Enantioselective addition of diethylzinc to aldehydes catalyzed by (R)-1-phenylethylamine-derived 1,4-amino alcohols

Article abstract of DOI:10.1016/j.tet.2015.07.031

A series of o-xylylene-type 1,4-amino alcohols, synthesized from (R)-1-phenylethylamine, were used as chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde. (S)-1-Phenyl-1-propanol was obtained with high enantioselectivity in all cases since the stereochemical outcome of the reaction was controlled by the chiral benzylic carbon bearing amino group. Highest catalytic activity was obtained by using (R)-1-{2-[1-(pyrrolidin-1-yl)ethyl]phenyl}cyclohexan-1-ol (1n) derived from (R)-1-(1-phenylethyl)pyrrolidine and cyclohexanone. Various chiral secondary alcohols were obtained by the reaction of diethylzinc and aldehydes in the presence of 1n within 2 h with good to high enantioselectivities.

Full text of DOI:10.1016/j.tet.2015.07.031

Tetrahedron 71 (2015) 6796e6802
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective addition of diethylzinc to aldehydes catalyzed by
(
R)-1-phenylethylamine-derived 1,4-amino alcohols
*
Masatoshi Asami , Naomichi Miyairi, Yukihiro Sasahara, Ken-ichi Ichikawa,
Naoya Hosoda, Suguru Ito
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University, Tokiwadai 79-5, Hodogaya-ku,
Yokohama 240-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2015
Received in revised form 10 July 2015
Accepted 11 July 2015
Available online 16 July 2015
A series of o-xylylene-type 1,4-amino alcohols, synthesized from (R)-1-phenylethylamine, were used as
chiral ligands for the enantioselective addition of diethylzinc to benzaldehyde. (S)-1-Phenyl-1-propanol
was obtained with high enantioselectivity in all cases since the stereochemical outcome of the reaction
was controlled by the chiral benzylic carbon bearing amino group. Highest catalytic activity was obtained
by using (R)-1-{2-[1-(pyrrolidin-1-yl)ethyl]phenyl}cyclohexan-1-ol (1n) derived from (R)-1-(1-
phenylethyl)pyrrolidine and cyclohexanone. Various chiral secondary alcohols were obtained by the
Keywords:
reaction of diethylzinc and aldehydes in the presence of 1n within
2 h with good to high
1
,4-Amino alcohols
o-Xylylene structure
-Phenylethylamine
enantioselectivities.
Ó 2015 Elsevier Ltd. All rights reserved.
1
Diethylzinc
Chiral secondary alcohols
1
. Introduction
(Fig. 1a and b).8 Both enantiomers of the corresponding chiral
secondary alcohols were obtained with high enantioselectivities by
using the diastereomeric 1,4-amino alcohols (R,S)-2 and (S,S)-2
with different absolute configurations at the chiral carbon bearing
amino group. The results are in contrast with those using 1,2-amino
alcohols where the stereochemical outcome of the reaction is
During the past few decades, a number of chiral 1,2- and 1,3-
amino alcohols have been developed and utilized as chiral li-
gands and chiral auxiliaries in various asymmetric reactions. The
asymmetric alkylation of aldehydes is one of the important method
for the preparation of chiral secondary alcohols, which are useful as
intermediate of natural products and pharmaceuticals. Since the
initial report by Oguni and Omi in 1984, the enantioselective ad-
dition of organozinc compounds to aldehydes has been well-
investigated using chiral 1,2- and 1,3-amino alcohol ligands.
Meanwhile, little attention has been paid to the reaction using
chiral 1,4-amino alcohols, since the high levels of enantioinduction
are generally difficult by chiral zinc catalysts containing relatively
flexible seven-membered ring structures generated from organo-
zinc compounds and 1,4-amino alcohol ligands.7
Recently, we reported the synthesis of novel diastereomeric 1,4-
amino alcohols 2 with o-xylylene structure from an enantiopure
chiral 1,4-diol, (S,S)-1,2-bis(1-hydroxypropyl)benzene, and their
use in the enantioselective addition of diethylzinc to aldehydes
1
generally determined by the chiral carbon bearing hydroxy
2
2,4,9
group.
Although the high selectivities were achieved in the
3
reactions using our novel 1,4-amino alcohols, the preparation of
them required multistep synthesis from commercially available
compounds. This prompted us to develop novel chiral 1,4-amino
alcohols with similar structure to 2 starting from chiral 1-
phenylethylamine (3) as both enantiomers of 3 are commercially
available. Herein, we report a short step synthesis of various 1,4-
amino alcohols 1 with o-xylylene structure starting from 3 and
their use in the enantioselective addition of diethylzinc to alde-
hydes (Fig. 1c).
2
,4e6
*
Corresponding author. Tel./fax: þ81 45 339 3968; e-mail address: m-asami@
ynu.ac.jp (M. Asami).
Fig. 1. 1,4-Amino alcohols with o-xylylene structure.
http://dx.doi.org/10.1016/j.tet.2015.07.031
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

M. Asami et al. / Tetrahedron 71 (2015) 6796e6802
6797
2
. Results and discussion
First, a stepwise methylation of (R)-1-phenylethylamine (3) was
carried out as shown in Scheme 1. Primary amine (R)-3 was stirred
in ethyl formate at room temperature for 12 days, and the reduction
of the resulting formamide (R)-4 with lithium aluminum hydride in
refluxing tetrahydrofuran gave (R)-N-methyl-1-phenylethylamine
(5). The secondary amine 5 was mixed with paraformaldehyde in
methanol at room temperature, followed by the hydrogenation in
the presence of palladium on carbon afforded (R)-N,N-dimethyl-1-
phenylethylamine (6a) in 86% yield from (R)-3.
Scheme 2. Synthesis of 1,4-amino alcohol 1j.
Enantioselective addition of diethylzinc to benzaldehyde was ex-
amined by using various 1,4-amino alcohols 1ae1j (Table 2). When
the reaction of benzaldehyde with 2.0 equiv of diethylzinc was
carried out in the presence of 1a in diethyl ether at room temper-
ature, the reaction was completed in 8 h to afford (S)-1-phenyl-1-
propanol in 84% yield with 95% ee (entry 1). The chiral secondary
alcohol was obtained with high enantiomeric excess, although
a diastereomeric mixture of 1a (dr¼3:2) was used in the reaction.
This result confirms that the enantioselectivity of the reaction is
controlled solely by the chiral carbon bearing amino group, as was
Scheme 1. Synthesis of (R)-N,N-dimethyl-1-phenylethylamine (6a).
