Synthesis of N-α-pyridylmethyl amino alcohols and application in catalytic asymmetric addition of diethylzinc to aromatic aldehydes

Article abstract of DOI:10.1016/S0957-4166(00)00336-0

A series of novel chiral ligands 2a-2f were conveniently prepared from β-amino alcohols through a two-step reaction and applied to catalyze the enantioselective addition of diethylzinc to benzaldehyde. Among them, ligand 2c was found to show the best asym

Full text of DOI:10.1016/S0957-4166(00)00336-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3543–3552
Synthesis of N-a-pyridylmethyl amino alcohols and
application in catalytic asymmetric addition of diethylzinc to
aromatic aldehydes
Yangjie Wu,* Hongying Yun, Yusheng Wu, Kuiling Ding and Ying Zhou
Department of Chemistry, Zhengzhou University, Zhengzhou 450052, PR China
Received 10 July 2000; accepted 28 August 2000
Abstract
A series of novel chiral ligands 2a–2f were conveniently prepared from b-amino alcohols through a
two-step reaction and applied to catalyze the enantioselective addition of diethylzinc to benzaldehyde.
Among them, ligand 2c was found to show the best asymmetric induction and catalyze the reaction of
various aromatic aldehydes to provide (R)-secondary alcohols in up to 98.3% ee. © 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Among asymmetric catalytic reactions for CꢀC bond formation, enantioselective addition of
diorganozinc reagents to aldehydes in the presence of a catalytic amount of chiral b-amino
alcohols is a convenient method for the preparation of optically active secondary alcohols.1
Various catalysts derived from b-amino alcohols have been reported to catalyze this kind of
reaction with excellent asymmetric induction.2 Recently, pyridine-derived carbinols3 including
C2-symmetric chiral ligands such as 2,2%-bispyridines, 2,6-disubstituted pyridines and plane-
extended pyridyl alcohols4 have been developed as chiral ligands in the enantioselective addition
of dialkylzinc to aldehydes, but they only gave moderate enantiomeric excess. Herein, we
demonstrate an efficient synthesis of novel chiral ligands, N-a-pyridylmethyl-b-amino alcohols
2a–e and N-benzyl amino alcohol 2f, through a two-step reaction approach and their applica-
tion to the highly enantioselective addition of diethylzinc to various aromatic aldehydes.
* Corresponding author. E-mail: wyj@mail.zzu.edu.cn
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00336-0

3544
Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
2. Results and discussion
2.1. Synthesis of N-h-pyridylmethyl amino alcohols 2a–2e and N-benzyl amino alcohol 2f
The synthesis of ligands 2a–2f is shown in Scheme 1. Compounds 1a, 1c, 1d and 1e were
prepared according to the literature method.5 (1R,2S)-(−)-norephedrine 1b is a commercially
available reagent. The synthesis of 2 is described as follows. (S)-Amino alcohol 1 and the
appropriate 2-pyridinecarboxaldehyde or benzaldehyde were mixed in dry benzene and refluxed
for 2 hours with a Dean–Stark trap. The Schiff base was obtained in quantitative yield. The
reduction of the Schiff base was carried out in dry 1,2-dichloroethane (DCE) with two
equivalents of sodium triacetoborohydride.6 The reaction mixture was stirred at room tempera-
ture for at least 24 hours. After work-up, 2a–2f were obtained in high yields (72–98%). The
characteristics of 2a–2f are listed in Section 4. Recently, Christopher et al. have reported the
synthesis of 2b using a similar method.7
Scheme 1. Synthesis of 2a–2f
2.2. Asymmetric addition of diethylzinc to benzaldehyde in the presence of 2
The novel chiral ligands 2a–2f prepared were then set out to check their asymmetric induction
efficiency for the addition of diethylzinc to benzaldehyde. The results were listed in Table 1.
Chiral ligand 2c shows the best asymmetric induction. Under the experimental conditions,
91.8% ee of the 1-phenylpropanol was achieved with the catalysis of 5 mol% 2c (entry 3).
