate 4 is intramolecularly reduced by the hydrosilyl group to
Tandem reactions enhance the efficiency of synthetic processes
because reactive and unstable synthetic intermediates can be used
without isolation and purification.1 We have recently reported that
P]O compounds as Lewis base catalysts promote the tandem
conjugate reduction/aldol reaction (the reductive aldol reaction) of
enones and aldehydes with trichlorosilane to provide
ketones in good yield with high stereoselectivity.2 Herein, we dis-
close a novel synthetic method of -amino alcohols 3 from alde-
hydes 1, enamines 2, and trichlorosilane in the presence of a Lewis
base catalyst (Fig. 1).
This method consists of a tandem CeC bond formation/re-
duction. The first CeC bond formation between aldehyde 1 and
give g
-amino alcohol 3.3ꢀ8 Similar to the reductive aldol reaction,2
we hypothesized that a Lewis base catalyst (LB)9 promotes this
reaction via activation of trichlorosilane.
Hosomi et al. have demonstrated that a tandem aldol/reduction
of dimethylsilyl enol ethers with aldehydes in the presence of
a catalytic amount of TBAF affords 1,3-diols.10 Additionally, related
reactions of enol ethers, electrophiles (acetals, aldehydes, or imines),
and nucleophiles (methanol, triethylsilane, allyltrimethylsilane,
etc.) in the presence of Lewis acids have also been reported.11
However, the corresponding reaction of enamines has yet to be
revealed.12,13
Enamines are valuable as enolate equivalents in organic syn-
thesis.14 Various transformations, including alkylation, acylation,
and Michael addition, have been developed. In these processes, the
amine moiety is hydrolytically removed during the workup to af-
ford the corresponding carbonyl compounds. In contrast, the cur-
rent method retains the amine moiety in the molecule as one of the
useful functional groups. Thus, this work demonstrates a new as-
pect of enamine chemistry.
b-hydroxy
g
Cl
Si
LB
H
Cl
O
OH
*
N
*
N
O
HSiCl3
N
+
*
R
R
R
H
Cl–
Lewis Base
Catalyst (LB)
1
2
3
4
Fig. 1. Synthesis of g-amino alcohols 3 from aldehydes 1 and enamines 2.
2. Optimization of reaction conditions
Initially, we investigated the reaction between benzaldehyde
(1a) and N-1-cyclohexenylpiperidine (2a) (Eq. 1). Aldehyde 1a
(1.0 equiv) was added to a solution of 2a (1.2 equiv) and
* Corresponding authors. Tel.: þ81 96 371 4680; fax: þ81 96 362 7692; e-mail
addresses: msugiura@kumamoto-u.ac.jp (M. Sugiura), nakajima@gpo.kumamoto-u.
ac.jp (M. Nakajima).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.075

532
T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
trichlorosilane (1.5 equiv) in dichloromethane in the absence or
presence of a Lewis base (20 mol %) (Table 1). The reactionproceeded
1) Jones Reagent
OH
N
OH
N
3
without a Lewis base at ꢀ40 ꢁC to give expected
g-amino alcohol 3a
acetone, rt, 14 h, 74%
(2)
2
in moderate yield with high diastereoselectivity (entry 1). As men-
tioned later, the major stereoisomer was 1,2-anti-2,3-anti. Either
decreasing or increasing the reaction temperature lowered the
chemical yield and/or diastereoselectivity (entries 2e4). The re-
action at rt was accompanied by the reduction of 2a to N-cyclo-
hexylpiperidine, which decreased the yield of 3a (entry 4). Hence,
the effect of Lewis base catalysts was investigated at ꢀ40 ꢁC (entries
5e9). Although all the Lewis bases examined improved the chemical
yield, only DMF and N-methyl-2-pyrrolidone (NMP) retained a high
diastereoselectivity (entries 6 and 8).
1
Ph
Ph
2) LiAlH4 (2.0 eq)
THF, rt, 0.5 h, 95%
syn,anti-3a
δH1 = 4.66 ppm
1,2 = 3.9 Hz
syn,anti : anti,anti
J
anti,anti-3a
= 6 : 94
1) Piperidine (3 eq)
p-TsOH, toluene
reflux, 44 h
2) H2, PtO2, EtOH
rt, 43 h, 49% (2steps)
(single isomer)
O
O
OH
N
3
(3)
2
Ph
Ph
syn,syn-3a
Ph
Ph
1
δH1 = 5.08 ppm
singlet
a) SiCl4 (1.5 eq)
CH2Cl2, rt, 1 h
OH
N
3
N
O
2
+
(4)
HSiCl3 (1.5 eq)
1
b) LiBH4 (2.0 eq)
anti,syn-3a
H
O
N
OH
N
3
–78 oC to rt, 2 h, 48%
Lewis Base (0 or 20 mol %)
δH1 = 5.09 ppm
+
2
(1)
anti,syn : other isomers
H
1
Ph
CH2Cl2
Ph
J1,2 = 10.1 Hz
1a
2a
= 55 : 45
1a
2a (1.2 eq)
anti,anti-3a
derivative using this procedure has been reported.16 Third anti,syn-
3a was prepared by treatment of 1a and 2a with SiCl4 followed by
LiBH4 (Eq. 4). anti,syn-3a, which was the major product of this
transformation, was isolated by column chromatography on silica
gel (the stereochemistry of this reactionwill be discussed in the next
section). The 1H NMR coupling constants between H1 and H2 were
reasonable for the assignments. Thus, it was confirmed that the re-
action of 1a and 2a with trichlorosilane afforded anti,anti-3a with
a high diastereoselectivity.
Table 1
Optimization of the reaction conditions
Entry
Lewis Basea
Conditions
Yield (%)
drb
1
2
3
4
5
6
7
8
9
d
ꢀ40 ꢁC, 1 h
35
3
96:1:1:2
95:0:1:4
96:4:0:0
97:3:0:0
89:10:1:0
98:1:trace:1
94:5:1:0
96:1:2:1
d
ꢀ78 ꢁC, 3 h
d
0
ꢁC, 1 h
58
36
67
56
68
64
80
d
rt, 1 h
Ph3PO
DMF
DMPU
NMP
HMPA
ꢀ40 ꢁC, 1 h
ꢀ40 ꢁC, 1 h
ꢀ40 ꢁC, 1 h
ꢀ40 ꢁC, 1 h
ꢀ40 ꢁC, 1 h
4. Mechanistic insight into the stereochemistry
82:17:1:trace
a
DMPU: N,N0-dimethylpropyreneurea, NMP: N-methyl-2-pyrrolidone.
Diastereomeric ratio of 3a (1,2-anti-2,3-anti:1,2-syn-2,3-anti:1,2-syn-2,3-syn:1,2-
To provide insight into the formation of assumed iminium ion
intermediate 4, the reaction of benzaldehyde (1a) and enamine 2a
was performed using SiCl4 instead of HSiCl3 in CD2Cl2 at rt. The
reaction was monitored by 1H NMR spectroscopy. The spectra
showed the consumption of 2a and most of 1a as well as the for-
mation of several species whose ratios gradually changed. After 5 h,
the spectrum remained constant, and the reaction mixture was
analyzed by 1He1H COSY analysis. The major component was
assigned to the 1,2-anti iminium ion (Eq. 5).17 A large J1,2 coupling
constant and small J2,7 coupling constants suggested that the
phenyl(silyloxy)methyl side chain was located in the pseudo axial
position due to 1,3-allylic strain between the side chain and the
methylene protons of the piperidine ring, which disfavors the
pseudo equatorial orientation.18
b
anti-2,3-syn). Determined by 1H NMR analysis of the crude products.
3. Assignment of the relative configuration
The major isomer of product 3a was isolated by column chro-
matography on silica gel as a crystalline compound.1H NMR analysis
in CDCl3 suggested the presence of intramolecular hydrogen bond-
ing between the hydroxy group and piperidino nitrogen as a broad
signal appeared at 9.3 ppm. NOESY analysis showed NOE correla-
tions between H1 and H3 and between H7ax and H1, supporting the
1,2-anti-2,3-anti configuration depicted in Fig. 2.15 Moreover, the
coupling constants were consistent with this assignment.
