trans-(1S,2S)-1-substituted-2-(N,N-dialkylamino)-1-indanol derivatives as chiral ligands in the catalytic enantioselective addition of diethylzinc to aldehydes

Article abstract of DOI:10.1016/S0957-4166(02)00183-0

A series of optically active trans-(1S,2S)-1-substituted-2-(N,N-dialkylamino)-1-indanol derivatives 1-6 were synthesized and applied in the catalytic enantioselective addition of diethylzinc to aldehydes. The enantiomeric purity of the addition products i

Full text of DOI:10.1016/S0957-4166(02)00183-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 945–951
trans-(1S,2S)-1-Substituted-2-(N,N-dialkylamino)-1-indanol
derivatives as chiral ligands in the catalytic enantioselective
addition of diethylzinc to aldehydes
Qianyong Xu,a,b,* Hongfang Yang,b Xinfu Panb and Albert S. C. Chanc
aNorthwest Institute of Nuclear Technology, PO Box 69, Xi’an 710024, PR China
bDepartment of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
cOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, PR China
Received 15 January 2002; accepted 11 April 2002
Abstract—A series of optically active trans-(1S,2S)-1-substituted-2-(N,N-dialkylamino)-1-indanol derivatives 1–6 were synthesized
and applied in the catalytic enantioselective addition of diethylzinc to aldehydes. The enantiomeric purity of the addition products
increased considerably with increasing bulk of the substituents both on the nitrogen atom and the hydroxy-bearing carbon atom
of the ligands. sec-Alcohols were obtained in good yields with enantiomeric excesses up to 93.1%. © 2002 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The catalytic abilities of these natural product deriva-
tives have been probed mostly to study the effects of
the substituents on the nitrogen atom5–8,10 and the
hydroxyl-bearing carbon atom of the ligand on the
enantioselectivity of the addition reaction.11 The mech-
anism of the process has been discussed for tertiary
b-amino alcohols and it has been shown that the abso-
lute configuration of the products correlate with the
configuration of the hydroxyl-bearing stereocenter of
the ligand.12,13
Carbonꢀcarbon bond formation is a fundamental and
indispensable method within organic chemistry and the
development of enantioselective carbonꢀcarbon bond
forming processes is one of the most challenging tasks
in the synthesis of enantiomerically enriched organic
compounds. In particular, the catalytic enantioselective
addition of dialkylzinc reagents to aldehydes has
attracted much attention in recent years because of its
potential for the efficient preparation of optically active
secondary alcohols,1 which are valuable structural
units, being found in many natural products. Addition-
ally, secondary alcohols can serve as useful synthetic
intermediates for various other functionalities, e.g.
halides, amines, ethers, esters etc.2 The discovery that
certain b-amino alcohols can promote the ethylation of
benzaldehyde by diethylzinc3 initiated a search for
efficient chiral auxiliaries for this type of reaction since
Oguni’s first report in 19844 and a myriad of b-amino
alcohols have been investigated as catalysts. Among
them, derivatives of natural products such as
ephedrine,5 norephedrine,6 camphor,7 pinane,8 and cin-
chona alkaloids9 have attracted widespread attention.
Chiral b-amino alcohols are common ligands in asym-
metric synthesis as they are readily accessible in enan-
tiomerically pure form in a few steps from natural
a-amino acid precursors. Thus, the stereoselective addi-
tion of dialkylzinc reagents to aldehydes, catalyzed by
chiral b-amino alcohols, has been extensively investi-
gated. The addition of a suitable chiral b-amino alcohol
to dialkylzinc compounds converts the relatively unre-
active reagent into a reactive complex.13 In this way,
sterically congested b-amino-alcohols, such as DAIB
and DPMPM, give excellent enantioselectivities.1,13
Amino indanol, which is another kind of sterically
congested b-amino alcohol, has been widely applied in
the asymmetric reduction of prochiral ketones to sec-
ondary alcohols,14 but has rarely been used as a catalyst
in the enantioselective addition of dialkylzinc to alde-
* Corresponding author. Fax: 86-29-3366333; e-mail: nintzhang@
hz163.net
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00183-0

946
Q. Xu et al. / Tetrahedron: Asymmetry 13 (2002) 945–951
hydes.15 Herein, we describe syntheses of new optically
active trans-(1S,2S)-1-substituted-2-(N,N-dialkyl-
amino)-1-indanol derivatives. Some initial results on the
catalytic activity of these chiral catalysts in the enan-
tioselective addition of diethylzinc to aldehydes are also
reported.
be seen, all the reactions proceeded smoothly to give
(R)-1-phenyl-1-propanol in good yields and with enan-
tiomeric excesses ranging from 78.9 to 93.1%. Further-
more, the enantioselectivities of the reaction were very
sensitive to the substituents on the chiral catalysts.
Enhancement of the bulk of the substituents on the
nitrogen-atom induced an increase in the enantioselec-
tivity (entries 1 versus 4, or 2 versus 5, or 3 versus 6).