Obviously, the presence of two bulky phenyl groups at hydroxy-attached carbon is crucial for
getting the best asymmetric induction. This conclusion was obtained from the results of entries
3–5 vs entries 1 and 2. The entries 1 and 2 in the catalysis of 2a and 2b, respectively, which have
no or only one phenyl group at hydroxy-bearing carbon, resulted in poor ees. On the other
hand, entries 3–5 in the catalysis of 2c, 2d and 2e, respectively, in which there are two bulky
phenyl groups, resulted in a dramatic enhancement in ees (63.1–91.8%). It is also interesting to
note that the a-pyridylmethyl group in 2c plays a very important role for the enantioselectivity
of the reaction (entry 3 vs 6 and 7). Thus, it may be concluded that both the bulky groups on
the a-carbon and the a-pyridylmethyl group at b-amino nitrogen are required for the high
asymmetric induction of 2c.

Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
3545
Table 1
Asymmetric addition of diethylzinc to benzaldehyde in the presence of 2a
Entry
Ligand
Solvent
Time (h)
Yieldb (%)
Eec (%)
Confignd
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
TꢀHe
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
5
5
5
5
5
69
80
98
81
92
85
71
2.5
3.3
R
S
91.8
63.1
77.2
34.5
4.7
R
R
R
R
R
6
12
1c
a The reaction was carried out in toluene with 5 mol% of catalyst and 2.5 equiv. of diethylzinc (4.17 M solution in
hexane) to benzaldehyde at rt.
b Isolated yields.
c Determined by HPLC using a chiral OD column.
d Configurations were determined by comparison of the optical rotations with the literature.8
e Toluene and hexane, 4/1 (v/v).
Furthermore, we examined the effects of the catalytic amount and temperature on the
asymmetric induction in the presence of 2c. The results are listed in Table 2.
From Table 2 it can be seen that reducing the ligand to benzaldehyde ratio from 10 to 3% did
not affect the ees, but reducing the ratio to 2% remarkably reduced the ee. Further reducing the
ratio to 1% significantly reduced both the yield and ee. On the other hand, increasing the ratio
to 20% also reduced the ee. The temperature had little effect on ees.
Table 2
Asymmetric addition of diethylzinc to benzaldehyde in the presence of 2c
Entry
Mol%, 2c
Temp., °C
Solventa
Time, h
Yield,b
%
% eec
Confignd
1
2
3
4
5
6
7
8
9
1
2
3
4
5
10
20
5
rt
rt
rt
rt
rt
rt
rt
0
−25
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
5
5
5
5
5
2
2
12
12
50
98
91
88
92
87
97
79
79
56.5
86.8
91.1
90.3
91.8
91.3
88.8
90.2
90.4
R
R
R
R
R
R
R
R
R
5
a Toluene and hexane, 4/1 (v/v).
b Isolated yields.
c Determined by HPLC using a chiral OD column.
d Configuration was determined by comparison of the optical rotation with the literature.8

3546
Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
2.3. Asymmetric addition of diethylzinc to aromatic aldehydes in the presence of 2c
Chiral ligand 2c was then examined for the asymmetric ethylation of a series of aromatic
aldehydes. The results are summarized in Table 3. It was found that 2c was effective to various
aromatic aldehydes, including ortho-, para- and meta-substituted benzaldehydes (entries 1–6),
ferrocenecarboxaldehyde (entry 7) and thiophene-2-carboxaldehyde (entry 8). The best asym-
metric induction as high as 98.3% ee was found by using ferrocenecarboxaldehyde as substrate.
The results were listed in Table 3.
Table 3
Asymmetric addition of diethylzinc to aromatic aldehydes in the presence of 2c
Entrya
Aldehyde
Solventb
Time (h)
Yieldc (%)
Eed (%)
Configne
1
2
3
4
5
6
7
8
9
p-ClC6H4CHO
p-MeOC6H4CHO
p-MeC6H4CHO
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
TꢀH
5
6
5
5
6
5
5
5
6
97
96
98
70
94
95
88
95
99
91.5
92.3
96.2g
90.2
80.9
88.1
98.3
94.4
78.4
R
R
R
R
R
R
m-ClC6H4CHO
a-Naphthaldehyde
o-MeOC6H4CHO
FcCHOf
Thiophene-2-carboxaldehyde
(E)-Cinnamaldehyde
ndh
Ri
R
a The reactions were carried out by using 5 mol% 2c at rt.
b Toluene and hexane, 4/1 (v/v).
c
Isolated yields.
d Determined by HPLC using a chiral OD column.
e
Determined by comparison of the specific rotation with the literature.