NOE
axial
NOE
H
Ph
OSiCl3
1
OH
N
3
1
H
7
H
9.3 ppm
H
Ph
2
H
7
2
O
1
Ph
4
5
2
O
SiCl4 (1.5 eq)
CD2Cl2, rt
3
N
N
Cl–
(5)
δH1 = 4.44 ppm
H
+
7
5
4
Ph
H
6
J
1,2 = 9.2 Hz
H
6
N
J
2,3 = 11.1 Hz
J
1,2 = 10.1 Hz
anti,anti-3a
J
= 4.8, 2.5 Hz
2,7
1a
2a
Fig. 2. Relative configuration of the major isomer of 3a.
1,2-anti
To further confirm the stereochemical outcome of the reaction,
the other diastereomers of 3a were prepared as follows. First anti,-
anti-3a was oxidized into the corresponding trans-ketone by Jones
reagent, and was subsequently reduced by LiAlH4 to give a mixture
of anti,anti- and syn,anti-3a (94:6) (Eq. 2). Compound syn,anti-3a
could be separated by column chromatography on silica gel. Second
syn,syn-3a was prepared by Pt-catalyzed hydrogenation of the b-
amino enone prepared from 2-benzoylcyclohexanone and piperi-
dine (Eq. 3). Preparation of the corresponding p-methoxylphenyl
As shown in Eq. 4, the reduction of this iminium ion with LiBH4
afforded anti,syn-3a as the major isomer. The hydride of LiBH4 likely
attacked the iminium carbon from the bottom side (axial attack) to
avoid the bulky phenyl(silyloxy)methyl group on the top side.
Based on this observation, it is speculated that the tandem re-
action of 1a and 2a with HSiCl3 generated a 1,2-anti iminium ion
intermediate similar to that with SiCl4. The formation of the 1,2-anti
isomer would be kinetically favored over that of the 1,2-syn isomer

T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
533
because the enamine can attack the HSiCl3-activated aldehyde via
HSiCl3 (1.5 eq)
NMP (20 mol %)
the antiperiplanar acyclic transition state shown in Fig. 3. Sterically
less congested transition state A would afford the 1,2-anti iminium
ion, whereas transition state B, which would lead to the 1,2-syn
isomer, has steric repulsion between the large trichlorosilyl group
coordinated by the Lewis base and the cyclohexane ring of the
enamine.19
O
OH
N
N
+
Ph
H
CH2Cl2
Ph
–40 oC, 1 h
1a
2b-2d
3b-3d
O
N
O
N
N
LB
OSiHCl2
LB
SiHCl3
2b
2c
2d
Ph
H
1
13%
dr = 87 : 13
73%
37%
dr = 60 : 40
O
a
a
a
dr = 98 : 2
2
Ph
H
N
a Diastereomeric ratio of 3 (1,2-anti-2,3-anti : Σ other isomers).
N
favored
Estimated by 1H-NMR analysis of the crude products.
1,2-anti
Cl–
A
Scheme 1. Reaction of 1a and cyclic enamines 2bed.
Lewis Base
(LB)
LB
OSiHCl2
LB
SiHCl3
H
1
1bee, which possessed a variety of aromatic rings, respectively,
afforded expected products 3eeh in good yields with high selec-
tivities (entries 2e5). However, hydrocinnamaldehyde (1f), a non-
conjugated aldehyde did not produce the desired product (entry 6).
Heteroaromatic aldehydes, 2-furfural (1g), and 2-pyridinecarbox-
aldehyde (1h) provided good yields albeit with inferior selectivities
(entries 7 and 8). Hence, the stereochemical course may be influ-
enced by coordination of the heteroatom to the silicon atom of
reaction intermediates.
O
Ph
2
Ph
H
N
disfavored
N
Cl–
1,2-syn
B
Fig. 3. Assumed transition states for CeC bond formation between 1a and 2a.
For the intramolecular reduction of the 1,2-anti iminium ion, the
hydride could readily transfer from the axial silyloxy group to the
iminium carbon to afford 1,2-anti-2,3-anti-3a (Fig. 4, first equation).
On theotherhand, hydride transfer in the1,2-syniminium ionwould
be disfavored due to steric repulsion between the phenyl group and
cyclohexane ring (Fig. 4, second equation). Even this unfavorable
hydride transfer might occur in the presence of a strong Lewis base.
Indeed, employing HMPA gave 1,2-syn-2,3-anti-3a toa largerextent;
thus, lowering the diastereoselectivity, but increasing the yield (see
Table 1, entry 9). However, the minor 1,2-syn iminium ion barely
reacted upon employing a weak Lewis base, such as DMF or NMP.
This may explain the moderate yield, but high selectivity.
Table 2
Reaction of 2c with various aldehydes
O
O
N
HSiCl3 (1.5 eq)
NMP (20 mol %)
N
OH
O
+
R
R
H
CH2Cl2
–40 oC, 1 h
3
2c
1
Entry
R in aldehyde (1)
3
Yield (%)
dra
1
2
3
4
5
6
7
8
Ph (1a)
3c
3e
3f
3g
3h
3i
73
72
55
61
52
0
98:2
99:1
99:1
97:3
98:2
d
p-MeOC6H4 (1b)
p-NO2C6H4 (1c)
1-Naphthyl (1d)
2-Naphthyl (1e)
PhCH2CH2 (1f)
2-Furyl (1g)
Cl
Si
OSiCl3
Ph
H
1
Cl
LB
Ph
H
O
1
H
2
1
SiCl3
2
H
H
Ph
O
H
2
N
3
3
3j
3k
69
70
90:10
15:85
fast
N
N
2-Pyridyl (1h)
a
Diastereomeric ratio of 3 (1,2-anti-2,3-anti:S other isomers). Estimated by 1H
Cl–
1,2-anti
anti,anti-3a
NMR analysis of the crude products.
Cl
Si
OSiCl3
Cl
LB
H
Ph
1
The reaction of acetophenone-derived enamine 2e with benz-
aldehyde (1a) showed a different tendency from that of cyclic en-
amine 2a or 2c. The use of NMP at ꢀ40 ꢁC produced not desired
product 5a, but a complicated mixture, including chalcone and the
dehydration product of 5a (allylic amine) (Table 3, entry 1). On the
other hand, employing Ph3PO instead of NMP gave 5a in moderate
yield with good 1,3-syn selectivity (entry 2). In this case, bulkiness
of the Lewis base might effectively suppress the side reactions.
Lowering the reaction temperature to ꢀ78 ꢁC improved the
chemical yield (entry 3). Notably, when the aldehyde component
was changed from benzaldehyde to 2-pyridinecarboxaldehyde
(1h), 1,3-anti diastereoselectivity was observed. In this case, using
Ph3PO at ꢀ40 ꢁC (entry 5) provided a better result than that of NMP
at ꢀ40 ꢁC or Ph3PO at ꢀ78 ꢁC (entries 4 and 6).
H
O
Ph
1
1
2
Ph
SiCl3
2
H
O
H
H
H
2
N
3
3
slow
N
N
Cl–
1,2-syn
syn,anti-3a
Fig. 4. Assumed transition states for intramolecular reduction of the iminium ions
derived from 1a with 2a.
5. Substrate scope
Using NMP (20 mol %) as a Lewis base catalyst, benzaldehyde
(1a) was reacted with other cyclic enamines 2bed at ꢀ40 ꢁC for 1 h
for comparison (Scheme 1). N-1-Cyclohexenylmorpholine (2c) gave
a slightly higher yield and diastereoselectivity than 2a, whereas
enamines 2b and 2d provided inferior results.20
As depicted in Fig. 5, the coordination of the pyridine nitrogen of
aldehyde 1h to the silicon atom explains the reversal in the dia-
stereoselectivity. In both TS1ae2e and TS1he2e, the morpholine
moiety was located in the pseudo equatorial position to minimize
the allylic strains. However, in TS1ae2e the phenyl group of the
Next, the reaction of enamine 2c with various aldehydes was
investigated under the same conditions (Table 2).21 Aldehydes

534
T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
Table 3
Reaction of 2e with 1a or 1h
7. Enantioselective catalysis
O
O
Finally, we investigated enantioselective catalysis of the reaction
using chiral Lewis base catalysts (Table 4). The reaction of benzal-
dehyde (1a) and enamine 2a at ꢀ40 ꢁC in the presence of BINAPO23
(Fig. 6) gave desired product 3a in good yield (76%) (entry 1). Al-
though the diastereoselectivity was high, the enantioselectivity
was very low. Meanwhile, when the same reaction was carried out
at ꢀ78 ꢁC, a moderate enantioselectivity (40% ee) was observed, but
the yield decreased to 43% (entry 2). When the reaction was con-
ducted at ꢀ78 ꢁC for 1 h then at ꢀ40 ꢁC for 1 h, the yield was largely
improved, but the enantiomeric excess decreased to 9% (entry 3).