The enantioselectivity of the alkylation also increased
with increasing bulk of the substituents on the hydroxy-
bearing carbon atom (entries 1–3 versus 4–6) and the
chiral ligand 6, which has bulky substituents on both
the nitrogen atom and the hydroxy-bearing carbon
atom, gave the best reactivity and enantioselectivity.5,6
2. Results and discussion
2.1. Synthesis of optically active trans-(1S,2S)-1-substi-
tuted-2-(N,N-dialkylamino)-1-indanol derivatives 1–6
The synthesis of trans-(1S,2S)-1-substituted-2-(N,N-
dialkylamino)-1-indanol derivatives 1–6 are summa-
rized in Scheme 1. The
protected as -N-ethoxycarbonyl-phenylalanine with
L-phenylalanine was first
L
ethyl chloroformate in quantitative yield. The ethoxy-
carbonyl derivative was transformed to its acid chloride
with PCl5, followed by Friedel–Crafts cyclization to
give (S)-2-[(ethoxycarbonyl)amino]-1-indanone 7.16 The
key intermediate 7 was converted by Grignard reactions
to the trans-(1S,2S)-1-substituted-2-(N-ethoxycar-
bonyl)amino-1-indanols 8–10. Their configurations of
the products were determined by two-dimensional
NOESY experiments: no NOE interaction between
C(2)H and R1 was observed (Fig. 1), which indicates
that C(2)H and R1 are distanced from each other.
Accordingly, the trans-(1S,2S)-configurations were
deduced. trans-(1S,2S)-1-Substituted-2-(N-ethoxycar-
bonyl)amino-1-indanols 8–10 were then deprotected
with KOH/ethanol solution to give 11–13, followed by
alkylation with iodoethane or 1-iodobutane to produce
trans-(1S,2S)-1-substituted-2-(N,N-dialkylamino)-1-ind-
anol derivatives 1–6.
Figure 1.
Table 1. The enantioselective addition of diethylzinc to
benzaldehyde catalyzed by chiral trans-(1S,2S)-1-substi-
tuted-2-(N,N-dialkylamino)-1-indanol derivatives 1–6a
O
OH
20% mol cat.1-6
+ ZnEt2
H
Entry
Catalyst
Yield (%)b
E.e. (%) (Config.)c
1
2
3
4
5
6
1
2
3
4
5
6
91
94
89
87
90
90
81.9 (R)
78.9 (R)
84.7 (R)
88.5 (R)
88.2 (R)
93.1 (R)
2.2. Enantioselective addition of diethylzinc to alde-
hydes catalyzed by trans-(1S,2S)-1-substituted-2-(N,N-
dialkylamino)-1-indanol derivatives 1–6
a The reactions were carried out in toluene/hexane (v/v 1/4) at 0°C
with 20 mol% chiral catalysts, ZnEt2/benzaldehyde=10.0/5.0
(mmol).
According to the general procedure (see Section 4), the
catalysts 1–6 were tested in the enantioselective addi-
tion reaction by the addition of 2.0 equiv. of diethylzinc
to benzaldehyde in the presence of 0.2 equiv. of the
catalyst in toluene/hexane (1/4, v/v) at 0°C to compare
their efficiency. The results are given in Table 1. As can
b Based on isolated product.
c The e.e. values were determined by GC analysis and the configura-
tions were determined by comparison of the specific rotation with
that of the known compound.
Scheme 1. Reagents and conditions: (a) CH3CH2OCOCl/MeOH; (b) PCl5; (c) AlCl3; (d) R1MgX, ether; (e) KOH/C2H5OH; (f) R2I,
K2CO3.

Q. Xu et al. / Tetrahedron: Asymmetry 13 (2002) 945–951
947
In view of the above results, chiral ligand 6 was used as
a catalyst in the enantioselective addition of diethylzinc
to a family of aldehydes comprising both aromatic and
aliphatic aldehydes and the results are shown in Table
2. It can be seen from the results that high enantioselec-
tivities (>80%) were generally obtained for aromatic
aldehydes (entries 1–9 and 11, 12) except for 4-pyridine-
carboxaldehyde (entry 10), which gave much lower
enantioselectivity. For this substrate, the nitrogen atom
on the heterocyclic ring and its corresponding addition
product, sec-alcohol, may promote the ethylation reac-
tion of 4-pyridinecarboxaldehyde with diethylzinc. It
then reduces the overall enantioselectivity. This is sup-
ported by the observation that (R)-1-phenyl-1-propanol
underwent autoinduction in the addition of diethylzinc
toward benzaldehyde in the presence of a catalytic
amount of achiral amine.17 These phenomena were also
observed in the enantioselective addition of diethylzinc
to the above substrate when catalyzed by chiral
pyridylphenol18 or brine derivatives.10d Moderately
enantioselective addition reactions (45.4ꢀ58.2% e.e.)
were observed for aliphatic aldehydes (entries 13–16).
nitrogen atom would increase the nucleophilicity of the
ethyl group of ZnEt2 and the ethyl migration from the
dizinc complex to benzaldehyde through transition
state 16 would give a catalyst/product complex 17.