Ferrocenecarboxaldehyde.
f
g Determined by comparison of the optical rotation value with the literature value.9
h Not determined.
i
Determined by comparison of the known elution order from a chiral OD column.10
Based on our experimental findings and related mechanism suggested by Corey,11 a possible
mechanism was proposed as shown in Scheme 2.
Firstly, diethylzinc reacts rapidly with the ligand 2c to give the corresponding zinc
monoalkoxide 3 and then converts to the zinc monoalkoxide–diethylzinc complex 4. The
coordination geometry of the zinc atom is essentially tetrahedral. The nucleophilicity of the ethyl
group of diethylzinc would be increased by coordination of the zinc atom with the oxygen atom
of the ligand. Secondly, the benzaldehyde coordinates with the zinc monoalkoxide. In order to
maintain the tetracoordinate status of zinc, the coordination of the 2-methylpyridyl group with
zinc would be replaced by benzaldehyde with zinc. This transformation resulted in the formation
of complex 5. Thirdly, transfer of an ethyl group from zinc to the nearby benzaldehyde carbonyl
group can occur via a six-membered cyclic structure to form the carbonyl adduct 6. Elimination
of zinc alkoxide from 6 produced the product 7 with regeneration of 3. This preferred
three-dimensional arrangement, shown more clearly in stereoformula 5, exposes the re face of

Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
3547
Scheme 2.
the formyl carbon to the attacking ethyl group and led to the R-configuration of adduct 7, in
accord with the experimental result.
3. Conclusion
In conclusion, a series of novel chiral ligands 2a–2f has been conveniently prepared from
b-amino alcohols through a two-step reaction and 2c was found to be highly efficient for
enantioselective addition of diethylzinc to aromatic aldehydes. The excellent asymmetric induc-
tion of 2c can be attributed to the presence of both steric hindrance of diphenyl groups at
hydroxy attached carbon and a-pyridylmethyl group at b-amino nitrogen as a side chain, which
provides the new understanding to design the novel chiral tridentate ligands for this type of
reaction. Further work is undergoing to extend the variety of this type of chiral ligands and the
applications of their metallic complexes to other types of asymmetric reactions.
4. Experimental
4.1. Instrumentation
Melting points were measured on a WC-1 apparatus and are uncorrected. Elemental analyses
1
were determined with a Carlo Erba 1160 analyzer. H NMR and 13C NMR spectra were
recorded on a Bruker DPX 400 spectrometer by using CDCl3 as the solvent and TMS as an
internal standard. IR spectra were recorded on a Shimadzu IR-408 spectrophotometer. Optical

3548
Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
rotations were measured with a Perkin–Elmer 341 polarimeter. HPLC analyses were carried out
on a Waters 600E type instrument equipped with a chiralcolumn (chiralcel OD, Daicel Chemical
Industries) and UV detector for determining the optical purity of the products. Preparative TLC
was performed on dry silica gel (60 F254) plates.
4.2. General methods
All reactions were carried out under an inert atmosphere of argon. Tetrahydrofuran and
toluene were freshly distilled from sodium benzophenone ketyl prior to use. 1,2-Dichloroethane
was freshly distilled from phosphoruspentoxide. Diethylzinc was prepared according to the
literature method and diluted to a 4.17 M solution with dry hexane.
4.2.1. (S)-2-Amino-3-methylbutan-1-ol 1a
L
-Valine was reduced by 2.5 molar equivalents of sodium borohydride and one molar
equivalent of iodine in THF under an argon atmosphere according to the literature proce-
dures.5a Work-up: purification by distillation (bp 75°C/6 mmHg); colorless solid; yield 88%; mp
32–34°C; [h]1D8=+22.9 (c 0.6, EtOH) (lit.5a [h]D20=+17 (c 5, EtOH)); IR (liq. film) wmax=3200,
1
2900, 1582, 1457, 1038 cm−1; H NMR (400 MHz, CDCl3) l 0.95 (m, 6H, 2CH3), 1.65 (m, 1H,
CH(CH3)2), 2.67 (m, 1H, CHNH2), 3.35 (m, 1H, CHAOH), 3.70 (m, 1H, CHBOH). Anal. calcd
for C5H13NO: C, 58.21; H, 12.70; N, 1.36. Found: C, 58.14; H, 12.67; N, 1.38.
