Synthesis of a C2-symmetric chiral bipyridyldiol ligand and its application in the enantioselective addition of diethylzinc to substituted benzaldehydes

Article abstract of DOI:10.1016/j.tetasy.2004.09.031

Herein the synthesis of a novel C₂-symmetric ligand comprising of a central bipyridine-pinene-derived core and two functionalized diphenylmethanol subunits is described. [8′-(Hydroxy-diphenyl-methyl)-10, 10,10′,10′-tetramethyl-[5,5′]bi[6-aza-tr

Full text of DOI:10.1016/j.tetasy.2004.09.031

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3561–3571
Synthesis of a C2-symmetric chiral bipyridyldiol ligand and
its application in the enantioselective addition of diethylzinc
to substituted benzaldehydes
Yi-Jing Chen, Rong-Xin Lin and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, ROC
Received 13 August 2004; accepted 29 September 2004
Abstract—Herein the synthesis of a novel C2-symmetric ligand comprising of a central bipyridine-pinene-derived core and two func-
tionalized diphenylmethanol subunits is described. [80-(Hydroxy-diphenyl-methyl)-10,10,100,100-tetramethyl-[5,50]bi[6-aza-tricy-
clo[7.1.1.02,7]undecyl]-2(7),3,5,20(70),30,50-hexaen-8-yl]-diphenyl-methanol 10 is a suitable catalyst for the enantioselective addition
of dialkylzinc to various aromatic aldehydes with asymmetric inductions of up to 99% ee. Importantly, the correlation of Hammett
substituent constants and enantiomeric excess, with the electron-donating group at the para-position and the electron-withdrawing
group at the meta-position of substituted benzaldehydes were demonstrated to give high enantioselectivity in alkylations using
diethylzinc.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
effective for the addition of diorganozinc reagents to
aldehydes, but the parent BINOL itself is relatively inert
to the reaction. The active catalytic species in the addi-
tion of diethylzinc to aldehydes can be assumed to be
monomeric zinc alkoxides; the cleavage of the higher
aggregates may lead to an activation of the catalyst sys-
tem.12 The addition of a chiral nitrogen activator to the
BINOLs–zinc catalyst system should be one of the most
efficient methods of activation, owing to its strong abil-
ity to coordinate the zinc cation, which facilitates the
alkyl transfer. Consequently, a monomeric zinc complex
Asymmetric catalysis of organic reactions to provide
enantiomerically enriched products is extremely impor-
tant in modern synthetic and pharmaceutical chemis-
try.1 In particular, enantioselective catalysis is one of
the most efficient processes for environmental protec-
tion. Consequently, the development of enantioselective
catalysts is one of the most important challenges in
modern organic chemistry. Extremely promising candi-
dates for such enantioselective catalysts are metal com-
plexes that bear chiral organic ligands. Among the
asymmetric catalysis of C–C bond-forming reactions,
the enantioselective addition of diorganozinc reagents
to aldehydes represents one of the most important and
fundamental asymmetric reactions.2 Since the first re-
port by Oguni and Omi,3 various chiral ligands, includ-
ing a-amino alcohols,4 BINOL,5 salen,6 TADDOL7,
pyridyl alcohol,8 and their derivatives, have been used
in this type of reaction. However, C2-symmetric binaph-
thols (BINOLs),9 have been relatively neglected, prob-
ably due to their lower catalytic activity and
enantioselectivity for the organozinc addition reaction.10
Recently, some modified BINOLs11 were reported to be
OH
OH
N
N
R
OH HO
Salen
R
R
R
BINOL
Ph
O
Ph
OH
OH
N
N
OH
O
HO
Ph
Ph
Ph
Ph Ph
TADDOL
Ph
*
Corresponding author. Tel.: +886 38633597; fax: +886 38630475;
e-mail: chinpiao@mail.ndhu.edu.tw
10
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.031