Regeneration of the catalyst 14 and liberation of the
product takes place in a subsequent step.
The anti-5/4/4-fused tricyclic transition state 16-Pro-S
and 16-Pro-R can be formed from 15 by transfer of the
ethyl group on the Zn atom to benzaldehyde both from
the Si-face and Re-face, respectively. In the transition
state 16-Pro-S, which leads to (S)-1-phenyl-1-propanol,
the strong steric interaction between Et and Ph disfa-
vors this structure, and R1 enforces the repulsion. On
the other hand, in the transition state 16-Pro-R, which
leads to (R)-1-phenyl-1-propanol, the steric interaction
between Ph and Et is absent, is the favored structure.
Therefore, in all cases, (R)-1-phenyl-1-propanol was
produced. With the increasing of the bulkiness of R1
and R2, they enforce the repulsion among R1, R2, Ph,
and the ethyl group on the Zn atom in 16-Pro-S, and it
gives a higher performance for 16-Pro-R and results in
a better stereochemical control. This accounts for the
excellent performances of the chiral ligand 6 described
above.
The chiral ligand-mediated addition of dialkylzinc to
aldehyde is a well-studied reaction. Although knowl-
edge of the actual active species are unclear, assuming
the dinuclear Zn complex proposed in the product-
forming transition state (TS) by Noyori,13 the anti-
configured 5/4/4-fused tricyclic transition model shown
in Fig. 2 is suggested. Zinc monoalkoxide 14, which is
formed from the reaction of ZnEt2 with ligand and
does not ethylate benzaldehyde, is converted to the zinc
monoalkoxide–diethylzinc complex 15 by diethylzinc.
Coordination of the zinc atom with the oxygen or
3. Conclusions
In conclusion, we have demonstrated that trans-
(1S,2S)-1-substituted-2-(N,N-dialkylamino)-1-indanol
derivatives 1–6, which could be easily prepared from
L
-phenylalanine in several steps, are efficient chiral
ligands in the enantioselective addition of diethylzinc to
Table 2. The enantioselective addition of diethylzinc to aldehydes catalyzed by ligand 6a
O
OH
20%mol cat. 6
+ ZnEt2
R
H
R
*
Entry
Substrate
Yield (%)b
E.e. (%) (Config.)c
1
2
3
4
5
6
7
8
Benzaldehyde
o-Anisaldehyde
p-Anisaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Tolualdehyde
90
88
91
90
90
83
96
94
90
79
91
95
93
80
77
86
93.1 (R)
74.2 (R)
89.7 (R)
90.6 (R)
86.2 (R)
92.3 (R)
83.0 (R)d
76.4 (R)d
87.6 (R)d
8.2 (R)d
86.7 (R)d
84.1 (R)d
45.4 (R)d
55.8 (R)e
50.2 (R)e
58.2 (R)e
3,4-Dimethoxybenzaldehyde
4-(Dimethylamino) benzaldehyde
p-Morpholinobenzaldehyde
4-Pyridinecarboxaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
trans-Cinnamaldehyde
Dodecylaldehyde
9
10
11
12
13
14
15
16
Nonylaldehyde
Cyclohexanecarboxaldehyde
a The reactions were carried out in toluene/hexane (1/4, v/v) at 0°C with 20 mol% chiral ligand 6, ZnEt2/aldehyde=10.0/5.0 (mmol).
b Based on isolated product.
c Unless otherwise specified, the e.e. values were determined by GC analysis and the configurations were determined by comparison of the specific
rotation with those of known compounds.
d The e.e. values were determined by HPLC.
e The e.e. values were determined by GC after acetylation.

948
Q. Xu et al. / Tetrahedron: Asymmetry 13 (2002) 945–951
CH3
R1
CH2
R1
ZnEt2
O
Zn Et
Et
O
Et
Zn
N
R2
Zn
N
R2
R2
R2
H
H
14
15
PhCHO
Si-face
Re-face
Me
H
H
H
Me
Ph
Et
Et
R1
R1
Ph
H
O
Zn
O
Zn
Et
Et
Zn
O
Zn
O
R2
N
R2
R2
N
R2
H
H
16-Pro-S
16-Pro-R
Et
Zn
Et
R1
Et
Zn
Et
R1
Et
O
Et
O
Zn
R2
O
Zn
O
N
R2
Ph
R2
N
Ph
H
H
R2
17-Pro-S
17-Pro-R
(S)-1-phenyl-propanol
(R)-1-phenyl-propanol
Figure 2.
aldehydes. The effects of the ligand structures on the
enantioselectivity were also examined. The predomi-
nance of sec-alcohol products with R-configuration was
explained by a mechanism involving the anti-5/4/4-
fused tricyclic transition state 16-Pro-R. The success of
the chiral ligand 6 relied on the greater steric effects
between R1, R2, Ph, and the ethyl group on zinc. This
chiral ligand promoted the ethylation of aldehydes by
diethylzinc with good enantioselectivities for a number
of aromatic aldehydes and with reasonable enantiose-
lectivities for aliphatic aldehydes. Further applications
of these ligands in other catalytic asymmetric reactions
are under investigation.
rasil-DEX CB capillary column on Varian CP-3380 GC
instrument with FID as detector and nitrogen as carrier
gas or with a Chiralcel-OD column on Varian SD-200
HPLC instrument with UV detector and hexane/2-
propanol as eluent. All solvents used were dried by
standard methods and aldehydes were purified using
standard, published methods before use.