4.2.2. (S)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol 1c
L
-Valine methyl ester hydrochloride reacted with an 8-fold excess of phenylmagnesium
bromide in THF at 0–10°C for 5 h. Work-up: purification by recrystallization from EtOH;
colorless needle; yield 67%; mp 97–98°C; [h]2D6=−127.0 (c 0.85, CHCl3) (lit.5b [h]D25=−127.7 (c
1
0.6, CHCl3)); IR (KBr) wmax=3300, 3206, 2887, 1583, 1484, 1440, 1168, 1040, 743, 691 cm−1; H
NMR (400 MHz, CDCl3) l 0.90 (d, J=7.2 Hz, 3H, CH3), 0.94 (d, J=7.2 Hz, 3H, CH3), 1.77
(m, 1H, CH(CH3)2), 3.88 (d, J=1.6 Hz, 1H, CHNH2), 7.15–7.21 (m, 2H, PhH), 7.26–7.34 (m,
4H, PhH), 7.48 (d, J=7.6 Hz, 2H, PhH), 7.60 (d, J=8.0 Hz, 2H, PhH). Anal. calcd for
C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C, 80.00; H, 8.28; N, 5.50.
4.2.3. (S)-2-Amino-4-methyl-1,1-diphenylpentan-1-ol 1d
This compound was prepared by similar procedures to those for 1c. Work-up: purification by
recrystallization from EtOH; colorless needle; yield 52%; mp 132–134°C; [h]2D6=−96.0 (c 1.0,
CHCl3) (lit.5b [h]D25=−95.12 (c 1.0, CHCl3)); IR (KBr) wmax=3250, 2900, 1585, 1441, 1174, 1050,
830, 737, 688 cm−1; 1H NMR (400 MHz, CDCl3) l 0.87 (d, J=6.8 Hz, 3H, CH3), 0.89 (d, J=6.8
Hz, 3H, CH3), 1.10 (m, 1H, CHACH(CH3)2), 1.27 (m, 1H, CHBCH(CH3)2), 1.60 (m, 1H,
CH(CH3)2), 4.00 (dd, J=10.4 Hz, J=2.0 Hz, 1H, CHNH2), 7.16–7.21 (m, 2H, PhH), 7.26–7.33
(m, 4H, PhH), 7.46 (d, J=0.8 Hz, 2H, PhH), 7.61 (d, J=0.8 Hz, 2H, PhH). Anal. calcd for
C18H23NO: C, 80.25; H, 8.61; N, 5.20. Found: C, 80.21; H, 8.63; N, 5.19.
4.2.4. (S)-2-Amino-1,1,3-triphenylpropan-1-ol 1e
This compound was prepared by similar procedures to those for 1c. Work-up: purification by
recrystallization from EtOH; colorless needle; yield 56%; mp 144–146°C; [h]1D8=−72.8 (c 0.5,
CHCl3) (lit.5b [h]D25=−88.5 (c 0.6, CHCl3)); IR (KBr) wmax=3300, 3025, 2998, 2925, 2850, 1596,
1488, 1447, 1050, 760, 745, 690 cm−1; 1H NMR (400 MHz, CDCl3) l 2.47 (m, 1H, CHAPh), 2.64

Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
3549
(m, 1H, CHBPh), 4.18 (dd, J=10.8 Hz, J=2.8 Hz, 1H, CHNH2), 7.17–7.35 (m, 11H, PhH),
7.58–7.66 (m, 4H, PhH). Anal. calcd for C21H21NO: C, 83.13; H, 6.98; N, 4.62. Found: C, 83.10;
H, 7.01; N, 4.60.