8
a
observed in our previous publication. Diastereomeric mixtures of
,4-amino alcohols 1b, 1c, and 1j were then used in the same re-
1
action, and the products were obtained with high enantiomeric
excesses (>90% ee) in all cases (entries 2, 3, and 10). Moreover, the
reaction using 1d with single chiral carbon center also produced
Next, a series of chiral 1,4-amino alcohols 1ae1i were synthe-
sized from (R)-6a and various carbonyl compounds (Table 1). The
tertiary amine (R)-6a was treated with tert-butyllithium in hexane
at room temperature for 24 h, and the reaction of the resulting
ortho-lithiated species with propanal in hexane/diethyl ether at
room temperature gave 1,4-amino alcohol 1a in 83% yield as a di-
astereomeric mixture (dr¼3:2, entry 1). Similarly, the reaction with
isobutyraldehyde and benzaldehyde afforded the corresponding
(S)-1-phenyl-1-propanol in 87% yield with 92% ee, clearly in-
dicating that the chirality at the benzylic carbon bearing hydroxy
group is unnecessary for the high levels of enantioinduction in this
10
reaction (entry 4). The introduction of two alkyl groups at ben-
zylic carbon bearing hydroxy group was effective to enhance the
reaction rate (entries 5e9), even though the reaction required 15 h
when 1d was used. Among them, good results were obtained by
using 1g (1.5 h, 82%, 95% ee) and 1h (2.5 h, 87%, 95% ee) containing
cyclopentane or cyclohexane rings, respectively (entries 7 and 8).
1,4-amino alcohols 1b and 1c in 83% and 79% yields as di-
astereomeric mixtures, respectively (entries 2 and 3). When para-
formaldehyde and symmetric ketones were used as electrophile,
the corresponding 1,4-amino alcohols 1de1i, in which benzylic
carbon bearing hydroxy group is achiral, were obtained in 23e62%
yield (entries 4e9). 1,4-Amino alcohol 1j was synthesized in two
steps from (R)-6a (Scheme 2). The addition of the ortho-lithiated
Table 2
Enantioselective addition of diethylzinc to benzaldehyde catalyzed by 1,4-amino
alcohols 1ae1j
(R)-6a to N,N-dimethylformamide afforded aldehyde (R)-7 in 81%
yield. The reaction of (R)-7 with methylmagnesium iodide in tet-
rahydrofuran at room temperature gave 1j in 78% yield as a di-
astereomeric mixture (dr¼3:2).
Table 1
Synthesis of amino alcohols 1ae1i
Entry
1,4-Amino alcohol
R1
R2
Time (h)
Yield (%)
eea (%)
1
2
3
4
5
6
7
8
9
1ab
Et
i-Pr
Ph
H
Me
Et
e(CH
e(CH
e(CH
Me
H
H
H
8
6
9
15
6
6
1.5
2.5
4
84
88
85
87
88
89
82
87
87
88
95
94
90
92
91
93
95
95
93
94
b
1b
b
1c
1d
1e
1f
H
Me
Et
e
R1
R2
Entry
1,4-Amino alcohol
Yield (%)
1g
1h
1i
2
2
2
)
4
)
5
)
6
a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Et
i-Pr
Ph
H
Me
Et
e(CH
e(CH
e(CH
H
H
H
H
Me
Et
83
83
79
e
a
e
a
b
10
1j
H
14
45
37
62
23
55
54
a
Determined by HPLC analysis.
Diastereomeric ratio was 3:2 by 1H NMR analysis.
b
b
2
)
2
)
2
)
4
5
6
e
e
e
b
c
To examine the effect of substituents on the amino group of the
,4-amino alcohols, cyclic tertiary amines (R)-6be6d were syn-
1
a
Diastereomeric ratio was 3:2 by 1H NMR analysis.
b
c
ꢀ
thesized from (R)-3 (Table 3). In the presence of 4.0 equiv of po-
tassium carbonate, the reaction of (R)-3 with 1,3-dibromopropane
The reaction with ketone was carried out at ꢁ78 C.
t-BuLi (1.0 equiv) and cycloheptanone (1.0 equiv) were used. The lithiation time
ꢀ
in acetonitrile at 50 C gave (R)-1-(1-phenylethyl)azetidine (6b) in
was 3.5 h.

6798
M. Asami et al. / Tetrahedron 71 (2015) 6796e6802
Table 3
As good results were obtained by using 1h (Table 2, entry 8) and
l (Table 5, entry 2), we examined the synthesis and the reaction of
,4-amino alcohol (R)-1n containing both cyclohexane and pyrro-
Synthesis of cyclic tertiary amines (R)-6be6d
1
1
lidine rings. According to the same procedure used for the synthesis
of 1h, (R)-1n was obtained from (R)-6c in 43% yield (Scheme 3). In
the presence of 10 mol% of (R)-1n, the reaction of benzaldehyde
with diethylzinc in diethyl ether was completed within 1 h to give
Entry
Compound
Temp
Time (h)
Yield (%)
(S)-1-phenyl-1-propanol in 92% yield with 95.3% ee (Scheme 4).
ꢀ
1
2
3
6b (n¼1)
6c (n¼2)
6d (n¼3)
50
C
120
8
8
61
86
94
The enantiomeric excess of the product was comparable to the one
using 1l (95.6% ee before rounding), and the product was obtained
with highest yield in the shortest reaction time among the 1,4-
amino alcohols examined in this study.
Reflux
Reflux
61% yield (entry 1). When the reaction was carried out using 1,4-
dibromobutane or 1,5-dibromopentane in refluxing acetonitrile,
the corresponding cyclic tertiary amines (R)-6c and (R)-6d were
obtained in 86% and 94% yields, respectively (entries 2 and 3).
The cyclic tertiary amines (R)-6be6d were then converted to
1,4-amino alcohols 1ke1m according to the same procedure used
for the synthesis of 1a (Table 4). That is, (R)-6be6d were treated
with tert-butyllithium in hexane, and the resulting ortho-lithiated
species were reacted with propanal in hexane/diethyl ether to give
Scheme 3. Synthesis of 1,4-amino alcohol (R)-1n.
1
ke1m in 59e82% yield as diastereomeric mixtures (entries 1e3).
Table 4
Synthesis of amino alcohols 1ke1m
Scheme 4. Enantioselective addition of diethylzinc to benzaldehyde catalyzed by 1,4-
amino alcohol (R)-1n.
The reaction of various aldehydes with diethylzinc was then
examined by using 1,4-amino alcohol (R)-1n (Table 6). In the re-
actions of aromatic aldehydes bearing bromo or methoxy groups, 1-
naphthaldehyde, and cyclohexanecarboxaldehyde, the corre-
sponding chiral secondary alcohols were obtained in high yields
with high enantioselectivities (85e96% ee, entries 1e5). The re-
actions of sterically less-hindered (E)-cinnamaldehyde and 3-
phenylpropanal afforded the corresponding products with mod-
erate enantioselectivities (entries 6 and 7).
Entry
1,4-Amino alcohol
Yield (%)
a
1
2
3
1k (n¼1)
1l (n¼2)
1m (n¼3)
82
72
b
b
59
a
Diastereomeric ratio was 7:3 by 1H NMR analysis.
Diastereomeric ratio was 3:2 by H NMR analysis.
b
1
The diastereomeric mixtures of 1,4-amino alcohols 1ke1m were
used in the reaction of benzaldehyde with diethylzinc under the
same reaction conditions as those used in Table 2 (Table 5). In all
cases, (S)-1-phenyl-1-propanol was obtained with high enantio-
selectivity (>93% ee), and a slightly better result than 1a was ob-
tained by using 1l (96% ee, entry 2).