4.2. (S)-2-[(Ethoxycarbonyl)amino]-1-indanone 7
An ice-cooled solution of L-phenylalanine (0.2 g, 1.21
mmol) in 1N NaOH (10 mL) was treated with solid
sodium carbonate (64 mg, 0.604 mmol) and ethyl chlo-
roformate (0.12 mL, 1.26 mmol). Stirring was contin-
ued for 0.5 h with cooling and a further 0.5 h without
cooling. The mixture was carefully acidified with con-
centrated HCl to pH 2ꢀ3. The resultant solution was
extracted with CH2Cl2 and the organic layer was
washed with water, dried over anhydrous sodium sul-
fate, concentrated under reduced pressure to give (S)-
N-(ethyoxycarbonyl)phenylalanine (0.28 g, 98% yield).
4. Experimental
4.1. General procedure
All reactions were carried out under Ar atmosphere.
Melting points were taken on a Kofler melting appara-
tus and are uncorrected. 1H and 13C NMR spectra were
measured with a Bruker AM-400 NMR spectrometer
with TMS as an internal reference. Electron ionization
mass spectra were obtained on a Hewlett–Packard
HP5988A mass spectrometer. Elemental analyses were
performed on a Carlo-Erba-1106 elemental analyzer.
Optical rotations were measured on a Jasco J-20C
automatic polarimeter. Enantiomeric excess (e.e.) deter-
mination was carried out with a Chrompack CP-Chi-
To an ice-cooled solution of (S)-N-(ethyoxycar-
bonyl)phenylalanine (0.30 g, 1.26 mmol) in ether (10
mL) was added solid PCl5 (0.28 g, 1.34 mmol). Stirring
was continued for 1 h with cooling and a further 0.5 h
without cooling. After concentration of the mixture at
30°C, the residue was dissolved in CH2Cl2 (10 mL) and
rapidly added dropwise to a suspension of AlCl3 (0.54
g, 4.01 mmol) in CH2Cl2 (20 mL). Stirring was contin-

Q. Xu et al. / Tetrahedron: Asymmetry 13 (2002) 945–951
949
ued for 1–2 h after completion of the addition. The
mixture was poured into ice-cold dilute HCl with vigor-
ous stirring, which was continued for 1 h. The layers
were separated, and the aqueous phase was extracted
with CH2Cl2 (3×15 mL). The combined organic layers
were washed with water, dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was
purified by flash chromatography (acetone:dichloro-
(dd, 1H, J=10.1, 15.3 Hz), 3.26 (dd, 1H, J=8.1, 15.3
Hz), 4.01 (q, 2H, J=7.2 Hz), 4.55 (dd, 1H, J=8.1, 10.1
Hz), 6.08 (br, 2H), 7.05–7.34 (m, 9H). EIMS (m/z): 297
(M+, 1), 279 (7), 250 (1), 224 (1), 208 (100), 178 (17),
165 (10), 105 (19), 77 (28).
4.4. trans-(1S,2S)-1-Substituted-2-amino-1-indanol 11–
13
methane:petroleum ether=1:2:2) to give
a white
solid (0.17 g, 61% yield). Mp 131–132°C; [h]2D0=+12.0
To a solution of trans-(1S,2S)-1-substituted-2-[(N-
ethoxycarbonyl)amino]-1-indanol 8–10 (0.85 mmol) in
ethanol (5 mL), was added 2N potassium hydroxide
solution (5 mL). The mixture was heated under reflux
for 4 h under an argon atmosphere and then extracted
with chloroform (3×20 mL). The combined organic
layers were washed with water and dried over anhy-
drous sodium sulfate. After concentration under
reduced pressure, the residue was purified by flash
chromatography to give trans-(1S,2S)-1-substituted-2-
amino-1-indanol 11–13.
1
(c 1.21, CH3OH); H NMR (400 MHz, CDCl3): 1.26
(t, 3H, J=6.9 Hz), 3.03 (dd, 1H, J=5.5, 16.6 Hz), 3.70
(dd, 1H, J=8.0, 16.6 Hz), 4.15 (q, 2H, J=6.9 Hz), 4.40
(m, 1H), 5.4 (br, 1H), 7.27–7.87 (m, 4H). EIMS (m/z):
219 (M+, 30), 191 (15), 174 (37), 146 (30), 130 (100),
91 (31), 77 (10).