4.3. Ligands 2a–2f; general procedure
Compound 1 (2 mmol) and 2-pyridinecarboxaldehyde (0.214 g, 2 mmol) or benzaldehyde
(0.212 g, 2 mmol) were dissolved in 30 ml dry benzene. The mixture was gently refluxed under
an inert atmosphere of argon. The released water from the reaction was separated by a
Dean–Stark trap. Normally 2 hours later, there was no water separated. The mixture was cooled
to rt and concentrated under reduced pressure. Then the Schiff base was obtained as a yellow
viscous oil or white solid in quantitative yield. IR indicated that there was only strong
absorption of CꢁN at 1640–1650 cm−1 and the absorption of CꢁO at 1700 cm−1 completely
disappeared. The Schiff base was dissolved in 7 ml dry DCE and then treated with sodium
triacetoxyborohydride (0.86 g, 4 mmol). The mixture was stirred under an argon atmosphere for
24 to 96 h at rt. Then the mixture was quenched by addition of saturated Na2CO3 aqueous
solution and extracted with dichloromethane. The dichloromethane extract was dried (Na2SO4)
and the solvent was evaporated to give the crude 2. After purification with preparative TLC (see
below for individual work-up) pure 2 was obtained as a colorless oil or white solid. (The oil will
turn dark during storage in air.)
4.3.1. (S)-3-Methyl-2-[(2-pyridylmethyl)amino]butan-1-ol 2a
Starting material: 0.206 g (2 mmol) 1a; reaction time: 24 h; work-up; purification by
preparative TLC developed with EtOAc. After purification, 2a was obtained as colorless oil in
98% yield. [h]2D0=+28.2 (c 1.0, CH2Cl2); IR (liq. film) wmax=3250, 2920, 2840, 1582, 1459, 1425,
1
1037, 747 cm−1; H NMR (400 MHz, CDCl3) l 0.96 (d, J=6.8 Hz, 3H, CH3), 1.02 (d, J=6.8
Hz, 3H, CH3), 1.90 (m, 1H, CH(CH3)2), 2.55 (m, 1H, CHNH), 3.55 (dd, J=11.2 Hz, J=7.2 Hz,
1H, CHAOH), 3.73 (dd, J=11.2 Hz, J=4.0 Hz, 1H, CHBOH), 4.07 (d, J=4.0 Hz, 2H, CH2Py),
7.21 (m, 1H, PyH), 7.27 (m, 1H, PyH), 7.67 (m, 1H, PyH), 8.56 (m, 1H, PyH-a). 13C NMR (400
MHz, CDCl3) l 18.84 (CH3), 19.59 (CH3), 29.60 (CH(CH3)2), 52.51 (CHNH), 61.40 (CH2OH),
64.87 (CH2NH), 122.07, 123.10, 136.66, 149.1, 160.12 (all PyꢀC). Anal. calcd for C11H18N2O: C,
68.00; H, 9.34; N, 14.42. Found: C, 68.21; H, 9.00; N, 14.36.
4.3.2. (1R,2S)-1-Phenyl-2-[(2-pyridylmethyl)amino]propan-1-ol 2b
Starting material: 0.302 g (2 mmol) 1b; reaction time: 48 h; work-up; purification by
preparative TLC developed with EtOAc/MeOH (10:1). After purification, 2b was obtained as
colorless oil in 98% yield. [h]D20=+3.9 (c 1.0, CH2Cl2); IR (KBr) wmax=3300, 3025, 2938, 2850,
1
1584, 1430, 744, 695 cm−1; H NMR (400 MHz, CDCl3) l 0.94 (d, J=6.4 Hz, 3H, CH3), 3.09
(m, 1H, CHCH3), 4.14 (s, 2H, CH2Py), 4.97 (d, J=2.4 Hz, 1H, CHPh), 7.24–7.35 (m, 7H, PhH,
PyH), 7.69 (m, 1H, PyH), 8.57 (d, J=4.4 Hz, 1H, PyH-a). 13C NMR (400 MHz, CDCl3) l
14.17 (CH3), 52.15 (CHNH), 58.81 (CHPh), 72.92 (CH2Py), 122.29, 122.37, 126.07, 126.99,
128.07, 136.75, 141.29, 149.27, 158.96 (all PhꢀC and PyꢀC). Anal. calcd for C15H18N2O: C,
74.35; H, 7.49; N, 11.56. Found: C, 74.29; H, 7.32; N, 11.58.