Chiral Lewis bases other than BINAPO (Fig. 6) were also tested
at ꢀ78 ꢁC, but they provided inferior results (entries 4e7). The
reaction of morpholine-derived enamine 2c with (S)-BINAPO
resulted in a low enantioselectivity even at ꢀ78 ꢁC (entry 7).
These results can be rationalized by assuming that the enan-
tioselectivity of the first CeC bond formation was very low, and that
kinetic resolution of the iminium ion intermediate occurred in the
subsequent intramolecular reduction process at low temperature
O
HSiCl3 (1.5 eq)
Lewis Base
(20 mol %)
O
OH
1
N
3
OH
1
N
3
N
+
+
R
H
R
Ph
R
Ph
CH2Cl2
conditions
Ph
1
2e
syn-5
anti-5
Entry
1
Lewis base
Conditions
5
Yield (%)
syn/antia
1
2
3
4
5
6
1a
1a
1a
1h
1h
1h
NMP
ꢀ40 ꢁC, 1 h
ꢀ40 ꢁC, 1 h
ꢀ78 ꢁC, 5 h
ꢀ40 ꢁC, 1 h
ꢀ40 ꢁC, 1 h
ꢀ78 ꢁC, 5 h
5a
5a
5a
5b
5b
5b
0
37
61
33
52
18
d
Ph3PO
Ph3PO
NMP
Ph3PO
Ph3PO
90:10
91:9
10:90
3:97
5:95
a
Diastereomeric ratio of 5.
H
H
3
1
H
N
Cl
H
Cl
Ph
2
O
O
Ph
O
N
Si
Ph
O
Ph
LB
H
OH
1
N
3
Table 4
O
Investigation of enantioselective catalysis
J
J
J
J
1,2-ax = 10.5 Hz
1,2-eq = 1.8 Hz
3,2-ax = 11.5 Hz
3,2-eq = 2.3 Hz
Ph
Ph
Cl–
X
X
N
syn-5a
HSiCl3 (1.5 eq)
(S)-BINAPO (10 mol %)
TS
1a-2e
O
N
OH
+
CH2Cl2
conditions
Ph
H
Ph
N
N
Ph
O
H
1
1a
2a or 2c
3a or 3c
H
Cl
H
2
O
O
Cl
N
Si
3
H
O
Ph
Entry
X in 2
Conditions
3
Yield (%)
dra
%eeb
LB
H
OH
1
N
3
ꢀ40 ꢁC, 1 h
3a
3a
3a
3a
3a
3a
3a
3c
76
43
88
44
44
25
18
61
94:6
97:3
94:6
98:2
97:3
93:7
86:14
96:4
8
40
9
33
8
O
N
1
2
3
CH2 (2a)
CH2 (2a)
CH2 (2a)
CH2 (2a)
CH2 (2a)
CH2 (2a)
CH2 (2a)
O (2c)
N
ꢀ78 ꢁC, 1 h
J
J
J
J
1,2-ax = 4.6 Hz
1,2-eq = 4.6 Hz
3,2-ax = 10.5 Hz
3,2-eq = 3.2 Hz
Ph
ꢀ78 ꢁC, 1h; ꢀ40 ꢁC, 1 h
ꢀ78 ꢁC, 1 h
Cl–
anti-5b
4c
5d
6e
7f
8
TS
1h-2e
ꢀ78 ꢁC, 1 h
ꢀ78 ꢁC, 1 h
15g
12
5
ꢀ78 ꢁC, 1 h
Fig. 5. Assumed transitions states for the reaction of enamine 2e with 1a or 1h.
ꢀ78 ꢁC, 1 h
benzaldehyde was preferably oriented in the pseudo equatorial
position to afford 1,3-syn product 5a. On the other hand, in TS1he2e
coordination to the silicon atom forced the pyridine ring to be lo-
cated in the pseudo axial position, leading to 1,3-anti product 5b.
Diastereomeric ratio of 3 (1,2-anti-2,3-anti:S other isomers). Estimated by 1H
NMR analysis of the crude products.
a
b
The enantiomeric excess of the major 1,2-anti-2,3-anti diastereomer.
(S)-SEGPHOSO (Fig. 6) was used instead of (S)-BINAPO.
(R,R)-DIOPO (Fig. 6) was used instead of (S)-BINAPO.
(R)-BIQNO (Fig. 6) was used instead of (S)-BINAPO.
(S)-BQNO (Fig. 6) was used instead of (S)-BINAPO.
The major enantiomer was opposite to that obtained with (S)-BINAPO.
c
d
e
6. Use of enamine 2c without isolation
f
g
To extend the synthetic efficiency, we investigated the use of
enamine 2c without purification. Cyclohexanone and morpholine
were mixed in diethyl ether in the presence of molecular sieves
(Fig. 7).24 For the reaction of enamine 2a, intramolecular reduction
was relatively slow and hence, effectively catalyzed by BINAPO to
show a moderate enantioselectivity at ꢀ78 ꢁC (Table 4, entry 2). The
yield was low because most of the other enantiomer of the anti
5 A22 (Eq. 6). After 25 h, the mixture was filtered through Celite and
ꢀ
concentrated under vacuum. The residue was diluted with dry
dichloromethane, and the solution was cooled to ꢀ40 ꢁC. NMP,
trichlorosilane, and benzaldehyde were successively added to the
solution, and the mixture was stirred for 1 h. After the usual
workup, product 3c was obtained in reasonable yield with high
diastereoselectivity. We expect that this procedure will be appli-
cable for enamines that are difficult to isolate.
O
O
P
O
P
O
P
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
P
O
P
O
P
O
O
O
HSiCl3 (1.5 eq)
NMP (20 mol %)
PhCHO (1.0 eq)
(S)-BINAPO
(S)-SEGPHOSO
(R,R)-DIOPO
MS 5Å
O
O
OH
N
Et2O, rt, 25 h
(6)
2c
+
N
N
then
CH2Cl2
–40 oC, 1 h
52 %
O
O
Ph
N
H
filtration and
concentration
N
N
O O
(S)-BQNO
Fig. 6. Chiral Lewis base catalysts used in this study.
(1.5 eq)
(1.8 eq)
3c
dr = 98 : 2
a
(R)-BIQNO
a Diastereomeric ratio (1,2-anti-2,3-anti : Σ other isomers).
Estimated by 1H-NMR analysis of the crude products.

T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
535
iminium intermediate remained intact. On the other hand, the anti
iminium ion intermediate derived from enamine 2c was suffi-
ciently reactive even at ꢀ78 ꢁC (Table 4, entry 8), presumably due to
the inductive effect of the oxygen atom in the morpholine ring, and
both enantiomers of the anti iminium ion reacted to give an almost
racemic product. Thus, further investigations are necessary to im-
prove the enantioselectivity.
were prepared according to the literatures.14c,25 All other chemicals
were purified based on standard procedures.
9.2. General procedure for the synthesis of g-amino alcohols
from aldehydes, enamines, and trichlorosilane using NMP
Trichlorosilane (0.75 mmol, ca. 3 M CH2Cl2 solution, 1.5 equiv)
was added to a solution of enamine 2 (0.6 mmol, 1.2 equiv) and
NMP (20 mol %) in dichloromethane (2 mL) at ꢀ40 ꢁC. Then alde-
hyde 1 (0.5 mmol, 1.0 equiv) was introduced to the mixture. After
stirring for 1 h, the reaction was quenched with satd aqueous
NaHCO3 (5 mL). The mixture was diluted with AcOEt (5 mL) and
stirred at rt for 1 h to precipitate the silicon byproducts. After fil-
tration through a Celite pad with AcOEt, the filtrate was extracted
with AcOEt (3ꢂ15 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (silica gel 15 g, hexane/AcOEt¼2/1eAcOEt/EtOH¼5/1) to
X
N
X
N
Chiral Lewis Base
Catalyst (LB*)
OH
O
+
HSiCl3
Ph
Ph
H
Cl
Si
LB*
X
Cl
O
C-C formation
Reduction
H
N
give corresponding
g-amino alcohol 3 or 5. The diastereomeric
Ph
Fast (X = CH2, O)
Slow (X = CH2)
Kinetic Resolution
ratio of 3a was determined by 1H NMR analysis of the crude product
and compared to the spectral data of the diastereomers (see Section
9.3e9.5). The diastereomeric ratios of 3bek were tentatively esti-
mated by analogy.