4.3. trans-(1S,2S)-1-Substituted-2-[(N-ethoxycar-
bonyl)amino]-1-indanol 8–10: general procedure
To the appropriate Grignard reagent R1MX (14 mmol)
in ether (10 mL) was added dropwise a solution of 7
(1.0 g, 4.57 mmol) in ether (10 mL) with ice bath
cooling. After the addition, the mixture was stirred
overnight at rt. When TLC indicated that the reaction
was finished, the mixture was quenched with saturated
aqueous ammonium chloride solution. The phases were
separated and aqueous phase was extracted with ether
(3×20 mL). The combined organic layers were washed
with brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was
purified by flash chromatography to give trans-(1S,2S)-
1-substituted-2-[(N-ethoxycarbonyl)amino]-1-indanol
8–10.
4.4.1. trans-(1S,2S)-1-Methyl-2-amino-1-indanol 11. A
white solid was obtained (95% yield) (ethyl acet-
ate:methanol=3:1). Mp 85–86°C; [h]2D0=+22.5 (c 0.60,
1
CH3OH); H NMR (400 MHz, DMSO-d6): 1.13 (s, 3H)
2.38 (dd, 1H, J=9.6, 15.2 Hz), 2.95 (dd, 1H, J=7.4,
15.2 Hz), 3.31 (dd, 1H, J=7.4, 9.6 Hz), 7.11–7.27 (m,
4H). EIMS (m/z): 163 (M+, 20), 145 (14), 119 (100), 103
(20), 91 (27), 77 (17).
4.4.2. trans-(1S,2S)-1-Ethyl-2-amino-1-indanol 12. A
white solid was obtained (94% yield) (ethyl acet-
ate:methanol=3:1). Mp 83–84°C; [h]2D0=+29.2 (c 0.60,
1
CH3OH); H NMR (400 MHz, DMSO-d6): 0.86 (t, 3H,
J=7.3 Hz), 1.44 (dt, 1H, J=7.3, 13.8 Hz), 1.66 (dt, 1H,
J=7.3, 13.8 Hz), 2.78 (dd, 1H, J=9.9, 15.3 Hz), 3.10
(dd, 1H, J=7.8, 15.3 Hz), 3.59 (dd, 1H, J=7.8, 9.4
Hz), 7.23–7.26 (m, 4H). EIMS (m/z): 177 (M+, 18), 148
(31), 131 (41), 119 (100), 91 (32), 77 (21).
4.3.1.
trans-(1S,2S)-1-Methyl-2-[(N-ethoxycarbonyl)-
amino]-1-indanol 8. A colorless liquid was obtained
(0.62 g, 57% yield) (ethyl acetate:petroleum ether=1:4);
[h]2D0=−7.6 (c 0.82, CH3OH); 1H NMR (400 MHz,
acetone-d6): 1.19 (t, 3H, J=7.2 Hz), 1.27 (s, 3H), 2.60
(dd, 1H, J=10.0, 15.1 Hz), 3.15 (dd, 1H, J=8.0, 15.1
Hz), 4.10 (q, 2H, J=7.2 Hz), 4.28 (dd, 1H, J=8.0, 10.0
Hz), 5.54 (br, 2H), 7.10–7.70 (m, 4H). EIMS (m/z): 235
(M+, 1), 217 (100), 189 (10), 146 (94), 130 (98), 119 (76),
91 (59), 77 (25).
4.4.3. trans-(1S,2S)-1-Phenyl-2-amino-1-indanol 13. A
white solid was obtained (98% yield) (ethyl acet-
ate:methanol=3:1). Mp 92–94°C. [h]2D0=+67.8 (c 0.51,
1
CH3OH). H NMR (400 MHz, DMSO-d6): 2.38 (dd,
1H, J=9.4, 15.6 Hz), 3.04 (dd, 1H, J=7.3, 15.6 Hz),
3.58 (dd, 1H, J=7.3, 9.4 Hz), 7.00–7.28 (m, 9H). EIMS
(m/z): 225 (M+, 4), 195 (100), 178 (18), 152 (7), 130
(15), 105 (11), 77 (27).
4.3.2.
trans-(1S,2S)-1-Ethyl-2-[(N-ethoxycarbonyl)-
amino]-1-indanol 9. A colorless solid was obtained (53%
yield) (ethyl acetate:petroleum ether=1:5). Mp 127–
128°C; [h]2D0=−9.7 (c 0.99, CH3OH); 1H NMR (400
MHz, acetone-d6): 0.87 (t, 3H, J=7.3 Hz), 1.22 (t, 3H,
J=7.2 Hz), 1.48 (m, 1H), 1.79 (m, 1H), 2.49 (dd, 1H,
J=10.2, 15.6 Hz), 3.02 (dd, 1H, J=8.0, 15.6 Hz), 4.06
(q, 2H, J=7.2 Hz), 4.33 (dd, 1H, J=8.0, 10.2 Hz),
7.17–7.71 (m, 4H). EIMS (m/z): 249 (M+, 1) 231 (6),
220 (34), 192 (45), 174 (18), 146 (37), 130 (100), 120
(50), 91 (72).