4.3.3. (S)-3-Methyl-2-[(2-pyridylmethyl)amino]-1,1-diphenylbutan-1-ol 2c
Starting material: 0.513 g (2 mmol) 1c; reaction time: 96 h; work-up; purification by
preparative TLC developed with EtOAc/hexane (1/4). After purification, 2c was obtained as a

3550
Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
colorless crystal in 81% yield; mp 119–121°C; [h]2D3=−68.0 (c 1.0, CH2Cl2); IR (KBr) wmax=3304,
1
3140, 3020, 2840, 1588, 1467, 1444, 1420, 1054, 759, 748, 710, 698 cm−1; H NMR (400 MHz,
CDCl3) l 0.79 (t, 3H, CH3), 0.95 (d, J=6.8 Hz, 3H, CH3), 2.02 (m, 1H, CH(CH3)2), 3.38 (d,
J=14 Hz, 1H, CHAPy), 3.52 (d, J=14 Hz, 1H, CHBPy), 3.62 (d, J=1.6 Hz, 1H, CHNH), 6.89
(d, J=8.0 Hz, 1H, PhH), 7.12–7.74 (m, 12H, PhH, PyH), 8.52 (d, J=4.8 Hz, 1H, PyH-a). 13C
NMR (400 MHz, CDCl3) l 16.00 (CH3), 22.52 (CH3), 28.91 (CH(CH3)2), 55.41 (CHNH), 68.78
(CH2NH), 78.61 (CꢀOH), 122.03, 122.37, 125.74, 126.06, 126.39, 127.86, 128.02, 136.29, 145.41,
149.14, 159.09 (all PhꢀC and PyꢀC). Anal. calcd for C23H26N2O: C, 79.73; H, 7.56; N, 8.09.
Found: C, 79.73; H, 7.63; N, 8.10.
4.3.4. (S)-4-Methyl-2-[(2-pyridylmethyl)amino]-1,1-diphenylpentan-1-ol 2d
Starting material: 0.539 g (2 mmol) 1d; reaction time: 48 h; work-up; purification by
preparative TLC developed with EtOAc/hexane (1/3). After purification, 2d was obtained as a
white solid in 91% yield; mp 97–98°C; [h]2D6=−51.8 (c 0.6, CH2Cl2); IR (KBr) wmax=3300, 3010,
1
2940, 1585, 1560, 1459, 1423, 1050, 750, 726, 705, 690 cm−1; H NMR (400 MHz, CDCl3) l 0.78
(d, J=6.4 Hz, 3H, CH3), 0.83 (d, J=6.8 Hz, 3H, CH3), 1.30 (m, 2H, CH2CH(CH3)2), 1.64 (m,
1H, CH(CH3)2), 3.30 (d, J=14 Hz, 1H, CHAPy), 3.48 (d, J=14 Hz, 1H, CHBPy), 3.71 (dd,
J=9.2 Hz, J=2.8 Hz, 1H, CHNH), 6.89 (d, J=7.6 Hz, 1H, PhH), 7.14–7.69 (m, 12H, PhH and
PyH), 8.51–8.52 (m, 1H, PyH); 13C NMR (400 MHz, CDCl3) l 21.58 (CH3), 23.95 (CH3), 25.23
(CH(CH3)2), 28.91 (CH2CH(CH3)2), 55.41 (CHNH), 68.78 (CH2Py), 78.61 (CꢀOH), 121.99,
122.37, 125.88, 126.13, 126.25, 126.48, 127.95, 128.07, 136.30, 145.15, 147.99, 149.16, 159.26 (all
PhꢀC and PyꢀC). Anal. calcd for C24H28N2O: C, 79.96; H, 7.83; N, 7.77. Found: C, 79.98; H,
7.82; N, 7.76.
4.3.5. (S)-2-[(2-Pyridylmethyl)amino]-1,1,3-triphenylpropan-1-ol 2e
Starting material: 0.607 g (2 mmol) 1e; reaction time: 48 h; work-up; purification by
preparative TLC developed with EtOAc/hexane (1/3). After purification, 2e was obtained as a
white solid in 89% yield; mp 80–82°C; [h]2D6=−49.0 (c 0.8, CH2Cl2); IR (KBr) wmax=3300, 3010,
1
1588, 1483, 1435, 1050, 734, 690 cm−1; H NMR (400 MHz, CDCl3) l 2.48 (m, 1H, CHAPh),
2.96 (m, 1H, CHBPh), 3.27 (m, 2H, CH2Py), 4.01 (dd, J=10.4 Hz, J=2.8 Hz, 1H, CHNH), 6.65
(d, J=8 Hz, 1H, PhH), 7.02–7.75 (m, 17H, PhH and PyH), 8.31 (d, J=4.8 Hz, 1H, PyH); 13C
NMR (400 MHz, CDCl3) l 37.72 (CH2Ph), 54.04 (CHNH), 65.98 (CH2NH), 78.58 (CꢀOH),
121.68, 121.86, 125.78, 126.12, 126.25, 126.47, 128.18, 128.94, 136.09, 139.48, 145.06, 147.34,
148.97, 158.77 (all PhꢀC and PyꢀC). Anal. calcd for C27H26N2O: C, 82.20; H, 6.64; N, 7.10.