Cl
Low ee
anti selective
Fast (X = O)
but
Low ee
almost racemic
Fig. 7. Mechanistic insight into the enantioselective catalysis.
9.2.1. Phenyl[2-(piperidin-1-yl)cyclohexyl]methanol (3a). anti,anti-
Isomer: colorless solid; TLC: Rf 0.31 (AcOEt/EtOH¼5/1, stained blue
with phosphomolybdic acid/EtOH); mp 121e123 ꢁC; IR (KBr, cmꢀ1
)
8. Conclusion
2914, 1444,1375, 1333, 1201, 1134, 1061, 1032, 766; 1H NMR (CDCl3):
d
0.79 (dddd, 1H, J¼3.7, 11.9, 13.3, 13.3 Hz), 0.95 (ddddd, 1H, J¼3.2,
We have demonstrated that tandem CeC bond formation/re-
duction of aldehydes, enamines, and trichlorosilane in the presence
3.2, 12.8, 12.8, 13.3 Hz), 1.07e1.33 (m, 4H), 1.47e1.83 (m, 8H),
1.86e1.95 (m, 1H), 2.21 (br t, 1H, J¼10.4 Hz), 2.56 (ddd, 1H, J¼3.6,
11.1, 11.1 Hz), 2.66 (br t, 1H, J¼9.8 Hz), 2.82 (br d, 1H, J¼9.8 Hz), 3.10
(br d, 1H, J¼10.4 Hz), 4.44 (d, 1H, J¼9.2 Hz), 7.21e7.26 (m, 1H),
of Lewis base catalysts affords
stereoselectivity. This method offers the first, concise synthetic
method of -amino alcohols from aldehydes and enamines. Further
g-amino alcohols with a high dia-
g
7.28e7.37 (m, 4H), 9.27 (br s, 1H); 13C NMR (CDCl3):
d 24.1, 24.5,
investigations to improve the yield and enantioselectivity as well as
to apply this method in the synthesis of useful molecules6ꢀ8 are
currently underway.
25.4, 25.6, 25.8 (br), 26.8 (br), 29.3, 43.0, 46.4 (br), 53.3 (br), 70.7,
82.3, 127.1, 127.3, 128.0, 143.8; HRMS (FAB): calcd for C18H28NO
(MþHþ) 274.2171, found 274.2169.
9. Experimental section
9.1. General
9.2.2. Phenyl[2-(pyrrolidin-1-yl)cyclohexyl]methanol (3b). anti,anti-
Isomer: colorless solid; TLC: Rf 0.26 (hexane/AcOEt¼1/1, stained
blue with phosphomolybdic acid/EtOH); mp 101e103 ꢁC; IR (KBr,
cmꢀ1) 2927, 2854, 1450, 1331, 1147, 1061, 1020, 758, 698; 1H NMR
Melting points were uncorrected. 1H and 13C NMR spectra were
measured in CDCl3 with JEOL JNM-ECX400 spectrometer otherwise
noted. Tetramethylsilane (TMS) (
(CDCl3):
d
0.80 (dddd, 1H, J¼3.7, 11.7, 12.4, 13.3 Hz), 0.98 (ddddd, 1H,
J¼3.7, 3.7, 12.8, 13.3, 13.3 Hz), 1.10e1.22 (m, 2H), 1.27 (dddd, 1H,
J¼3.2, 11.3, 12.1, 12.8 Hz), 1.53 (apparent d, 1H, J¼13.3 Hz), 1.65
(dddd,1H, J¼3.7, 9.2,11.0,13.3 Hz),1.71e1.82 (m, 5H),1.86 (apparent
d, 1H, J¼12.4 Hz), 2.75 (br s, 2H), 2.87 (ddd, 1H, J¼3.7, 11.0, 11.0 Hz),
2.87 (br s, 2H), 4.46 (d, 1H, J¼9.2 Hz), 7.21e7.26 (m, 1H), 7.28e7.35
d
¼0 ppm) and CDCl3 ( ¼77.0 ppm)
d
were used for internal standards for 1H and 13C NMR analyses, re-
spectively. Infrared spectra were recorded on JEOL JIR-6500W. Mass
spectra were measured with JEOL JMS-DX303HF mass spectrome-
ter. Optical rotations were recorded on JASCO P-1010 polarimeter.
High pressure liquid chromatography (HPLC) was performed with
JASCO P-980 and UV-1575. Thin-layer chromatography (TLC)
analysis was carried out using Merck silica gel plates. Visualization
was accomplished with UV light, phosphomolybdic acid, and/or
anisaldehyde. Column chromatography was performed using Kanto
(m, 4H), 9.22 (br s, 1H); 13C NMR (CDCl3):
d 23.2, 23.5 (br), 25.5,
29.4, 44.9, 47.2 (br), 64.2, 82.6, 127.1, 127.3, 128.0, 143.9; HRMS
(FAB): calcd for C17H26NO (MþNaþ) 282.1834, found 282.1837.
Other isomers: 1H NMR (CDCl3):
tectable carbinol protons).
d
4.69 (d, J¼4.1 Hz), 5.29 (s) (de-
Chemical Silica Gel 60N (spherical, neutral. 63e210
m
m). All re-
9.2.3. [2-(Morpholin-4-yl)cyclohexyl]phenylmethanol (3c). anti,anti-
Isomer: colorless solid; TLC: Rf 0.26 (hexane/AcOEt¼1/1, stained
blue with phosphomolybdic acid/EtOH); mp 124e126 ꢁC; IR (KBr,
cmꢀ1) 2954, 2854, 1452, 1446, 1117, 999, 760, 700; 1H NMR (CDCl3):
actions were performed under argon atmosphere using oven- and
heat gun-dried glassware equipped with a rubber septum and
a magnetic stirring bar.
Dichloromethane (dehydrated) was purchased from Kanto
Chemical and stored over 4 A MS prior to use. All other solvents were
d
0.80 (dddd, 1H, J¼3.2, 11.9, 13.2, 13.2 Hz), 0.97 (ddddd, 1H, J¼3.2,
ꢀ
3.2, 12.8, 13.2, 13.2 Hz), 1.09e1.34 (m, 3H), 1.53 (apparent d, 1H,
J¼13.2 Hz),1.68e1.84 (m, 2H),1.90e1.98 (m,1H), 2.51e2.68 (m, 3H),
2.96 (br s, 2H), 3.67 (br s, 2H), 3.89 (br s, 2H), 4.48 (d, 1H, J¼9.2 Hz),
7.22e7.29 (m, 1H), 7.30e7.35 (m, 4H), 8.66 (br s, 1H); 13C NMR
purified based on standard procedures. Trichlorosilane (>98%) and
tetrachlorosilane were purchased from Tokyo Kasei Kogyo (TCI) and
used without further purification. A dichloromethane solution of
trichlorosilane (ca. 3 M) was prepared and stocked in a screw-top
test tube with a Teflon packing. (S)-BINAPO was prepared by oxi-
dation of (S)-BINAP with hydrogenperoxide in acetone.23c Enamines
(CDCl3):
d 24.1, 25.2, 25.4, 29.2, 43.0, 45.7 (br), 51.7 (br), 66.9 (br),
67.3 (br), 70.3, 82.2, 127.19, 127.24, 128.0, 143.2; HRMS (FAB): calcd
for C17H26NO2 (MþHþ) 276.1964, found 276.1961. Other isomers: 1H

536
T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
NMR (CDCl3):
carbinol protons).