4.5. trans-(1S,2S)-1-Substituted-2-(N,N-dialkylamino)-
1-indanol 1–6
To a solution of trans-(1S,2S)-1-substituted-2-amino-1-
indanol 1–6 (1.27 mmol) and sodium carbonate (0.81 g,
7.6 mmol) in acetonitrile (10 mL) was added 1-iodobu-
tane (0.61 mL, 7.6 mmol). After the reaction mixture
was refluxed for 24 h, water (5 mL) was added. Then
the reaction mixture was extracted with ethyl acetate
(3×15 mL), and the combined organic layers were
washed with brine, dried over anhydrous sodium sul-
fate. After concentration under reduced pressure, the
residue was purified by flash chromatography to give
4.3.3.
trans-(1S,2S)-1-Phenyl-2-[(N-ethoxycarbonyl)-
amino]-1-indanol 10. A colorless solid was obtained
(54% yield) (ethyl acetate:petroleum ether=1:5). Mp
90–91°C; [h]2D0=−122.0 (c 0.81, CH3OH); 1H NMR
(400 MHz, acetone-d6): 1.09 (t, 3H, J=7.2 Hz), 2.90

950
Q. Xu et al. / Tetrahedron: Asymmetry 13 (2002) 945–951
trans-(1S,2S)-1-substituted-2-(N,N-dialkylamino)-1-
indanol 1–6.
(m/z): 289 (M+, 2), 246 (9), 142 (100), 91 (9). Anal.
calcd for C19H31NO: C, 78.84; H, 10.79; N, 4.84.
Found: C, 78.69; H, 10.67; N, 4.60%.
4.5.1. trans-(1S,2S)-1-Methyl-2-(N,N-diethylamino)-1-
indanol 1. A white solid was obtained (73% yield). Mp
4.5.6. trans-(1S,2S)-1-Phenyl-2-(N,N-dibutylamino)-1-
indanol 6. A pale yellow liquid was obtained (53%
1
63–64°C; [h]2D0=+34.6 (c 0.55, CH3OH); H NMR (400
1
MHz, DMSO-d6): 1.00 (t, 6H, J=7.2 Hz), 1.27 (s, 3H),
2.67 (dd, 1H, J=10.2, 14.9 Hz), 2.76 (m, 2H), 2.94 (m,
3H), 3.24 (dd, 1H, J=7.4, 10.2 Hz), 7.12–7.29 (m, 4H);
13C NMR (DMSO-d6): 10.94, 23.32, 34.98, 43.84, 73.29,
82.92, 123.19, 124.95, 127.35, 127.98, 138.62, 151.24.
EIMS (m/z): 219 (M+, 1), 190 (1), 86 (100). Anal. calcd
for C14H21NO: C, 76.67; H, 9.65; N, 6.39. Found: C,
76.58; H, 9.60; N, 6.45%.
yield); [h]2D0=−21.2 (c 0.64, CH3OH). H NMR (400
MHz, DMSO-d6): 0.76 (t, 6H, J=7.3 Hz), 1.07 (m,
4H), 1.24 (m, 4H), 2.21 (m, 2H), 2.41 (m, 2H), 2.91 (dd,
1H, J=10.1, 15.5 Hz), 2.99 (dd, 1H, J=7.6 15.5 Hz),
3.72 (dd, 1H, J=7.6, 10.1 Hz), 7.15–7.27 (m, 9H); 13C
NMR (DMSO-d6): 14.37, 21.07, 29.23, 30.48, 51.79,
76.93, 86.20, 125.06, 125.28, 127.00, 127.79, 127.98,
128.47, 140.77, 145.22, 149.73. EIMS (m/z): 337 (M+,
2), 319 (1), 294 (4), 264 (2), 209 (5), 142 (100), 77 (8).
Anal. calcd for C23H31NO: C, 81.85; H, 9.26; N, 4.15.
Found: C, 81.77, H, 9.11; N, 4.03%.
4.5.2.
trans-(1S,2S)-1-Ethyl-2-(N,N-diethylamino)-1-
indanol 2. A pale yellow liquid was obtained (78%
yield); [h]2D0=+35.8 (c 0.53, CH3OH); H NMR (400
1
MHz, DMSO-d6): 0.86–1.01 (m, 9H), 1.57 (m, 1H), 1.84
(m, 1H), 2.56 (dd, 1H, J=9.8, 14.6 Hz), 2.76 (m, 2H),
2.92 (m, 3H), 3.26 (dd, 1H, J=7.2, 9.8 Hz), 7.16–7.27
(m, 4H); 13C NMR (DMSO-d6): 8.01, 10.99, 28.04,
35.07, 44.02, 74.17, 85.14, 124.89, 125.08, 126.70,
128.04, 139.57, 148.87. EIMS (m/z): 233 (M+, 1), 204
(1), 174 (1), 159 (1), 131 (3), 86 (100). Anal. calcd for
C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.30;
H, 9.81; N, 6.15%.