Table 6
Enantioselective addition of diethylzinc to various aldehydes catalyzed by 1,4-amino
alcohol (R)-1n
Table 5
Enantioselective addition of diethylzinc to benzaldehyde catalyzed by 1,4-amino
alcohols 1ke1m
Entry
R
Time (h)
Yield (%)
eea (%)
1
2
3
4
5
6
7
2-BrC
1-Naphthyl
2-MeOC
4-MeOC
6
H
4
1
1.5
1
1.75
2
2
85
94
95
92
75
82
87
95
96
92
85
94
54
48
6
H
H
4
4
6
c-C
(E)-PhCH]CH
PhCH CH
6 11
H
Entry
1,4-Amino alcohol
Time (h)
Yield (%)
eea (%)
94
96
93
b
2
2
1.75
1
2
3
1k (n¼1)
10
8
20
89
85
83
c
d
1l (n¼2)
a
Determined by HPLC analysis.
c
1m (n¼3)
a
Determined by HPLC analysis.
b
c
Diastereomeric ratio was 7:3 by 1H NMR analysis.
1
Diastereomeric ratio was 3:2 by H NMR analysis.
The ee was 95.6% before rounding.
We tentatively assume the stereochemical pathway of the re-
d
7,8a,11
action using 1,4-amino alcohols 1 as shown in Fig. 2.
The

M. Asami et al. / Tetrahedron 71 (2015) 6796e6802
6799
reaction of 1,4-amino alcohol 1 with diethylzinc produces zinc
complex A, which acts as an actual catalyst in the enantioselective
reaction. The coordination of another diethylzinc and aldehyde to A
forms a transition structure B, which leads to the formation of the
chiral secondary alcohol with S-configuration. A pseudo-boat
conformation would be the most suitable structure of the seven-
membered ring of B, in which the methyl group of the benzylic
carbon bearing amino group occupy the pseudo-equatorial position
to avoid the steric repulsion with the substituents of the amino
group regardless of the configuration of another benzylic carbon
bearing hydroxy group. Moreover, the R group of aldehyde and the
ethyl group of another diethylzinc should avoid the steric repulsion
with the ethyl group of the seven-membered zinc complex. These
considerations explain the experimental results that the stereo-
chemical outcome of the reaction was controlled solely by the ab-
solute configuration of the benzylic carbon bearing amino group.
plus; detector, UV-2075). The enantiomeric excesses were de-
termined by HPLC using Daicel Chiralcel OD-H, OB, or AS-H
(25 cmꢂ0.46 cm i.d.) column. Elemental analyses were carried
out on a Vario EL III Elemental analyzer. TLC analyses were done on
silica-gel 60 F254-precoated aluminum backed sheets (E. Merck).
Preparative TLC separations were performed on silica-gel-coated
plates (Wakogel B-5F, 20 cmꢂ20 cm). Wakogel C-200 and Silica
gel 60 N (spherical, neutral, 63e210
mm) were used for column
chromatography. Diethyl ether (dehydrated) and tetrahydrofuran
(dehydrated, stabilizer free) were purchased from Kanto Chemical
Co., Inc. Other solvents were purified and dried according to stan-
dard procedures. All new compounds were fully characterized by IR
1
13
and H, C NMR spectroscopy and elemental analysis. Although
13
some C NMR signals of 1,4-amino alcohols 1 were not detected
owing to the incidental overlapping or the broadening nature, other
analytical data are sufficient for the characterization of these
compounds.
4
.2. Synthesis of (R)-N,N-dimethyl-1-phenylethylamine (6a)12a
An ethyl formate (106 mL) solution of (R)-1-phenylethylamine
(3, 10.4 g, 85.5 mmol) was stirred at room temperature for 12
days. The mixture was concentrated to give crude (R)-N-(1-
phenylethyl)formamide (4), which was used in the next step
without further purification.
To a THF (50 mL) suspension of lithium aluminum hydride
(
4.24 g, 112 mmol), a THF (50 mL) solution of crude (R)-4 was added
ꢀ
dropwise at 0 C. After the reaction mixture was refluxed for 4.5 h,
water and Et
cipitate was removed by suction filtration. The filtrate was washed
with water and brine, and dried over anhydrous Na SO and an-
hydrous Na CO . After removal of the solvent under reduced
2
O were added to the mixture and the resulting pre-
2
4
2
3
pressure, crude (R)-N-methyl-1-phenylethylamine (5) was ob-
tained and used in the next step without further purification.
To a methanol (40 mL) solution of (R)-5 was added a methanol
Fig. 2. Proposed reaction mechanism for enantioselective addition of diethylzinc to
aldehydes using 1.
(50 mL) solution of paraformaldehyde (3.41 g, 113 mmol), and the
reaction mixture was stirred at room temperature for 3 h. To the
mixture was added 10% Pd/C (3.44 g) and the mixture was stirred
3
. Conclusion
under H
2
atmosphere (1 atm balloon) at room temperature for
4
0 h. The mixture was filtered through Celite to remove Pd/C. After
In conclusion, various 1,4-amino alcohols 1 with o-xylylene
the filtrate was concentrated under reduced pressure, crude
product was distilled under reduced pressure (84e86 C/
skeleton were synthesized from easily available (R)-1-
phenylethylamine (3) and used in the enantioselective addition of
diethylzinc to benzaldehyde. In all cases, 1-phenyl-1-propanol with
S-configuration was obtained with high enantioselectivity. The
chirality of the benzylic carbon bearing hydroxy group was un-
necessary for the high levels of enantioinduction in this reaction,
and the best result was obtained by using (R)-1n containing both
pyrrolidine and cyclohexane rings in the structure. The reactions of
various aldehydes using (R)-1n were completed at room tempera-
ture within 2 h to give the corresponding chiral secondary alcohols
with good to high enantioselectivities. New 1,4-amino alcohols
developed in this study would find applications as chiral ligands
and chiral auxiliaries in other asymmetric reactions.
ꢀ
32 mmHg) to give (R)-N,N-dimethyl-1-phenylethylamine (6a) in
8
6% yield (10.9 g).
ꢀ
12a
ꢀ
Colorless oil; bp 84e86 C/32 mmHg (Kugelrohr) (lit. 62 C/
1
8
1
2
1 mmHg); [
a
]
D
þ64.3 (c 1.0, CHCl
766, 1452, 1370, 1348, 1257, 1153, 1078, 955, 756, 700 cm
): (ppm) 7.20e7.35 (m, 5H), 3.23 (q,
J¼6.6 Hz, 1H), 2.19 (s, 6H), 1.37 (d, J¼6.6 Hz, 3H); C NMR
67.8 MHz, CDCl ): (ppm) 143.7, 127.9, 127.2, 126.6, 65.8, 43.0, 20.1.
3
); IR (neat): nmax 2976, 2815,
ꢁ
1 1
;
H
NMR (270 MHz, CDCl
3
d
13
(
3
d
4.3. Typical experimental procedure for the synthesis of 1,4-
amino alcohols 1ae1i
To a stirred solution of (R)-N,N-dimethyl-1-phenylethylamine
(6a, 149 mg, 1.0 mmol) in hexane (2.1 mL), a pentane solution of
t-BuLi (1.6 M, 0.94 mL) was added dropwise through a syringe at
4
4
. Experimental section
ꢀ
.1. General
0 C. The reaction mixture was stirred at room temperature for 24 h,
2
and Et O (2.6 mL) was added to the mixture. To the mixture was
All air-sensitive experiments were carried out under an atmo-
added an Et
2
O (2.0 mL) solution of propanal (116 mg, 2.0 mmol) at
ꢀ
sphere of argon unless otherwise noted. IR spectra were recorded
0 C and the mixture was stirred at room temperature for 30 min.
After the mixture was cooled to 0 C, saturated aqueous ammonium
chloride solution and 2 M aqueous HCl were added to the mixture.