d
4.71 (d, J¼3.6 Hz), 5.09 (d, J¼2.3 Hz) (detectable
(film on NaCl, cmꢀ1) 3055, 2929, 2852, 1452, 1119, 1061, 1003, 860,
823, 746; 1H NMR (CDCl3):
0.79e1.01 (m, 2H), 1.09e1.22 (m, 2H),
d
1.28 (dddd, 1H, J¼3.2, 12.4, 12.4, 12.4 Hz), 1.49 (apparent d, 1H,
J¼12.8 Hz), 1.74e1.88 (m, 2H), 1.94 (apparent d, 1H, J¼12.4 Hz),
2.56e2.71 (m, 3H), 2.98 (dd, 2H, J¼2.3, 11.4 Hz), 3.71 (br s, 2H),
3.91 (br s, 2H), 4.67 (d, 1H, J¼9.2 Hz), 7.41e7.48 (m, 2H), 7.52 (dd,
1H, J¼1.4, 8.2 Hz), 7.73 (s, 1H), 7.78e7.85 (m, 3H), 8.80 (br s, 1H);
9.2.4. [2-(Morpholin-4-yl)cyclopentyl]phenylmethanol (3d). anti,anti-
Isomer: colorless oil; TLC: Rf 0.14 (AcOEt/EtOH¼5/1, stained blue
with phosphomolybdic acid/EtOH); IR (NaCl, cmꢀ1) 2956, 2850,
1452, 1265, 1119, 1014, 874, 762, 702; 1H NMR (CDCl3):
d 1.10e1.33
(m, 2H), 1.48e1.74 (m, 4H), 2.07 (dddd, 1H, J¼7.8, 9.6, 10.1, 11.0 Hz),
2.58e2.68 (m, 2H), 2.77e2.88 (m, 2H), 3.04 (ddd, 1H, J¼7.8, 10.1,
10.1 Hz), 3.71e3.83 (m, 4H), 4.54 (d, 1H, J¼9.6 Hz), 6.92 (br s, 1H),
13C NMR (CDCl3):
d 24.1, 25.2, 25.4, 29.2, 42.9, 45.7 (br), 51.8 (br),
66.9 (br), 67.4 (br), 70.4, 82.3, 125.1, 125.4, 125.7, 126.1, 127.5, 127.8,
132.9, 133.0, 140.6 (one aromatic carbon is overlapped); HRMS
(FAB): calcd for C21H28NO2 (MþHþ) 326.2120, found 326.2111.
7.22e7.26 (m, 1H), 7.29e7.38 (m, 4H); 13C NMR (CDCl3):
d 21.0, 21.2,
26.0, 45.8, 49.4 (br), 67.3, 73.2, 81.4, 126.5, 127.4, 128.2, 144.0; HRMS
Other isomers: 1H NMR (CDCl3):
tectable carbinol protons).
d
4.89 (d, J¼3.7 Hz), 5.26 (s) (de-
(FAB): calcd for C16H24NO2 (MþNaþ) 284.1626, found 284.1647.
Other isomers: 1H NMR (CDCl3):
carbinol proton).
d
4.94 (d, J¼5.0 Hz) (detectable
9.2.9. (Furan-1-yl)[2-(morpholin-4-yl)cyclohexyl]methanol
(3j). anti,anti-Isomer: colorless solid; TLC: Rf 0.44 (hexane/
AcOEt¼1/1, stained blue with phosphomolybdic acid/EtOH); mp
110e112 ꢁC; IR (KBr, cmꢀ1) 2931, 2850, 1450, 1151, 1117, 1059, 1034,
9.2.5. (4-Methoxyphenyl)[2-(morpholin-4-yl)cyclohexyl]methanol
(3e). anti,anti-Isomer: colorless oil; TLC: Rf 0.35 (hexane/AcOEt¼1/1,
stained blue with phosphomolybdic acid/EtOH); IR (film on NaCl,
cmꢀ1) 2929, 2852, 1514, 1452, 1244, 1117, 1036, 1001, 860, 833; 1H
1005, 858, 733; 1H NMR (CDCl3):
d
0.81 (dddd, 1H, J¼3.7, 12.4, 12.4,
12.6 Hz), 1.02e1.35 (m, 4H), 1.59 (apparent d, 1H, J¼11.5 Hz),
1.78e1.86 (m, 1H), 1.93 (apparent d, 1H, J¼12.8 Hz), 2.01 (dddd, 1H,
J¼4.1, 9.6, 11.0, 11.0 Hz), 2.52 (ddd, 1H, J¼3.2, 11.0, 11.4 Hz),
2.54e2.63 (m, 2H), 2.93 (apparent d, 2H, J¼9.6 Hz), 3.66 (br s, 2H),
3.85 (br s, 2H), 4.56 (d, 1H, J¼9.6 Hz), 6.22 (d, 1H, J¼2.8 Hz),
6.28e6.32 (m, 1H), 7.38 (d, 1H, J¼1.4 Hz), 8.62 (br s, 1H); 13C NMR
NMR (CDCl3):
d
0.77 (dddd,1H, J¼3.7,11.9,13.3,13.3 Hz), 0.97 (ddddd,
1H, J¼3.2, 3.2,12.8,13.3,13.3 Hz),1.07e1.32 (m, 3H),1.54 (apparent d,
1H, J¼13.3 Hz),1.70 (dddd,1H, J¼3.9, 9.2,11.5,13.3 Hz),1.80 (apparent
d,1H, J¼12.8 Hz),1.93 (apparent d,1H, J¼12.4 Hz), 2.52e2.68 (m, 3H),
2.95 (br s, 2H), 3.67 (br s, 2H), 3.79 (s, 3H), 3.87 (br s, 2H), 4.44 (d,1H,
J¼9.2 Hz), 6.86 (d, 2H, J¼8.5 Hz), 7.24 (d, 2H, J¼8.5 Hz) 8.58 (br s,1H);
(CDCl3):
d 24.1, 25.1, 25.4, 28.8, 40.7, 45.8 (br), 51.7 (br), 67.11 (br),
13C NMR (CDCl3):
d
24.1, 25.3, 25.5, 29.2, 43.1, 45.7 (br), 51.8 (br), 55.1,
67.20 (br), 70.1, 75.0, 107.1, 109.6, 141.8, 155.2; Anal. calcd for
C15H23NO3 C, 67.90; H, 8.74; N, 5.28; found C, 67.70; H, 8.76; N, 5.16.
66.9 (br), 67.4 (br), 70.3, 81.7, 113.3, 128.2, 135.6, 158.7; HRMS (FAB):
calcd for C18H27NO3Na (MþNaþ) 328.1889, found 328.1883. Other
Other isomers: 1H NMR (CDCl3):
J¼2.3 Hz) (detectable carbinol protons).
d
4.63 (d, J¼3.6 Hz), 5.10 (d,
isomers: 1H NMR (CDCl3):
d
4.66 (s) (detectable carbinol proton).
9.2.6. [2-(Morpholin-4-yl)cyclohexyl](4-nitrophenyl)methanol
(3f). anti,anti-Isomer: colorless solid; TLC: Rf 0.19 (hexane/AcOEt¼1/
1, stained bluewith phosphomolybdicacid/EtOH);mp 116e118 ꢁC;IR
(KBr, cmꢀ1) 3078, 2931, 2850,1605,1514,1454,1350,1130,1113,1005,
9.2.10. [2-(Morpholin-4-yl)cyclohexyl](pyridin-2-yl)methanol
(3k). anti,anti-Isomer: colorless oil; TLC: Rf 0.30 (AcOEt/EtOH¼5/1,
stained blue with phosphomolybdic acid/EtOH); IR (NaCl, cmꢀ1
)
2927, 2852, 1591, 1452, 1433, 1117, 1068, 1003, 860, 785; 1H NMR
(CDCl3):
856; 1H NMR (CDCl3):
d
0.86 (dddd,1H, J¼3.7,11.4,12.8,13.3 Hz), 0.97
d
0.85e0.98 (m, 1H), 1.02 (ddddd, 1H, J¼3.2, 3.2, 12.8, 12.8,
(ddddd, 1H, J¼3.2, 3.2, 12.8, 12.8, 13.3 Hz), 1.08e1.35 (m, 3H), 1.56
(apparent d, 1H, J¼12.8 Hz), 1.68 (dddd, 1H, J¼3.7, 9.2, 11.0, 12.8 Hz),
1.82 (apparent d, 1H, J¼12.8 Hz), 1.96 (apparent d, 1H, J¼12.8 Hz),
2.56e2.71 (m, 3H), 2.84e3.07 (m, 2H), 3.67 (br s, 2H), 3.93 (br s, 2H),
4.61 (d, 1H, J¼9.2 Hz), 7.50 (d, 2H, J¼8.7 Hz), 8.19 (d, 2H, J¼8.7 Hz),
12.8 Hz), 1.10e1.22 (m, 2H), 1.29 (dddd, 1H, J¼3.7, 12.4, 12.4,
12.4 Hz), 1.55 (apparent d, 1H, J¼12.8 Hz), 1.80 (apparent dq, 1H,
J¼12.8, 2.8 Hz), 1.90e2.02 (m, 2H), 2.56e2.65 (m, 2H), 2.92e3.00
(m, 2H), 3.77 (br s, 4H), 4.66 (d, 1H, J¼8.7 Hz), 7.17 (ddd, 1H, J¼0.9,
4.8, 7.3 Hz), 7.37 (br d,1H, J¼7.8 Hz), 7.67 (ddd,1H, J¼1.8, 7.3, 7.8 Hz),
9.02 (br s,1H); 13C NMR (CDCl3):
d
24.2, 25.1, 25.3, 29.0, 43.0, 45.8 (br),
8.50 (br s, 1H), 8.58 (br d, 1H, J¼4.8 Hz); 13C NMR (CDCl3):
d 24.2,
51.8 (br), 66.8 (br), 67.5 (br), 70.4, 81.4,123.4,128.2,147.3,150.7; Anal.