4.6. General procedure for asymmetric addition of
diethylzinc to aldehydes
To a solution of catalyst 1 (2.0 mmol) in toluene (1 mL)
and hexane (4 mL) at 0°C was added a 1.0 M solution
of diethylzinc in hexane (10.0 mL, 10.0 mmol). After
stirring for 30 min at 0°C, freshly distilled benzaldehyde
(5.0 mmol) was added. The reaction mixture was stirred
at 0°C for 12 h. After addition of 1N HCl (10 mL), the
phases were separated. The water layer was extracted
with ethyl acetate (3×20 mL). The combined organic
layers were washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pres-
sure. After purification by flash chromatography (ethyl
acetate:petroleum ether 1:5), the enantiomeric excess
was determined by GC.
4.5.3. trans-(1S,2S)-1-Phenyl-2-(N,N-diethylamino)-1-
indanol 3. A pale yellow liquid was obtained (85%
1
yield); [h]2D0=−31.6 (c 0.49, CH3OH); H NMR (400
MHz, DMSO-d6): 0.76 (t, 6H, J=6.9 Hz), 2.34 (m,
2H), 2.57 (m, 2H), 2.86 (dd, 1H, J=10.8, 15.4 Hz), 3.03
(dd, 1H, J=7.2, 15.4 Hz), 3.70 (dd, 1H, J=7.2, 10.8
Hz), 7.13–7.26 (m, 9H); 13C NMR (DMSO-d6): 12.35,
33.77, 44.43, 76.55, 86.53, 125.04, 125.25, 126.94,
127.78, 127.80, 127.85, 128.48, 140.63, 145.19, 149.83.
EIMS (m/z): 281 (M+, 2), 252 (2), 86 (100). Anal. calcd
for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C,
81.21; H, 8.10; N, 5.07%.
References
1. For review, see: (a) Noyori, R.; Kitamura, M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 49; (b) Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833; (c) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; Wiley: New York, 1994,
pp. 255–297.
4.5.4. trans-(1S,2S)-1-Methyl-2-(N,N-dibutylamino)-1-
indanol 4. A pale yellow liquid was obtained (43%
1
yield); [h]2D0=+26.9 (c 0.64, CH3OH); H NMR (400
2. (a) Soai, K.; Watanabe, M.; Koyano, M. J. Chem. Soc.,
Chem. Commun. 1989, 534; (b) Soai, K.; Yokoyama, S.;
Hayasaka, T. J. Org. Chem. 1991, 56, 4264; (c) Wilken,
J.; Winter, M.; Stahl, I.; Martens, J. Tetrahedron: Asym-
metry 2000, 11, 1067; (d) Okamoto, M.; Tabe, M.; Fujii,
T.; Tanaka, T. Tetrahedron: Asymmetry 1995, 6, 767; (e)
Langer, F.; Schwink, L.; Devasagayaaraj, A.; Chavant,
P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229; (f)
Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130; (g) Lutjens, H.; Knochel, P. Tetrahedron:
Asymmetry 1994, 5, 1161; (h) Soai, K.; Hirose, Y.; Niwa,
S. J. Fluorine Chem. 1992, 59, 5; (i) Soai, K.; Hirose, Y.;
Sakata, S. Bull. Chem. Soc. Jpn. 1992, 65, 1734.
MHz, DMSO-d6): 0.91 (t, 6H, J=7.4 Hz), 1.27 (m,
7H), 1.44 (m, 4H), 2.67 (m, 2H), 2.80 (m, 3H), 2.93 (dd,
1H, J=7.2, 14.9 Hz), 3.28 (dd, 1H, J=7.2, 9.0 Hz),
7.12–7.34 (m, 4H); 13C NMR (DMSO-d6): 14.46, 21.34,
23.32, 29.00, 34.68, 51.38, 74.11, 82.92, 123.21, 125.02,
127.38, 128.03, 138.91, 151.28. EIMS (m/z): 275 (M+,
5), 232 (26), 214 (4), 186 (2), 142 (100), 91 (11). Anal.
calcd for C18H29NO: C, 78.49; H, 10.61; N, 5.09.
Found: C, 78.55; H, 10.53; N, 5.19%.
4.5.5.
trans-(1S,2S)-1-Ethyl-2-(N,N-dibutylamino)-1-
indanol 5. A pale yield liquid was obtained (44% yield);
[h]2D0=+41.4 (c 0.72, CH3OH); 1H NMR (400 MHz,
DMSO-d6): 0.84–0.93 (m, 9H), 1.30 (m, 4H), 1.45–1.59
(m, 5H), 1.88 (m, 1H), 2.66 (m, 2H), 2.81 (m, 3H), 2.94
(dd, 1H, J=7.3, 14.9 Hz), 3.31 (dd, 1H, J=7.3, 10.1
Hz), 7.14–7.26 (m, 4H); 13C NMR (DMSO-d6): 8.01,
14.48, 21.35, 27.98, 28.89, 34.90, 51.42, 74.87, 85.11,
124.83, 125.05, 126.67, 127.99, 130.64, 148.86. EIMS
3. Mukaiyama, T.; Soai, K.; Sato, T.; Shimizu, H.; Suzuki,
K. J. Am. Chem. Soc. 1979, 101, 1455.
4. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
5. (a) Chaloner, P. A.; Perera, S. A. R. Tetrahedron Lett.