Found: C, 82.20; H, 6.63; N, 7.09.
4.3.6. (S)-3-Methyl-2-benzylamino-1,1-diphenylbutan-1-ol 2f
This compound was prepared by the similar procedures for 2a except that using 2 mmol
benzaldehyde instead of 2-pyridinecarboxaldehyde. Starting material 0.513 g (2 mmol) 1c;
reaction time: 48 h; work-up; purification by preparative TLC developed with EtOAc/hexane
(1/4). After purification, 2f was obtained as colorless crystals in 72% yield; mp 133–134°C;
[h]2D8=−40.8 (c 0.5, CH2Cl2); IR (KBr) wmax=3290, 3025, 2992, 2900, 1590, 1485, 1443, 1049,
1
750, 738, 720, 700 cm−1; H NMR (400 MHz, CDCl3) l 0.92 (m, 3H, CH3), 0.976 (d, J=7.2 Hz,
3H, CH3), 2.06 (m, 1H, CH(CH3)2), 3.28 (d, J=12 Hz, CHAPh), 3.46 (d, J=12 Hz, 1H,
CHBPh), 3.65 (s, 1H, CHNH), 7.10–7.19 (m, 4H, PhH), 7.22–7.33 (m, 7H, PhH), 7.57 (d, J=7.6
Hz, 2H, PhH), 7.72 (d, J=8.0 Hz, 2H, PhH). 13C NMR (400 MHz, CDCl3) l 15.99 (CH3),

Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
3551
22.68 (CH3), 28.72 (CH(CH3)2), 54.99 (CHNH), 68.51 (CH2NH), 78.64 (CꢀOH), 125.80,
126.08, 126.20, 127.25, 127.91, 128.09, 128.43 (all PhꢀC and PyꢀC). Anal. calcd for
C24H27NO: C, 83.44; H, 7.88; N, 4.06. Found: C, 83.43; H, 7.89; N, 4.06.
4.4. A typical procedure for the enantioselective addition of diethylzinc to aromatic aldehydes
in the presence of chiral 2
To a solution of chiral 2 (0.01 mmol) in toluene (0.5 ml) was added diethylzinc (4.17 M in
n-hexane, 2.5 mmol) by syringe and the mixture was stirred for 1 h at rt. Then an aromatic
aldehyde (0.2 mmol) was added and the mixture was stirred for 5–12 h at rt. Aqueous
hydrochloric acid (1N) was added to quench the reaction. The resulting mixture was
extracted with ether, and the extract was washed with brine, dried with anhydrous Na2SO4
and evaporated under reduced pressure. The residue was purified by column chromatography
1
on preparative TLC (hexane/AcOEt=4/1). The product was identified with comparing the H
NMR and IR spectra with those of authentic samples. Experimental results were summarized
in Tables 1–3. Optical purities (% ee) were determined by HPLC using a chiral OD column
or by optical rotation. Conditions of HPLC analyses: chiral column, Chiralcel OD, 4.6×250
mm; detection, 216-nm light. For 1-phenylpropanol: eluent, 2% 2-propanol in hexane; flow
rate, 1 ml/min; retention time (min), S isomer 16.79, R isomer 14.53. For 1-(p-
chlorophenyl)propanol: 3% 2-propanol in hexane; 0.5 ml/min; S isomer 20.24, R isomer
21.79. For 1-(p-methoxyphenyl)propanol: 3% 2-propanol in hexane; 0.5 ml/min; S isomer
35.06, R isomer 29.93. For 1-(o-methoxyphenyl)propanol: 3% 2-propanol in hexane; 0.5
ml/min; S isomer 23.75, R isomer 25.83. For 1-(1-naphthyl)propanol: 3% 2-propanol in
hexane; 0.5 ml/min; S isomer 19.04, R isomer 40.11. For 1-(m-chlorophenyl)propanol: 3%
2-propanol in hexane; 0.5 ml/min; S isomer 21.43, R isomer 23.20. For 1-ferrocylpropanol:
0.45% 2-propanol in hexane; 1.5 ml/min; minor isomer 25.99, major isomer 24.35. For
1-(2-thienyl)propanol: 0.5% 2-propanol in hexane; 1.5 ml/min; S isomer 27.36, R isomer
24.89. For (E)-1-phenylpent-1-en-3-ol: 3% 2-propanol in hexane; 1 ml/min; S isomer 33.20, R
isomer 18.30.