calcd forC17H24N2O4$0.5H2OC, 61.99; H, 7.65;N, 8.50;foundC, 62.07;
H, 7.79; N, 8.32. No other isomers could be detected.
25.3, 25.5, 28.8, 42.4, 67.3 (br), 70.1, 82.4, 122.2, 122.4, 136.4, 148.9,
162.0; HRMS (FAB): calcd for C16H24N2O2Na (MþNaþ) 299.1735,
found 299.1726. Other isomers: 1H NMR (CDCl3):
J¼4.3 Hz), 5.12 (s) (detectable carbinol protons).
d 4.76 (s), 4.97 (d,
9.2.7. [2-(Morpholin-4-yl)cyclohexyl](naphthalene-1-yl)methanol
(3g). anti,anti-Isomer: colorless oil; TLC: Rf 0.30 (hexane/AcOEt¼1/
1, stained blue with phosphomolybdic acid/EtOH); IR (film on NaCl,
cmꢀ1) 2927, 2852, 1452, 1119, 1061, 864, 798, 779, 735; 1H NMR
9.2.11. 3-(Morpholin-4-yl)-1,3-diphenylpropan-1-ol (5a). 1,3-syn-
Isomer: colorless oil; TLC: Rf 0.16 (hexane/AcOEt¼1/1, stained blue
with phosphomolybdic acid/EtOH); IR (film on NaCl, cmꢀ1) 2920,
(CDCl3):
d
0.78e1.04 (m, 3H),1.16 (dddd,1H, J¼3.2, 3.2,12.8,12.8 Hz),
2850, 1452, 1265, 1117, 1063, 1024, 760, 702; 1H NMR (CDCl3):
d 1.82
1.32 (dddd, 1H, J¼3.7, 12.4, 12.8, 12.8 Hz) 1.44 (apparent d, 1H,
J¼12.4 Hz), 1.79 (apparent d, 1H, J¼12.8 Hz), 1.98 (apparent d, 1H,
J¼12.4 Hz), 2.06e2.17 (m,1H), 2.60e2.76 (m, 3H), 2.99e3.09 (m, 2H),
3.73 (br s, 2H), 3.95 (br s, 2H), 5.30 (d, 1H, J¼9.2 Hz), 7.42e7.51 (m,
3H), 7.56 (d, 1H, J¼6.8 Hz), 7.77 (d, 1H, J¼7.8 Hz), 7.82e7.88 (m, 1H),
(ddd, 1H, J¼1.8, 2.3, 14.8 Hz), 2.37 (br s, 2H), 2.46 (ddd, 1H, J¼10.5,
11.5, 14.8 Hz), 2.67e2.78 (m, 2H), 3.66e3.80 (m, 4H), 4.01 (dd, 1H,
J¼2.3, 11.5 Hz), 5.02 (dd, 1H, J¼1.8, 10.5 Hz), 6.86 (br s, 1H), 7.13 (d,
2H, J¼6.4 Hz), 7.22e7.28 (m, 1H), 7.29e7.37 (m, 5H), 7.38e7.45 (m,
2H); 13C NMR (CDCl3):
d 38.6, 49.5 (br), 67.1, 70.1, 75.43, 75.46,
8.39 (d, 1H, J¼7.8 Hz), 8.69 (br s, 1H); 13C NMR (CDCl3):
d
24.2, 25.3,
125.4, 127.1, 127.9, 128.1, 128.3, 128.8, 135.4, 144.8; HRMS (FAB):
25.4, 29.4, 43.3, 45.9 (br), 51.9 (br), 66.9 (br), 67.5 (br), 70.8, 79.1,
124.2, 125.2, 125.4, 125.5, 127.7, 128.7, 131.6, 133.8, 139.0 (one aro-
matic carbon is overlapped); HRMS (FAB): calcd for C21H27NO2Na
(MþNaþ) 348.1934, found 348.1924. Other isomers: 1H NMR (CDCl3):
calcd for C19H24NO2 (MþHþ) 298.1807, found 298.1833. 1,3-anti-
Isomer: 1H NMR (CDCl3):
proton).
d
5.08 (dd, 1H, J¼4.6, 4.6 Hz) (the carbinol
d
4.66 (d, J¼9.2 Hz) (detectable carbinol proton).
9.2.12. 3-(Morpholin-4-yl)-3-phenyl-1-(pyridin-2-yl)propan-1-ol
(5b). 1,3-anti-Isomer: colorless oil; TLC: Rf 0.43 (AcOEt/EtOH¼5/1,
stained blue with phosphomolybdic acid/EtOH); IR (film on NaCl,
cmꢀ1) 2956, 2852, 1591,1452, 1117, 1070, 768, 704; 1H NMR (CDCl3):
9.2.8. [2-(Morpholin-4-yl)cyclohexyl](naphthalene-2-yl)methanol
(3h). anti,anti-Isomer: colorless oil; TLC: Rf 0.29 (hexane/
AcOEt¼1/1, stained blue with phosphomolybdic acid/EtOH); IR
d
2.22 (ddd, 1H, J¼3.2, 4.6, 14.4 Hz), 2.33 (br s, 2H), 2.57e2.69 (m,

T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
537
2H), 2.74 (ddd, 1H, J¼4.6, 10.5, 14.4 Hz), 3.59 (dd, 1H, J¼3.2, 10.5 Hz),
3.68e3.80 (m, 4H), 5.11 (dd, 1H, J¼4.6, 4.6 Hz), 6.67 (br s, 1H),
7.09e7.19 (m, 3H), 7.26e7.35 (m, 3H), 7.55e7.60 (m, 1H), 7.70 (ddd,
1H, J¼1.8, 7.6, 7.6 Hz), 8.52 (dd, 1H, J¼0.9, 4.1 Hz); 13C NMR (CDCl3):
(br s, 1H), 7.29e7.38 (m, 4H); 13C NMR (CDCl3):
24.2, 25.5, 26.8, 47.5, 54.2 (br), 65.0, 77.1, 125.6, 126.1, 127.6, 143.4;
HRMS (FAB): calcd for C18H27NONa (MþNaþ) 296.1990, found
296.1983.
d
19.4, 22.8, 23.8,
d
35.4, 49.8 (br), 66.33, 66.36, 67.2, 73.03, 73.12, 120.2, 121.8, 127.7,
128.1, 128.7, 136.2, 136.4, 148.9, 163.7; HRMS (FAB): calcd for
C18H22N2O2Na (MþNaþ) 321.1579, found 321.1584. 1,3-syn-Isomer:
9.5. Preparation of anti,syn-3a
1H NMR (CDCl3):
proton).
d
5.02 (dd, 1H, J¼2.1, 10.3 Hz) (the carbinol
Benzaldehyde (52.8 mg, 0.5 mmol, 1.0 equiv) and SiCl4
(0.086 mL, 0.75 mmol, 1.5 equiv) was added to a solution of en-
amine 2a (0.6 mmol, 1.2 equiv) in dichloromethane (2 mL) under an
argon atmosphere at 0 ꢁC. The reaction was immediately allowed to
reach rt and stirred for 1 h. The mixture was added to LiBH4
(1 mmol) in THF (2 mL) via a cannula under an argon atmosphere
at ꢀ78 ꢁC. The mixture was allowed to warm to rt over 2 h and
quenched with satd aqueous NaHCO3 (5 mL). The mixture was di-
luted with AcOEt (5 mL) and stirred for 1 h to precipitate silicon
byproducts. After filtration through a Celite pad with AcOEt, the
filtrate was extracted with AcOEt (3ꢂ5 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (silica gel 15 g, hexane/AcOEt¼2/
1eAcOEt/EtOH¼5/1) to give anti,syn-3a (37.6 mg, 27%).