1987, 28, 3013; (b) Chaloner, P. A.; Langadianous, E.
Tetrahedron Lett. 1990, 31, 5185; (c) Corey, E. J.; Han-
non, F. J. Tetrahedron Lett. 1987, 28, 5233; (d) Corey, E.

Q. Xu et al. / Tetrahedron: Asymmetry 13 (2002) 945–951
951
13. (a) Kitamura, M.; Oka, H.; Noyori, R. Tetrahedron 1999,
55, 3605; (b) Yamakawa, M.; Noyori, R. Organometallics
1999, 18, 128; (c) Kitamura, M.; Suga, S.; Oka, H.;
Noyori, R. J. Am. Chem. Soc. 1998, 120, 9800.
14. (a) Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthe-
sis 1998, 937; (b) Hong, Y.; Gao, Y.; Nie, X.; Zepp, C.
M. Tetrahedron Lett. 1994, 35, 6631; (c) Hett, R.;
Senanayake, C. H.; Wald, S. A. Tetrahedron Lett. 1998,
39, 1705; (d) Kaptein, B.; Elsenberg, H.; Minnaard, A. J.;
Broxterman, Q. B.; Hulshof, L. A.; Koek, J.; Vries, T. R.
Tetrahedron: Asymmetry 1999, 10, 1413; (e) Sibi, M. P.;
Cook, G. R.; Liu, P. Tetrahedron Lett. 1999, 40, 2477; (f)
Jones, S.; Atherton, J. C. C. C. Tetrahedron: Asymmetry
2000, 11, 4543.
15. (a) Simone, B. D.; Savoia, D.; Tagliavini, E.; Umani-
Ronchi, A. Tetrahedron: Asymmetry 1995, 6, 301; (b)
Sola, L.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.;
Riera, A. Tetrahedron: Asymmetry 1997, 8, 1559.
16. (a) McClure, D. E.; Arison, B. H.; Jones, J. H.; Baldwin,
J. J. J. Org. Chem. 1981, 46, 2431; (b) McClure, D. E.;
Lumma, P. K.; Arison, B. H.; Jones, J. H.; Baldwin, J. J.
J. Org. Chem. 1983, 48, 2675.
J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237; (e)
Soai, K.; Nishi, M.; Ito, Y. Chem. Lett. 1987, 2405; (f)
Itsuno, S.; Frechet, J. M. J. J. Org. Chem. 1987, 52, 4140.
6. Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. J.
Chem. Soc., Chem. Commun. 1987, 1690.
7. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J.
Am. Chem. Soc. 1986, 108, 6071; (b) Kitamura, M.;
Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028.
8. Cherng, Y.-J.; Fang, J.-M.; Lu, T.-J. J. Org. Chem. 1999,
64, 3207.
9. Smaardijk, A. A.; Wynberg, H. J. Org. Chem. 1987, 52,
135.
10. (a) Kawanami, Y.; Mitsuie, T.; Miki, M.; Sakamoto, T.;
Nishitani, K. Tetrahedron 2000, 56, 175; (b) Trentmann,
W.; Mehler, T.; Martens, J. Tetrahedron: Asymmetry
1997, 8, 2033; (c) Wilken, J.; Kossenjans, M.; Groger, H.;
Martens, J. Tetrahedron: Asymmetry 1997, 8, 2007; (d)
Dai, W. M.; Zhu, H. J.; Hao, X. J. Tetrahedron: Asym-
metry 2000, 11, 2315; (e) Vidal-Ferran, A.; Moyano, A.;
Pericas, M. A.; Riera, A. J. Org. Chem. 1997, 62, 4970.
11. (a) Xu, Q.; Wang, G.; Pan, X.; Chan, A. S. C. Tetra-
hedron: Asymmetry 2001, 12, 381; (b) Xu, Q.; Wang, H.;
Pan, X.; Chan, A. S. C.; Yang, T. K. Tetrahedron Lett.
2001, 42, 6171.
17. (a) Li, S. J.; Jiang, Y. Z.; Mi, A. Q.; Yang, G. J. Chem.
Soc., Chem. Commun. 1993, 885; (b) Ding, K. L.; Ishii,
A.; Mikami, K. Angew. Chem., Int. Ed. Engl. 1999, 38,
497.
18. Zhang, H. C.; Xue, F.; Mak, T. C. W.; Chan, K. S. J.
Org. Chem. 1996, 61, 8002.
12. Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am.
Chem. Soc. 1987, 109, 7111.