The aqueous layer was separated and the organic layer was
extracted with 2 M aqueous HCl three times. To the combined
aqueous layer was added 6 M aqueous NaOH until the solution
1
13
ꢀ
on a HORIBA FT-730 spectrometer. H and C NMR spectra were
recorded on JEOL JNM-EX-270 or Bruker DRX-300 spectrometer
using tetramethylsilane as an internal standard. Optical rotations
were measured on a JASCO P-1000 automatic polarimeter. HPLC
analyses were carried out with JASCO instruments (pump, PU-2080

6800
M. Asami et al. / Tetrahedron 71 (2015) 6796e6802
becomes alkaline (pH 14). The aqueous layer was then extracted
with dichloromethane three times, and the combined organic layer
127.3, 126.1, 73.3, 40.7, 33.7, 33.4 (one signal was not detected).
Anal. Calcd for C13 21NO: C, 75.32; H, 10.21; N, 6.76. Found: C,
H
was dried over anhydrous Na
2
3
CO . After removal of solvent under
75.42; H, 10.27; N, 6.81.
reduced pressure, crude product was purified by sililca-gel column
chromatography (hexane/triethylamine¼10:1) to give 1-{2-[(R)-1-
4.3.6. (R)-3-{2-[1-(Dimethylamino)ethyl]phenyl}pentan-3-ol
21
(
dimethylamino)ethyl]phenyl}propan-1-ol (1a) in 83% yield
(1f). Pale yellow oil; [
a
]
D
ꢁ18.0 (c 1.0, CHCl
3
); IR (neat): nmax 3398,
(
172 mg).
2966, 2937, 2874, 2823, 2783, 1456, 1371, 1167, 1039, 980, 957,
ꢁ1
1
755 cm
;
H NMR (300 MHz, CDCl ): d (ppm) 9.17 (br s, 1H),
3
4
.3.1. 1-{2-[(R)-1-(Dimethylamino)ethyl]phenyl}propan-1-ol
7.09e7.27 (m, 4H), 4.03 (br s, 1H), 2.23 (s, 6H), 1.69e2.00 (m, 4H),
1.47 (d, J¼7.0 Hz, 3H), 0.79 (t, J¼7.5 Hz, 3H), 0.75 (t, J¼7.5 Hz, 3H);
2
3
(
1a). Pale yellow oil; diastereomeric ratio¼3:2; [
a
]
D
ꢁ4.4 (c 1.0,
13
CHCl
3
); IR (neat):
n
max 3383, 2975, 2938, 2872, 2817, 1449, 1371,
3
C NMR (75.5 MHz, CDCl ): d (ppm) 144.7,140.7,128.4,128.0,126.0,
ꢁ
1 1
1097, 1076, 1040, 972, 951, 761 cm
;
H NMR (300 MHz, CDCl
3
):
124.6, 78.7, 40.2, 37.5, 36.0, 7.4 (one signal was not detected). Anal.
Calcd for C15 25NO: C, 76.55; H, 10.71; N, 5.95. Found: C, 76.66; H,
10.81; N, 6.14.
d
(ppm) 7.21e7.46 (m, 4H), 4.78 (dd, J¼6.6, 6.9 Hz, 0.6H), 4.68 (dd,
H
J¼6.6, 7.8 Hz, 0.4H), 4.34 (q, J¼6.8 Hz, 0.6H), 4.02 (q, J¼7.0 Hz, 0.4H),
.21 (s, 3.6H), 2.20 (s, 2.4H), 2.00e2.08 (m, 2H), 1.43 (d, J¼6.8 Hz,
.2H), 1.38 (d, J¼7.0 Hz, 1.8H), 1.08 (t, J¼7.5 Hz, 1.8H), 0.97 (t,
2
1
4.3.7. (R)-1-{2-[1-(Dimethylamino)ethyl]phenyl}cyclopentan-1-ol
13
20
J¼7.3 Hz, 1.2H); C NMR (67.8 MHz, CDCl
40.9, 140.5, 128.7, 128.1, 127.4, 127.2, 126.7, 126.5, 125.3, 76.2, 70.4,
1.4, 57.8, 40.9, 39.2, 30.5, 27.0, 12.6, 11.3, 8.1 (two signals were not
detected). Anal. Calcd for C13 21NO: C, 75.32; H, 10.21; N, 6.76.
Found: C, 75.32; H, 10.27; N, 6.78.
3
):
d
(ppm) 143.1, 143.0,
(1g). Pale yellow oil; [
2971, 2950, 2867, 2827, 2783, 1446, 1371, 1039, 1006, 760 cm ; H
NMR (300 MHz, CDCl ): (ppm) 8.94 (br s, 1H), 7.18e7.47 (m, 4H),
4.48 (br s,1H), 2.20 (s, 6H),1.66e2.35 (m, 8H), 1.39 (d, J¼7.0 Hz, 3H);
a
]
D
ꢁ51.1 (c 1.0, CHCl
3
); IR (neat): nmax 3367,
ꢁ
1 1
1
6
3
d
H
13
C NMR (75.5 MHz, CDCl
26.2, 82.8, 41.6, 41.4, 39.5, 24.2, 23.4 (two signals were not
detected). Anal. Calcd for C15 23NO: C, 77.21; H, 9.93; N, 6.00.
Found: C, 77.30; H, 10.04; N, 6.13.
3
): d (ppm) 146.7, 140.2,128.2,127.3, 126.8,
1
4.3.2. 2-Methyl-1-{2-[(R)-1-(dimethylamino)ethyl]phenyl}propan-1-
H
2
1
ol (1b). Pale yellow oil; diastereomeric ratio¼3:2; [
a
]
D
þ10.1 (c 1.0,
3
CHCl ); IR (neat): nmax 3398, 2974, 2955, 2869, 2817, 2774, 1468,
ꢁ
1 1
1448, 1370, 1076, 1037, 1008, 950, 759 cm
;
H NMR (300 MHz,
4.3.8. (R)-1-{2-[1-(Dimethylamino)ethyl]phenyl}cyclohexan-1-ol
1
2b
17
CDCl
3
):
d
(ppm) 7.19e7.48 (m, 4H), 4.44 (d, J¼9.4 Hz, 0.6H), 4.29 (q,
(1h).