9.3. Preparation of syn,anti-3a
Jones reagent (0.16 mL of 1.23 M solution, 0.19 mmol) [prepared
from CrO3 (1.41 g), water (10 mL), and concd H2SO4 (1.2 mL)] was
added to a solution of anti,anti-3a (42.5 mg, 0.16 mmol, 1.0 equiv) in
acetone (1.6 mL) at rt. After being stirred for 14 h, the solution was
evaporated. The resulting residue was diluted with water (0.8 mL).
After cooling at 0 ꢁC, 15% aqueous NaOH (0.22 mL) was added to the
solution, and extracted by dichloromethane (4ꢂ5 mL). The com-
bined organic layers were washed by water (1ꢂ5 mL) and brine
(1ꢂ5 mL), dried over anhydrous Na2SO4, filtered, and evaporated.
The residue was purified by column chromatography on silica gel
(silica gel 15 g, hexane/AcOEt¼3/1 to 1/1) to give the corresponding
1,2-trans-ketone (31.6 mg, 74%). Then, LiAlH4 (3.1 mg, 0.093 mmol)
9.5.1. Phenyl[2-(piperidin-1-yl)cyclohexyl]methanol (3a). anti,syn-
Isomer: colorless solid; TLC: Rf 0.36 (AcOEt/EtOH¼5/1, stained blue
was added to
a solution of the 1,2-trans-ketone (12.6 mg,
0.046 mmol) in THF (0.38 mL) under an argon atmosphere at rt.
After being stirred for 0.5 h, the reaction was quenched by adding
water (3.4 mL), aqueous NaOH (6M, 3.4 mL), and water (10.2 mL). The
mixture was stirred for 2 h and filtered through a Celite pad with
dichloromethane. The filtrate was evaporated to give 3a (12.1 mg,
95%, anti,anti/syn,anti¼94/6).
with phosphomolybdic acid/EtOH); mp 129e131 ꢁC; IR (KBr, cmꢀ1
)
2943, 1446, 1362, 1342, 1275, 1103, 1041, 972, 870, 758; 1H NMR
(CDCl3):
d
1.12 (dddd, 1H, J¼4.1, 4.1, 13.7, 13.7 Hz), 1.22e1.37 (m, 4H),
1.45 (dddd, 1H, J¼3.7, 3.7, 13.7, 13.7, 13.7 Hz), 1.62e1.82 (m, 6H),
1.86e2.06 (m, 4H), 2.25e2.34 (m, 1H), 2.49 (ddd, 1H, J¼3.2, 3.4,
12.8 Hz), 3.18 (br s, 1H), 3.48 (br s, 1H), 5.09 (d, 1H, J¼10.1 Hz),
7.20e7.29 (m, 1H), 7.31e7.48 (m, 4H), 8.93 (br s, 1H); 13C NMR
9.3.1. Phenyl[2-(piperidin-1-yl)cyclohexyl]methanol (3a). syn,anti-
Isomer: colorless solid; TLC: Rf 0.47 (AcOEt/EtOH¼5/1, stained
blue with phosphomolybdic acid/EtOH); mp 121e123 ꢁC; IR (KBr,
(CDCl3):
d 20.5, 24.2, 24.4, 26.0 (br), 26.2, 26.6 (br), 27.4, 40.0, 49.5
(br), 53.5 (br), 67.6, 73.9,127.0,127.1,128.1,144.4; HRMS (FAB): calcd
for C18H28NO (MþHþ) 274.2171, found 274.2164.
cmꢀ1) 2912, 1446, 1375, 1333, 1201, 1134, 1061, 1032, 787, 758; 1
H
NMR (CDCl3):
d
0.69 (dddd, 1H, J¼3.7, 11.9, 12.8, 13.3 Hz), 0.83
(ddddd, 1H, J¼3.2, 3.2, 13.0, 13.0, 13.3 Hz), 1.08e1.31 (m, 4H),
1.49e1.82 (m, 9H), 2.12e2.30 (m, 2H), 2.42e2.84 (m, 2H),
3.00e3.19 (m, 1H), 4.66 (d, 1H, J¼3.9 Hz), 7.21e7.27 (m, 2H),
9.6. Observation of iminium ion intermediate by NMR
spectroscopy
7.29e7.36 (m, 3H), 8.43 (br s, 1H); 13C NMR (CDCl3):
d 23.7, 24.7,
Under an argon atmosphere, benzaldehyde (0.15 mmol,
1.0 equiv) was added to a solution of enamine 2a (0.18 mmol,
1.2 equiv) in deuterated dichloromethane (0.6 mL) in an NMR tube
at rt. After cooling at ꢀ78 ꢁC, SiCl4 (0.23 mmol, 1.5 equiv) was in-
troduced to the mixture. The mixture was stood at rt for 5 h, before
NMR measurements were conducted.17
24.8 (br), 24.9, 26.4, 26.9 (br), 29.9, 42.5, 46.8 (br), 53.3 (br), 64.6,
79.7, 126.6, 127.4, 127.5, 142.9; HRMS (FAB): calcd for C18H28NO
(MþHþ) 274.2171, found 274.2188.
9.4. Preparation of syn,syn-3a
A solution of 2-benzoylcyclohexanone (202.1 mg, 1.0 mmol),
piperidine (0.3 mL, 3.0 mmol), and p-toluenesulfonic acid mono-
hydrate (4 mol %) was heated under reflux in toluene (10 mL) using
a DeaneStark apparatus. After being stirred for 44 h, the reaction
mixture was cooled to rt and evaporated. To the residue was added
dry EtOH (3 mL) and platinum oxide (10 mg) under an argon at-
mosphere at rt. Then, the argon was replaced by hydrogen, and the
reaction mixture was stirred for 43 h at rt. The mixture was filtered
through a Celite pad with EtOH, and the filtrate was evaporated.
The residue was purified by column chromatography on silica gel
(silica gel 15 g, hexane/AcOEt¼2/1eAcOEt/EtOH¼5/1) to give
syn,syn-3a (133.7 mg, 49%).
9.7. Reaction of benzaldehyde with enamine 2c prepared
beforehand
Cyclohexanone (0.16 mL, 1.5 mmol) and morpholine (0.16 mL,
1.8 mmol) was mixed in diethyl ether (1.5 mL) in the presence of
ꢀ
molecular sieves 5 A pellet (600 mg) at rt. After being stirred for
25 h at rt, the mixture was filtered through a Celite pad in a pipet
and concentrated under vacuum. The residue was diluted with
dichloromethane (4 mL) and cooled to ꢀ40 ꢁC. NMP (20 mol %),
trichlorosilane (ca. 3 M, 1.5 mmol), and benzaldehyde (112.5 mg,
1.06 mmol) were successively added to the solution, and the mix-
ture was stirred at ꢀ40 ꢁC for 1 h. The reaction was quenched by
satd aqueous NaHCO3. The mixture was stirred at rt for 1 h, filtered
through a Celite pad, and extracted with AcOEt (3ꢂ5 mL). The
combined organic layers were dried over anhydrous Na2SO4, fil-
tered, and evaporated. The residue was purified by column chro-
matography on silica gel (silica gel 15 g, hexane/AcOEt¼2/1eAcOEt/
EtOH¼5/1) to give anti,anti-3c (151.4 mg, 52%).
9.4.1. Phenyl[2-(piperidin-1-yl)cyclohexyl]methanol (3a). syn,syn-
Isomer: yellow oil; TLC: Rf 0.27 (AcOEt/EtOH¼5/1, stained blue
with phosphomolybdic acid/EtOH); IR (NaCl, cmꢀ1) 2931, 2852,
2808, 1450, 1448, 1126, 1101, 977, 701; 1H NMR (CDCl3):
d 1.02e1.18
(m, 2H), 1.36e1.78 (m, 12H), 2.14 (apparent d, 1H, J¼12.8 Hz), 2.62
(br s, 2H), 2.88e3.41 (m, 3H), 5.08 (s, 1H), 7.18e7.23 (m, 1H), 7.25

538
T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
ꢁ
ꢁ
4373e4377; (e) Gonzalez, A. Z.; Roman, J. G.; Alicea, E.; Canales, E.; Soderquist,
J. A. J. Am. Chem. Soc. 2009, 131, 1269e1273; (f) Crotti, S.; Bertolini, F.; Macchia, F.;
Pineschi, M. Org. Lett. 2009, 11, 3762e3765.