Acknowledgements
We are grateful to the National Natural Sciences Foundation of the People’s Republic of
China (No. 29872034) for financial support.
References
1. For general discussion and comprehensive reviews, see (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Hayashi, T. In Asymmetric Catalysis; Ojima, I., Ed.; VCH: New York, 1993;
Chapter 7.1. (c) Brunner, H.; Zettlmeier, W. Handbook of Enantioselective Catalysis; VCH: Weinheim, 1993. (d)
Lin, G. Q.; Chen, Y. Q.; Chen, X. Z.; Li, Y. M. Chiral Synthesis: Asymmetric Reactions and Their Applications;
Science Press: Beijing, 2000. (e) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (f) Noyori, R.; Kitamura, M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 49.

3552
Y. Wu et al. / Tetrahedron: Asymmetry 11 (2000) 3543–3552
2. For recent examples, see (a) Reddy, K. S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Synthesis 2000, 165.
(b) Hailes, H. C.; Madden, J. Synlett 1999, 105. (c) Aurich, H. G.; Biesemeier, F.; Geiger, M.; Harms, K. Liebigs
Ann. 1997, 423. (d) Li, Z.; Upadhyay, V.; DeCamp, A. E.; Dimichele, L.; Reider P. J. Synthesis 1999, 1453. (e)
Kitamura, M.; Suga, S.; Miwa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832. (f) Prasad, K. R. K.; Joshi,
N. N. J. Org. Chem. 1997, 62, 3770.
3. (a) Williams, D. R.; Fromhold, M. G. Synlett 1997, 523. (b) Ishizaki, M.; Fujita, K-i.; Shimamoto, H.;
Nakagawa, Y.; Moriya, N.; Tateishi, H.; Ochi, H.; Takayoshi, S.; Isobe, K. Tetrahedron: Asymmetry 1995, 6,
1165. (c) Kotsuki, H.; Hayakawa, H.; Tateishi, H.; Wakao, M. Tetrahedron: Asymmetry 1998, 9, 3203. (d)
Chelucci, G.; Soccolini, F. Tetrahedron: Asymmetry 1992, 3, 1235. (e) Zhang, H.; Xue, F.; Mak, T. C. W.; Chan,
K. S. J. Org. Chem. 1996, 61, 8002. (f) Soai, K.; Niwa, S.; Hori, H. Chem. Commun. 1990, 982. (g) Shibata, T.;
Morioka, H.; Tanji, S.; Hayase, T.; Kodaka, Y.; Soai, K. Tetrahedron Lett. 1996, 37, 8783.
4. Kang, J.; Kim, H. Y.; Kim, J. H. Tetrahedron: Asymmetry 1999, 10, 2523.
5. (a) McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3468. (b) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama,
S. J. Chem. Soc., Chem. Commun. 1983, 469.
6. The utilities of triacetoborohydride in reduction, see: Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
7. Christopher, G. F.; Paul, M. Tetrahedron: Asymmetry 2000, 11, 1845.
8. Soai, K.; Watanabe, M. J. Chem. Soc., Chem. Commun. 1990, 43.
9. Chaloner, P. A.; Renuka Perera, S. A. Tetrahedron Lett. 1987, 28, 3013.
10. Hayashi, M.; Kaneko, T.; Oguni, N. J. Chem. Soc., Perkin Trans. 1 1991, 25.
11. Corey, E. J.; Yuen, Po-Wai; Hannon, F. J.; Wierda, D. A. J. Org. Chem. 1990, 55, 784.
.