Pale yellow oil; [
a
]
D
ꢁ12.5 (c 1.0, EtOH); IR (neat):
n
max
J¼6.8 Hz, 0.6H), 4.20 (q, J¼7.0 Hz, 0.4H), 4.19 (d, J¼9.4 Hz, 0.4H), 2.19
3422, 2929, 2856, 2824, 2783, 1446, 1371, 1270, 1038, 957,
754 cm
ꢁ1
1
(
(
0
s, 3.6H), 2.18 (s, 2.4H),1.96e2.41 (m,1H),1.37 (d, J¼6.8 Hz, 3H),1.22
d, J¼6.8 Hz, 1.8H), 1.17 (d, J¼6.8 Hz, 1.2H), 0.88 (d, J¼6.8 Hz, 1.8H),
;
H NMR (300 MHz, CDCl ): (ppm) 8.74 (br s, 1H),
3
d
7.12e7.42 (m, 4H), 4.06 (br s, 1H), 2.21 (s, 6H), 1.48 (d, J¼7.2 Hz, 3H),
13
13
.67 (d, J¼6.8 Hz, 1.2H); C NMR (75.5 MHz, CDCl
3
):
d
(ppm) 142.8,
1.22e2.00 (m, 10H); C NMR (75.5 MHz, CDCl
140.2, 129.3, 128.0, 127.2, 125.9, 74.2, 41.0, 40.8, 40.3, 25.9, 22.3, 22.2
(one signal was not detected). Anal. Calcd for C16 25NO: C, 77.68; H,
10.19; N, 5.66. Found: C, 77.53; H, 10.19; N, 5.90.
3
): d (ppm) 148.6,
1
1
9
7
42.6, 141.3, 140.2, 130.4, 127.5, 127.3, 127.0, 126.73, 126.67, 126.5,
26.1, 82.9, 74.8, 59.1, 58.0, 39.8, 39.6, 34.3, 30.7, 20.3, 20.1,19.7,10.2,
.2 (one signal was not detected). Anal. Calcd for C14 23NO: C,
H
H
5.97; H, 10.47; N, 6.33. Found: C, 75.89; H, 10.52; N, 6.35.
4
.3.9. (R)-1-{2-[1-(Dimethylamino)ethyl]phenyl}cycloheptan-1-ol
21
4
.3.3. {2-[(R)-1-(Dimethylamino)ethyl]phenyl}(phenyl)methanol
(1i). Pale yellow oil; [
3099, 2923, 2857, 2823, 2782, 1456, 1443, 1370, 1039, 948,
a
]
D
ꢁ34.8 (c 1.0, CHCl
3
); IR (neat): nmax 3401,
12b
27
(
1c).
Pale yellow oil; diastereomeric ratio¼3:2; [
.0, EtOH); IR (neat): max 3331, 3060, 3026, 2978, 2945, 2863, 2829,
784, 1491, 1449, 1177, 1074, 1038, 941, 761, 735, 700 cm ; H NMR
): (ppm) 8.93 (br s,1H), 6.69e7.47 (m, 9H), 6.19 (s,
a
]
D
þ49.4 (c
ꢁ
1
1
2
2
n
751 cm
7.09e7.40 (m, 4H), 4.07 (br s, 1H), 2.21 (s, 6H), 1.52e2.28 (m, 12H),
1.47 (d, J¼6.9 Hz, 3H); C NMR (75.5 MHz, CDCl
139.5, 129.3, 128.0, 127.1, 125.8, 77.7, 45.0, 44.7, 41.0, 29.3, 29.1, 23.2,
22.7 (three signals were not detected). Anal. Calcd for C17 27NO: C,
78.11; H, 10.41; N, 5.36. Found: C, 77.93; H, 10.58; N, 5.39.
; H NMR (300 MHz, CDCl ): d (ppm) 8.83 (br s, 1H),
3
ꢁ
1 1
13
(
300 MHz, CDCl
3
d
3
): d (ppm) 150.3,
0
0
.4H), 5.76 (s, 0.6H), 4.50 (q, J¼6.8 Hz, 0.4H), 3.61 (q, J¼6.8 Hz,
.6H), 2.27 (s, 2.4H), 2.11 (s, 3.6H), 1.42 (d, J¼6.8 Hz, 1.2H), 1.12 (d,
H
13
J¼6.8 Hz, 1.8H); C NMR (75.5 MHz, CDCl
3
): d (ppm) 145.3, 145.0,
1
1
3
C
5
43.9, 142.5, 140.8, 140.3, 131.5, 128.4, 128.2, 128.0, 127.9, 127.5,
27.3, 127.1, 126.90, 126.87, 126.7, 126.3, 125.4, 77.6, 72.2, 58.3, 57.9,
9.1, 38.9, 7.8, 7.7 (one signal was not detected). Anal. Calcd for
21NO: C, 79.96; H, 8.29; N, 5.49. Found: C, 79.84; H, 8.34; N,
4.4. Synthesis of 1-{2-[(R)-1-(dimethylamino)ethyl]phenyl}
ethan-1-ol (1j)
17
H
.51.
(R)-2-[1-(Dimethylamino)ethyl]benzaldehyde (7) was synthe-
sized by the similar method to that of 1ae1i using DMF as the
electrophile. To a stirred solution of (R)-7 (200 mg, 1.1 mmol) in THF
4
.3.4. (R)-{2-[1-(Dimethylamino)ethyl]phenyl}methanol
12b
17
(1d).
Pale yellow oil; [
363, 2976, 2945, 2863, 2829, 2784, 1451, 1075, 1022, 762 cm ; H
a
]
D
þ15.0 (c 1.0, EtOH); IR (neat):
n
max
1
2
(5.7 mL), an Et O solution of methylmagnesium iodide (1.0 M,
ꢁ
1
3
2.0 mL) was added dropwise through a syringe at room tempera-
ture. The reaction mixture was stirred at the same temperature for
1 h, and saturated aqueous ammonium chloride solution was added
NMR (300 MHz, CDCl
3
):
d (ppm) 7.50 (br s, 1H), 7.23e7.34 (m, 4H),
4
2
d
.80 (d, J¼12.1 Hz,1H), 4.50 (d, J¼12.1 Hz,1H), 4.03 (q, J¼6.8 Hz,1H),
1
3
ꢀ
.22 (s, 6H), 1.42 (d, J¼6.8 Hz, 3H); C NMR (75.5 MHz, CDCl
3
):
to the mixture at 0 C. After the resulting precipitate was filtered
(ppm) 141.6, 141.0, 130.3, 127.6, 127.5, 127.4, 65.1, 60.9, 40.0, 9.6.
off, the organic layer of the filtrate was separated and the aqueous
layer was extracted with dichloromethane three times. The com-
bined organic layer was washed with water and brine, and dried
Anal. Calcd for C11
H, 9.67; N, 7.96.
H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.73;
2 3
over anhydrous Na CO . After removal of the solvent under reduced
4
.3.5. (R)-2-{2-[1-(Dimethylamino)ethyl]phenyl}propan-2-ol
pressure, crude product was purified by preparative thin-layer
chromatography (hexane/triethylamine¼10:1) to give 1-{2-[(R)-1-
(dimethylamino)ethyl]phenyl}ethan-1-ol (1j) in 78% yield
12b
27
(1e).