9.8. Enantioselective reaction of benzaldehyde with enamine
2a catalyzed by (S)-BINAPO
6. For syntheses of biologically active g-amino alcohols, see: (a) Katz, L.; Karger, L.
S.; Cohen, M. S. J. Org. Chem. 1954, 19, 1225e1230; (b) Shibahara, S.; Kondo, S.;
Maeda, K.; Umezawa, H.; Ohno, M. J. Am. Chem. Soc. 1972, 94, 4353e4354; (c)
Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem. Soc. 1982, 104,
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Bioorg. Med. Chem. Lett. 2003, 13, 2413e2418; (e) Kozikowski, A. P.; Chen, Y.-Y. J.
Org. Chem. 1981, 46, 5248e5250; (f) Fischer, G.; Mutel, V.; Trube, G.; Malherbe,
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2,129,771C). (g) Carlier, P. R.; Lo, M. M.-C.; Lo, P. C.-K.; Richelson, E.; Tatsumi, M.;
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Haight, A. R.; Stuk, T. L.; Allen, M. S.; Bhagavatula, L.; Fitzgerald, M.; Hannick, S.
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Trichlorosilane (0.75 mmol, ca. 3 M CH2Cl2 solution) was added
to a solution of enamine 2a (0.6 mmol), and (S)-BINAPO (32.9 mg,
10 mol %) in dichloromethane (2 mL) at ꢀ40 ꢁC. Then benzaldehyde
(1a) (55.4 mg, 0.52 mmol) was introduced to the mixture. After
being stirred for 1 h, the reaction was quenched with satd aqueous
NaHCO3 (5 mL). The mixture was diluted with AcOEt (5 mL) and
stirred at rt for 1 h to precipitate silicon byproducts. After filtration
through a Celite pad with AcOEt, the filtrate was extracted with
AcOEt (3ꢂ5 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and evaporated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (silica gel 15 g, hexane/AcOEt¼2/1eAcOEt/EtOH¼5/1) to give
anti,anti-3a (62.0 mg, 43%, 40% ee).
ꢁ
rison, B. A.; Verdine, G. L. Org. Lett. 2003, 5, 633e636; (k) Metro, T.-X.; Pardo, D.
G.; Cossy, J. J. Org. Chem. 2008, 73, 707e710; (l) Bates, R. W.; Sa-Ei, K. Tetrahe-
dron 2002, 58, 5957e5978.
9.8.1. Phenyl[2-(piperidin-1-yl)cyclohexyl]methanol (3a). anti,anti-
7. For a review on chiral
M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767e796.
8. Chiral -amino alcohols have been used as chiral catalysts for enantioselective
g-amino alcohols in asymmetric synthesis, see: Lait, S.
Isomer: [
a
]
32 ꢀ3.9 (c 1.02, CHCl3) for 40% ee; HPLC (Chiralcel OD-H,
D
g
hexane/2-Propanol¼39/1, flow rate¼1.0 mL/min, UV detection at
arylation or alkylation of aldehydes, see: (a) Wang, X.-B.; Kodama, K.; Hirose, T.;
254 nm) tR¼9.0 min (minor), 11.1 min (major).
Yang, X.-F.; Zhang, G.-Y. Tetrahedron: Asymmetry 2010, 21, 75e80; (b) Szakonyi,
ꢁ
ꢁ
€ €
Z.; Balazs, A.; Martinek, T. A.; Fulop, F. Tetrahedron: Asymmetry 2006, 17,
199e204 and references cited therein.
9. For reviews on Lewis base organocatalysts, see: (a) Orito, Y.; Nakajima, M.
Synthesis 2006, 1391e1401; (b) Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem.
2007, 29e36; (c) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560e1638.
Acknowledgements
ꢃ
ꢁ
This work partially supported by a Grant-in-Aid of Scientific
Research from the Ministry of Education, Science, Sports, and Cul-
ture of Japan.
10. Miura, K.; Nakagawa, T.; Suda, S.; Hosomi, A. Chem. Lett. 2000, 150e151.
11. (a) Mukaiyama, T.; Wariishi, K.; Saito, Y.; Hayashi, M.; Kobayashi, S. Chem. Lett.
1988, 1101e1104; (b) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40,
1083e1086; (c) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40,
4751e4754; (d) Ghosh, A. K.; Kawahama, R. J. Org. Chem. 2000, 65, 5433e5435;
(e) Ghosh, A. K.; Kawahama, R.; Wink, D. Tetrahedron Lett. 2000, 41, 8425e8429;
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12. Lewis acid-promoted aldol-type reactions between aldehydes (or acetals) and
enamines have been reported, see: (a) Takazawa, O.; Kogami, K.; Hayashi, K.
Bull. Chem. Soc. Jpn. 1985, 58, 2427e2428; (b) Takazawa, O.; Kogami, K.; Hay-
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Supplementary data
Supplementary data related to this article can be found online
version, at doi:10.1016/j.tet.2010.10.075. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
References and notes
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15. For NMR spectra and the assignment of anti,anti-3a, see Supporting data.
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17. For NMR spectra of the reaction mixture and the assignment of the 1,2-anti
iminium ion intermediate, see Supporting data.
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M. Chem. Commun. 2009, 3585e3587.
3. For syntheses of g-amino alcohols via reduction of b-amino ketones, see: (a)
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onstrated, see: Ref. 14d.
Barluenga, J.; Olano, B.; Fustero, S. J. Org. Chem. 1985, 50, 4052e4056; (b)
ꢁ
Barluenga, J.; Fernandez-Marí, F.; Viado, A. L.; Aguilar, E.; Olano, B. J. Org.
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compounds with silyl ketene acetals promoted by SiCl4 and Lewis base cata-
lysts, see: Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem.
Soc. 2005, 127, 3774e3789 The equilibrium between the 1,2-anti and 1,2-syn
iminium ion intermediates at low temperature is unlikely, because the longer
reaction time did not improve the chemical yield.
20. The product yields were not correlated with the nucleophilicity of the en-
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Am. Chem. Soc. 2000, 122, 6510e6511; (d) Csomos, P.; Bernath, G.; Sohar, P.;
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ꢀ
22. For use of molecular sieve 5 A for enamine synthesis, see: Taguchi, K.; West-
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1369e1370 See also Ref.2.
4. For syntheses of
g-amino alcohols via reduction of b-hydroxy imines, see:
(a) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2003, 125,
11276e11282; (b) Cimarelli, C.; Giuli, S.; Palmieri, G. Eur. J. Org. Chem. 2006,
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9619e9626.
5. For syntheses of g-amino alcohols via CeC bond formations, see: (a) Toujas, J.-L.;
Toupet, L.; Vaultier, M. Tetrahedron 2000, 56, 2665e2672; (b) Anzai, M.; Yanada,
R.; Fujii, N.; Ohno, H.; Ibuka, T.; Takemoto, Y. Tetrahedron 2002, 58, 5231e5239;
(c) Murai, T.; Sano, H.; Kawai, H.; Aso, H.; Shibahara, F. J. Org. Chem. 2005, 70,
8148e8153; (d) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48,

T. Kashiwagi et al. / Tetrahedron 67 (2011) 531e539
539
24. The first CeC bond formation would be almost anti selective as depicted in Fig.
3 (see also Ref. 19) at low temperature. However, the enantioselectivity of this
step would be low. If the enantio-determining step had been mainly this step,
the enantiomeric excess of product 3a obtained under the conditions of entry 3
(Table 4) would have been at least 24% according to the results shown in
entries 1 and 2. This assumption is evidently inconsistent with the actual result
(9% ee). Therefore, the kinetic resolution of the anti iminium ion via the second
intramolecular reduction would be mainly enantio-determining.
€
€
25. (a) Hunig, S.; Lucke, E.; Brenninger, W. Org. Synth. 1973, Coll. Vol. 5, 808e809;
(b) White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213e214.