Pale yellow oil; [
374, 2976, 2864, 2817, 2783, 1443, 1372, 1170, 957, 759 cm ; H
a
]
D
þ0.2 (c 2.0, EtOH); IR (neat):
n
max
1 1
ꢁ
3
2
0
NMR (300 MHz, CDCl
4
3
3
):
d
(ppm) 9.33 (br s, 1H), 7.13e7.36 (m, 4H),
(171 mg). Pale yellow oil; diastereomeric ratio¼3:2; [
0.99, CHCl ); IR (neat): max 3371, 2976, 2863, 2816, 1456, 1371,
1095, 1071, 1053, 1009, 952, 898, 762 cm
a]
D
ꢁ10.6 (c
ꢁ1
; H NMR (300 MHz,
.11 (br s, 1H), 2.23 (s, 6H), 1.64 (s, 3H), 1.57 (s, 3H), 1.47 (d, J¼7.0 Hz,
3
n
13
1
H); C NMR (75.5 MHz, CDCl
3
):
d
(ppm) 148.1, 139.7, 129.2, 128.1,

M. Asami et al. / Tetrahedron 71 (2015) 6796e6802
6801
CDCl
3
):
d
(ppm) 7.89 (br s, 1H), 7.20e7.51 (m, 4H), 5.08e5.17 (m,
11.2,10.9 (four signals were not detected). Anal. Calcd for C14
C, 76.67; H, 9.65; N, 6.39. Found: C, 76.45; H, 9.68; N, 6.34.
H
21NO:
1
2
H), 4.36 (q, J¼6.8 Hz, 0.6H), 3.82 (q, J¼6.8 Hz, 0.4H), 2.22 (s, 3.6H),
.21 (s, 2.4H),1.61 (d, J¼6.4 Hz,1.8H),1.58 (d, J¼6.4 Hz,1.2H),1.49 (d,
13
J¼6.8 Hz, 1.2H), 1.39 (d, J¼6.8 Hz, 1.8H); C NMR (75.5 MHz, CDCl
3
):
4.6.2. 1-{2-[(R)-1-(Pyrrolidin-1-yl)ethyl]phenyl}propan-1-ol
2
1
d
(ppm) 144.1, 143.9, 141.1, 140.6, 128.8, 127.6, 127.5, 126.9, 126.78,
(1l). Pale yellow oil; diastereomeric ratio¼3:2; [
CHCl ); IR (neat): max 3378, 2969, 2933, 2874, 2803, 1449, 1370,
1142, 1091, 973, 762 cm
a
]
D
þ7.3 (c 1.0,
126.76, 125.1, 68.5, 64.7, 63.7, 57.7, 41.7, 39.0, 23.1, 20.1, 14.4, 7.6 (one
3
n
ꢁ
1
1
signal was not detected). Anal. Calcd for C12
N, 7.25. Found: C, 74.35; H, 10.11; N, 7.23.
H19NO: C, 74.57; H, 9.91;
;
H NMR (300 MHz, CDCl
3
): (ppm)
d
7.16e7.42 (m, 4H), 6.94 (br s, 1H), 4.89 (t, J¼7.0 Hz, 0.6H), 4.86 (t,
J¼7.0 Hz, 0.4H), 4.34 (q, J¼6.8 Hz, 0.4H), 3.67 (q, J¼6.8 Hz, 0.6H),
2.40e2.64 (m, 4H), 1.88e2.02 (m, 2H), 1.66e1.80 (m, 4H), 1.55 (d,
4
.5. Typical experimental procedure for the synthesis of cyclic
J¼6.8 Hz, 1.8H), 1.44 (d, J¼6.8 Hz, 1.2H), 1.07 (t, J¼7.5 Hz, 1.8H), 1.05
tertiary amines (R)-6be6d
1
3
(
1
t, J¼7.5 Hz, 1.2H); C NMR (75.5 MHz, CDCl
3
): d (ppm) 142.6, 142.5,
42.3, 142.0, 128.9, 127.3, 127.2, 127.10, 127.08, 126.9, 126.7, 125.8,
To a mixture of 1,3-dibromopropane (1.50 g, 7.4 mmol) and
potassium carbonate (3.43 g, 24.8 mmol) in acetonitrile (40 mL)
was added an acetonitrile (22 mL) solution of (R)-1-
phenylethylamine (3, 752 mg, 6.2 mmol), and the mixture was
stirred at 50 C for 120 h. After the mixture was filtered, the filtrate
was concentrated under reduced pressure. Crude product was
7
2.4, 71.3, 64.0, 55.6, 51.6, 48.0, 29.1, 28.4, 23.4, 23.2, 18.3, 12.3, 11.3,
23NO: C, 77.21; H, 9.93; N, 6.00. Found: C,
11.1. Anal. Calcd for C15
H
77.24; H, 10.19; N, 6.26.
ꢀ
4
.6.3. 1-{2-[(R)-1-(Piperidin-1-yl)ethyl]phenyl}propan-1-ol
2
2
(
1m). Pale yellow oil; diastereomeric ratio¼3:2; [
a
]
D
ꢁ21.3 (c
purified by silica-gel column chromatography (hexane to hexane/
ꢀ
1.0, CHCl
3
); IR (neat):
n
max 3381, 2972, 2933, 2854, 1451, 1372,
triethylamine¼10:1) and distilled under reduced pressure (64 C/
ꢁ
1
1
1157, 1116, 1048, 970, 764 cm
; H NMR (300 MHz, CDCl ):
3
10 mmHg) to give (R)-1-(1-phenylethyl)azetidine (6b) in 61% yield
d
(ppm) 7.19e7.46 (m, 4H), 4.77 (t, J¼7.0 Hz, 0.6H), 4.64 (t,
(
612 mg).
J¼7.0 Hz, 0.4H), 4.35 (q, J¼6.8 Hz, 0.6H), 4.12 (q, J¼6.8 Hz, 0.4H),
12c
ꢀ
2.40e2.65 (br m, 4H), 1.79e2.07 (m, 2H), 1.31e1.62 (m, 9H), 1.07
4
.5.1. (R)-1-(1-Phenylethyl)azetidine (6b).
Colorless oil; bp 64 C/
); IR (neat): max 2963, 2817,
492, 1449, 1290, 1221, 1186, 1030, 761, 700 cm
300 MHz, CDCl ):
(ppm) 7.20e7.31 (m, 5H), 3.25 (q, J¼6.6 Hz,1H),
.03e3.22 (m, 4H), 1.97e2.01 (m, 2H), 1.20 (d, J¼6.6 Hz, 3H);
NMR (75.5 MHz, CDCl ): (ppm) 143.4, 128.3, 127.1, 126.9, 68.8,
13
1
8
(t, J¼7.3 Hz, 1.8H), 0.95 (t, J¼7.3 Hz, 1.2H); C NMR (75.5 MHz,
CDCl ): (ppm) 143.4, 143.3, 140.9, 140.3, 129.3, 128.5, 127.5,
27.2, 126.5, 126.4, 125.4, 77.1, 70.4, 61.2, 58.4, 30.4, 26.6, 26.0,
25.8, 24.3, 24.2, 11.8, 11.4, 11.3, 8.9 (three signals were not
detected). Anal. Calcd for C16 25NO: C, 77.68; H, 10.19; N, 5.66.
10 mmHg; [
a]
D
þ94.4 (c 1.1, CHCl
3
n
ꢁ1
1
3
d
1
(
3
;
H NMR
1
3
d
13
C
H
3
d
Found: C, 77.43; H, 10.22; N, 5.70.
5
3.9, 20.9, 16.6.
.5.2. (R)-1-(1-Phenylethyl)pyrrolidine (6c).12d Colorless oil; bp
4.6.4. (R)-1-{2-[1-(Pyrrolidin-1-yl)ethyl]phenyl}cyclohexan-1-ol
4
2
0
ꢀ
12e
ꢀ
18
(1n). Pale yellow oil; [
a
]
D
þ1.5 (c 1.2, CHCl
3
); IR (neat): nmax 3417,
6
7 C/2 mmHg (lit. 111 C/13 mmHg for racemic mixture); [
); IR (neat): max 2970, 2779, 1491, 1452, 1143,
62, 700 cm ; H NMR (300 MHz, CDCl ): (ppm) 7.19e7.35 (m,
H), 3.17 (q, J¼6.6 Hz, 1H), 2.51e2.58 (m, 2H), 2.32e2.40 (m, 2H),
a]
D
2
968, 2929, 2846, 2803, 1460, 1371, 1266, 1140, 1034, 1000, 976,
þ60.3 (c 1.0, CHCl
3
n
ꢁ
1
1
ꢁ1
1
750 cm
; H NMR (270 MHz, CDCl ): d (ppm) 8.91 (br s, 1H),
3
7
5
3
d
7
.06e7.38 (m, 4H), 3.63 (br s, 1H), 2.48 (br s, 4H), 1.62 (d, J¼6.9 Hz,
13
1
3
3H), 1.19e1.99 (m, 14H); C NMR (67.8 MHz, CDCl
41.2, 130.1, 128.9, 126.8, 125.8, 74.8, 51.6, 42.0, 40.9, 26.0, 23.5, 22.4,
2.3. Anal. Calcd for C18 27NO: C, 79.07; H, 9.95; N, 5.12. Found: C,
78.82; H, 10.09; N, 5.15.
3
): d (ppm) 148.4,
1
.69e1.82 (m, 4H), 1.40 (d, J¼6.6 Hz, 3H); C NMR (75.5 MHz,
1
2
CDCl ): (ppm) 145.7, 128.2, 127.2, 126.8, 66.0, 53.0, 23.4, 23.2.
3
d
H
4
.5.3. (R)-1-(1-Phenylethyl)piperidine (6d).12f Colorless oil; bp
ꢀ
12g
ꢀ
1
20e130 C/2.3 mmHg (Kugelrohr) (lit. 110e116 C/4 mmHg for
18
S isomer); [
a
]
D
þ27.0 (c 1.0, CHCl
3
); IR (neat): nmax 2971, 2933, 2851,
790, 2751, 1491, 1451, 1372, 1320, 1258, 1118, 939, 756, 700 cm
4.7. Typical experimental procedure for the addition of di-
ꢁ1
2
;
ethylzinc to aldehydes
1
H NMR (300 MHz, CDCl
3
): d (ppm) 7.18e7.33 (m, 5H), 3.38 (q,
J¼6.8 Hz, 1H), 2.29e2.41 (m, 4H), 1.50e1.58 (m, 4H), 1.33e1.41 (m,
2
To an Et O (2.0 mL) solution of (R)-1n (41 mg, 0.15 mmol)
13
2
H), 1.36 (d, J¼6.8 Hz, 3H); C NMR (75.5 MHz, CDCl
3
): d (ppm)
under an atmosphere of argon was added a hexane solution of
143.9, 128.0, 127.7, 126.6, 65.2, 51.5, 26.3, 24.6, 19.4.
ꢀ
diethylzinc (1.05 M, 2.9 mL) through a syringe at 0 C, and the
mixture was stirred at room temperature for 30 min. After the
ꢀ
4
.6. Synthesis of 1,4-amino alcohols 1ke1n
mixture was cooled to 0 C, an Et
2
O (2.0 mL) solution of benzal-
dehyde (159 mg, 1.5 mmol) was added and the reaction mixture
was stirred at room temperature for 1 h. Saturated ammonium
chloride solution and 2 M aqueous HCl were added to the reaction
mixture. The organic layer was separated and the aqueous layer
was extracted with dichloromethane three times. The combined
organic layer was washed with water and brine, and dried over
1
,4-Amino alcohols 1ke1n were synthesized by the similar
method to that of 1ae1i.
4
(
.6.1. 1-{2-[(R)-1-(Azetidin-1-yl)ethyl]phenyl}propan-1-ol
ꢀ
1k). White solid; diastereomeric ratio¼7:3; mp 117.4e118.0 C;
2
1
[
a
]
D
þ43.6 (c 1.0, CHCl
851, 1444, 1373, 1222, 1184, 1091, 976, 776 cm
300 MHz, CDCl ):
(ppm) 7.18e7.44 (m, 4H), 4.94 (t, J¼6.8 Hz, 1H),
.86 (q, J¼6.6 Hz, 0.3H), 3.56 (q, J¼6.6 Hz, 0.7H), 3.06e3.23 (m, 4H),
3
); IR (KBr):
n
max 3192, 2969, 2927, 2874,
2 4
anhydrous Na SO . After removal of the solvent under reduced
ꢁ
1
1
2
(
3
1
;
H NMR
pressure, crude product was purified by silica-gel column chro-
matography (hexane/ethyl acetate¼6:1) to give (S)-1-phenyl-1-
propanol (188 mg, 92%). The ee was determined to be 95% by
HPLC analysis using a chiral column (Daicel Chiralcel OD-H
(25 cmꢂ0.46 cm i.d.); 254 nm UV detector; eluent, hexane/i-
3
d
.78e2.06 (m, 4H), 1.38 (d, J¼6.6 Hz, 2.1H), 1.32 (d, J¼6.6 Hz, 0.9H),
13
1
.10 (t, J¼7.3 Hz, 2.1H), 1.05 (t, J¼7.3 Hz, 0.9H); C NMR (75.5 MHz,
CDCl ): (ppm) 142.6, 142.4, 140.2, 140.0, 129.0, 127.3, 127.2, 127.1,
26.3, 126.0, 71.8, 71.0, 53.4, 51.6, 30.6, 29.4, 18.3, 16.9, 16.52, 16.49,
3
d
PrOH¼97:3; flow rate, 0.5 mL/min; t
R
, 18.4 min for minor peak,
1
22.1 min for major peak).

6802
M. Asami et al. / Tetrahedron 71 (2015) 6796e6802
4
.7.1. 1-(2-Bromophenyl)-1-propanol. Daicel
Chiralcel
OD-H
2. Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, NY, 1994, Chapter 5.
(
25 cmꢂ0.46 cm i.d.); eluent, hexane/i-PrOH¼99:1; flow rate,
3
4
. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823e2824.
. (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757e824; (b) Soai, K.; Niwa, S. Chem.
Rev. 1992, 92, 833e856; (c) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
0
R
.5 mL/min; t , 33.4 min for R isomer, 36.4 min for S isomer.
1
991, 30, 49e69.
4
.7.2. 1-(1-Naphthyl)-1-propanol. Daicel
Chiralcel
OD-H
5
. For some recent examples of the reaction using 1,2-amino alcohols, see: (a)
Rachwalski, M. Tetrahedron: Asymmetry 2014, 25, 219e223; (b) Stoyanova, M. P.;
Shivachev, B. L.; Nikolova, R. P.; Dimitrov, V. Tetrahedron: Asymmetry 2013, 24,
(
25 cmꢂ0.46 cm i.d.); eluent, hexane/i-PrOH¼90:10; flow rate,
0
R
.5 mL/min; t , 14.4 min for S isomer, 24.9 min for R isomer.
1
426e1434; (c) Le ꢀs niak, S.; Rachwalski, M.; Jarzy nꢀ ski, S.; Obijalska, E. Tetrahe-
dron: Asymmetry 2013, 24, 1336e1340; (d) Szakonyi, Z.; Csillag, K.; F u€ l o€ p, F.
Tetrahedron: Asymmetry 2011, 22, 1021e1027; (e) Wang, M.-C.; Wang, Y.-H.; Li,
G.-W.; Sun, P.-P.; Tian, J.-X.; Lu, H.-J. Tetrahedron: Asymmetry 2011, 22, 761e768;
4
.7.3. 1-(2-Methoxyphenyl)-1-propanol. Daicel
Chiralcel
OB
(
0
25 cmꢂ0.46 cm i.d.); eluent, hexane/i-PrOH¼90:10; flow rate,
(
f) Binder, C. M.; Bautista, A.; Zaidlewicz, M.; Krzemi nꢀ ski, M. P.; Oliver, A.;
R
.5 mL/min; t , 10.6 min for S isomer, 13.6 min for R isomer.
Singaram, B. J. Org. Chem. 2009, 74, 2337e2343; (g) Wu, Z.-L.; Wu, H.-L.; Wu, P.-
Y.; Uang, B.-J. Tetrahedron: Asymmetry 2009, 20, 1556e1560.
6. For some recent examples of the reaction using 1,3-amino alcohols, see: (a)
Marinova, M.; Kostova, K.; Tzvetkova, P.; Tavlinova-Kirilova, M.; Chimov, A.;
Nikolova, R.; Shivachev, B.; Dimitrov, V. Tetrahedron: Asymmetry 2013, 24,
4
.7.4. 1-(4-Methoxyphenyl)-1-propanol. Daicel
Chiralcel
OB
(
0
25 cmꢂ0.46 cm i.d.); eluent, hexane/i-PrOH¼90:10; flow rate,
R
.5 mL/min; t , 17.1 min for S isomer, 20.5 min for R isomer.
1453e1466; (b) Trost, B. M.; Bartlett, M. J.; Weiss, A. H.; Jacobi von Wangelin, A.;
Chan, V. S. Chem.dEur. J. 2012, 18, 16498e16509; (c) Patil, M. N.; Gonnade, R. G.;
Joshi, N. N. Tetrahedron 2010, 66, 5036e5041; (d) Yang, X.-F.; Hirose, T.; Zhang,
G.-Y. Tetrahedron: Asymmetry 2008, 19, 1670e1675; (e) Yang, X.-F.; Wang, Z.-H.;
Koshizawa, T.; Yasutake, M.; Zhang, G.-Y.; Hirose, T. Tetrahedron: Asymmetry
4
.7.5. 1-Cyclohexyl-1-propanol (as the corresponding 4-
methoxybenzoate). Daicel Chiralcel AS-H (25 cmꢂ0.46 cm i.d.); el-
uent, hexane/i-PrOH¼99.9:0.1; flow rate, 0.5 mL/min; t
R
, 11.9 min
2
007, 18, 1257e1263.
7. (a) Rachwalski, M.; Jarzy nꢀ ski, S.; Le ꢀs niak, S. Tetrahedron: Asymmetry 2013, 24,
21e425; (b) Zheng, B.; Li, S.-N.; Mao, J.-Y.; Wang, B.; Bian, Q.-H.; Liu, S.-Z.;
for R isomer, 13.4 min for S isomer.
4
Zhong, J.-C.; Guo, H.-C.; Wang, M. Chem.dEur. J. 2012, 18, 9208e9211; (c)
Capracotta, S. S.; Comins, D. L. Tetrahedron Lett. 2009, 50, 1806e1808; (d) Scarpi,
D.; Occhiato, E. G.; Guarna, A. Tetrahedron: Asymmetry 2009, 20, 340e350; (e)
Demyanovich, V. M.; Shishkina, I. N.; Zefirov, N. S. Chirality 2001, 13, 507e509;
4
.7.6. (E)-1-Phenyl-1-penten-3-ol. Daicel
Chiralcel
OD-H
(
25 cmꢂ0.46 cm i.d.); eluent, hexane/i-PrOH¼95:5; flow rate,
0
R
.5 mL/min; t , 22.2 min for R isomer, 37.3 min for S isomer.
(f) Hanyu, N.; Mino, T.; Sakamoto, M.; Fujita, T. Tetrahedron Lett. 2000, 41,
4
587e4590; (g) Genov, M.; Dimitrov, V.; Ivanova, V. Tetrahedron: Asymmetry
4
.7.7. 1-Phenyl-3-pentanol. Daicel Chiralcel OB (25 cmꢂ0.46 cm
1997, 8, 3703e3706; (h) Uemura, M.; Miyake, R.; Nakayama, K.; Shiro, M.;
Hayashi, Y. J. Org. Chem. 1993, 58, 1238e1244; (i) Watanabe, M.; Araki, S.;
Butsugan, Y.; Uemura, M. J. Org. Chem. 1991, 56, 2218e2224.
. (a) Asami, M.; Nagai, A.; Sasahara, Y.; Ichikawa, K.; Ito, S.; Hosoda, N. Chem. Lett.
2
i.d.); eluent, hexane/i-PrOH¼99.5:0.5; flow rate, 0.3 mL/min; t
R
,
6
4.3 min for R isomer, 73.9 min for S isomer.
8
9
015, 44, 345e347; (b) Asami, M.; Wada, M.; Furuya, S. Chem. Lett. 2001,
1110e1111.
Acknowledgements
. Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.;
Kaneko, T.; Matsuda, Y. J. Organomet. Chem. 1990, 382, 19e37.
1
0. Although Uemura et al. and Demyanovich et al. reported that moderate
This work was supported by Japan Society for the Promotion of
Science KAKENHI Grant Number 24550113. The authors are grateful
to Mr. Shinji Ishihara (Instrumental Analysis Center, Yokohama
National University) for his technical assistance in the elemental
analyses.
enantioselectivities were observed in the reaction using 1a and 1d,7 high
selectivities were observed in our experiments with high reproducibility.
11. Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327e6335.
e,i
1
2. (a) Chantrapromma, K.; Ollis, W. D.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1
983, 1049e1061; (b) Demyanovich, V. M.; Shishkina, I. N.; Zefirov, N. S. Chi-
rality 2004, 16, 486e492; (c) De Kimpe, N.; De Smaele, D. Tetrahedron Lett. 1994,
5, 8023e8026; (d) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.;
Maytum, H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131,
766e1774; (e) Shapiro, S. L.; Soloway, H.; Freedman, L. J. Am. Chem. Soc. 1958,
0, 6060e6064; (f) Girard, N.; Pouchain, L.; Hurvois, J.-P.; Moinet, C. Synlett
1
3
References and notes
1
8
1
. For reviews, see: (a) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
67e796; (b) Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, 2699e2715; (c) Ager,
D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835e875.
2006, 1679e1682; (g) Beaufort-Droal, V.; Pereira, E.; Th eꢀ ry, V.; Aitken, D. J.
Tetrahedron 2006, 62, 11948e11954.
7