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Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
is expected to form in a similar manner to a chiral salen–
zinc complex.5j,13
produce ketone 6. Product 5 could be decarboxylated
by treatment with H2SO4 to give ketone 6. Moreover,
compound 6 was treated with iodine in pyridine to yield
pyridinium salt 7, which when reacted with enone 1 and
ammonium acetate produced bipyridine 8. Bipyridyldiol
10 was prepared by treatment of compound 8 with n-
butyllithium, and in a one-pot reaction where 2equiv
of benzophenone were added in two successive steps to
produce 9 and 10. Compound 9 was converted to 10
by treatment 9 with n-butyllithium and benzophenone.
Kishi et al.,14 von Zelewsky et al.,15 and Malkov et al.16
described the synthesis of ligand 8 and its derivatives.
According to the above reports, compound 10 is
designed to fulfill the requirements of C2-symmetric,
TADDOL-like steric hinder, salen-like, and bipyridine-
type ligand for activating diethylzinc. Herein we report
the synthesis of compound 10 and the addition of
diethylzinc to substituted benzaldehydes with the cata-
lysis of a chiral bipyridyldiol 10 in the presence of
Ti(O-i-Pr)4.
The ozonolysis of the furan group of compound 3 pro-
duced a carboxylic acid. Following esterification by
diazomethane, we obtained compound 4 along with
unexpected compound 5. To rationalize the formation
of compound 5, the reaction mechanisms shown in
Scheme 2 are proposed. A 1,3-dipolar addition of ozone
to the double bond of the furanyl group of compound 3
yields the initial ozonide. However, initial ozonide is ex-
tremely unstable and cleaves to an aldehyde and a zwit-
terion intermediate. Recombination of aldehyde and
zwitterion yields ozonide 11. Ozonide 11 then cleaves
through the intermediate 12 to yield ketene 13, which re-
acts with the contaminated moisture to produce 14, and
then treats with diazomethane to produce methyl ester
5.
2. Results and discussion
The synthesis of ligand 10 is outlined in Scheme 1. (1R)-
(+)-a-Pinene was readily photooxygenated in the pres-
ence of acetic anhydride, pyridine, DMAP, and TPP
to yield directly a,b-unsaturated ketone 1.17 Moreover,
2-acetylfuran was heated with iodine in pyridine at
100–110°C for 3h and then recrystallized from ethanol
to produce pyridinium salt 2.18 Compounds 1 and 2
were heated with ammonium acetate in glacial acetic
acid at 100–110°C overnight to yield furyl-pyridine
3.14,19 Compound 3 was oxidized by ozonolysis and
treated via diazomethane to afford esters 4 and 5 (ca.
2:1). Compound 4 is the common product of ozonolysis,
which was reduced by LiAlH4 to produce a primary
alcohol. The primary alcohol was oxidized via a Swern
oxidation to yield an aldehyde, which was then reacted
with MeMgBr to produce a secondary alcohol. The sec-
ondary alcohol was oxidized via a Swern oxidation to
The asymmetric alkylation of benzaldehyde using dieth-
ylzinc, in the presence of chiral ligand 10 and Ti(O-i-Pr)4
in various solvents (Table 1) at room temperature gave
the following enantiomeric excesses of 1-phenyl-1-pro-
panol: in toluene (91%), in tetrahydrofuran (91%), in
acetonitrile (89%), and in hexane (14%). Therefore tolu-
ene was selected as the reaction solvent in the following
a
O
1
d
c
97%ee
O
N
+
N
N
O
O
CO2Me
N+
I-
O
O
b
O
CO2Me
4
5
3
2
5
i
Ph
Ph
Ph
Ph
N
OH
N
O
N
N
OH
N
N
l
k
j
e-h
+
4
N
OH
Ph
I-
N
N+
Ph
O
10
6
7
9
8
Scheme 1. Reagents and conditions: (a) O2, TPP, DMAP, Ac2O, pyridine, CH2Cl2, Na-lamp (400W), 50%; (b) I2, pyridine, 100-110°C, 56%; (c)
NH4OAc, AcOH, 100–110°C, 84%; (d) O3, CH2Cl2–CH3OH (2:1), À78°C; CH2N2, Et2O, 0°C, 4 (42%), 5 (21%); (e) LiAlH4, THF, rt, 72%; (f)
(COCl)2, DMSO, CH2Cl2, Et3N, À78°C, 91%; (g) CH3MgI, Et2O, rt, 77%; (h) (COCl)2, DMSO, CH2Cl2, Et3N, À78°C, 100%; (i) H2SO4, AcOH,
H2O, reflux, 88%; (j) I2, pyridine, 100–110°C; (k) 1, NH4OAc, AcOH, 100–110°C, 39%; (l) n-BuLi, Et2O, 0°C to rt, benzophenone, Et2O, À78°C, 9
(82%), 10 (8%).

Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
3563
O3
CH2N2
N
O
N
O
N
N
O
N
N
O
O
O
O
O
H
O
O
O
C
O
O
MeO
O
HO
O
H2O
3
11
12
13
14
5
H
Scheme 2. The proposed mechanisms for producing product 5.
Table 1. Enantiomeric excess (ee%) of the alkylation of benzaldehyde
in the presence of Ti(IV)–10 complex in various solvents
of ligand 10 and Ti(O-i-Pr)4 in toluene was stirred at
room temperature for 10min after which a solution of
Et2Zn (1M in hexane) was added and stirred for
10min. Lastly the aldehydes were added and stirred at
room temperature for 30h. The reaction was quenched
by adding 1M HCl. After purification by flash chroma-
tography, the enantiomeric excess of the product was
determined by HPLC, with the yields, % ee and specific
rotation were shown in Table 3. The absolute configura-
tions of all products were determined by comparing the
sign of the specific rotations.22
OH
O
Et2Zn, 5 mol % 10
*
H
rt. 30 h
Entry
Solvents
Ee (%)
1
2
3
4
Toluene
THF
91
91
89
14
CH3CN
Hexane
The electronic effects in asymmetric hydroborations20
and epoxidations21 have been reported. However, there
appears to have been no systematic study of how purely
electronic effects influence the degree of asymmetric
induction. The correlation of Hammett substituent
constants and enantiomeric excesses of the alkylation
of meta-substituted benzaldehydes using diethylzinc,
was very high correlation. Importantly the stronger
electron-withdrawing substituents on the meta-position
exhibited higher enantiomeric excesses (m-NO2, >99%;
m-CN, >99%; m-Cl, 98%), while the stronger electron-
releasing substituents on the meta-position showed
lower enantiomeric excesses (m-NMe2, 7%; m-Me, 44%;
m-OMe, 83%) (Fig. 1). On the other hand, the stronger
electron-releasing substituents on the para-position
exhibited higher enantiomeric excesses (p-NMe2, 94%;
p-OMe, 91%; p-Me, 65%), while the stronger electron-
withdrawing substituents on the para-position displayed
lower enantiomeric excesses (p-Cl, 7%; p-CN, 11%; p-
NO2, 47%) (Fig. 2). Moreover, the stronger electron-
withdrawing and electron-releasing substituents on the
ortho-position displayed lower enantiomeric excesses
(o-NO2, 3%; o-OMe, 6%), while the weaker electron-
withdrawing and electron-releasing substituents on the
ortho-position showed higher enantiomeric excesses
(o-Cl, 92%; o-Me, >99%) (Fig. 3).
reactions. The same reactions were conducted in toluene
at various temperatures (Table 2), enantiomeric excesses
of 1-phenyl-1-propanol: 0°C (91%), 20°C (91%), 40°C
(59%), 60°C (33%), and 80°C (6%). Therefore the fol-
lowing asymmetric reactions were performed in toluene
at room temperature. The asymmetric alkylation of
benzaldehyde using diethylzinc in toluene was per-
formed in the absence of Ti(O-i-Pr)4, and the reaction
remained incomplete even under stirring at room tem-
perature for three days. This phenomenon showed the
binaphthols (BINOLs)5 with low catalytic activity for
the organozinc addition reaction, although the reactivity
could be improved by the addition of a nitrogen activa-
tor to the BINOLs–zinc catalyst system.5j Chiral ligand
10 integrated the diol and bipyridyl moieties, with the
former performed as a BINOL-like system while the
bipyridyl group performed as a nitrogen activator.
Table 2. Enantiomeric excess (ee%) of the alkylation of benzaldehyde
in the presence of Ti(IV)–10 complex at various temperatures
OH
O
Et2Zn, 5 mol % 10
*
H
toluene, 30 h
Entry
Temp (°C)
Ee (%)
1
2
3
4
5
0
20
40
60
80
91
91
59
33
6
3. Conclusion
In conclusion we have developed a novel chiral bipyridi-
nyldiol 10. This compound was prepared from highly
enantiopure (>97% ee) (1R)-(+)-a-pinene. Bipyridinyl-
diol 10 can act as an interesting chiral catalyst in the
enantioselective addition of diethylzinc to various sub-
stituted benzaldehydes, providing alcohols of (S)-config-
uration with enantiomeric excesses generally ranging
The asymmetric alkylation of substituted benzaldehyde
using diethylzinc was performed in the presence of cata-
lyst Ti(IV)–10 complex as described below. A solution

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Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
Table 3. The Hammett substituent constants (ro, rm, and rp) and enantiomeric excess (ee%) of the alkylation of substituted benzaldehydes with
Ti(IV)–10 complex
OH
O
1.5 eq Ti(O-i-Pr)4,
5 mol % chiral ligand 10
*
H
+
Et2Zn
R
R
rt. 30 h
18
½aŠ (c, CHCl3)
Entry
R
Yieldb (%)
Ee (%)
Substituent constants22a
Configuration
D
1
o-OMe
m-OMe
p-OMe
o-Me
79
75
70
72
78
82
85
96
54
13
21
24
32
28
41
94
67
6
ro, +0.12
rm, +0.12
rp, À0.27
ro, +0.29
rm, À0.07
rp, À0.17
ro, +1.28
rm, +0.37
rp, +0.23
ro, +1.99
rm, +0.71
rp, +0.78
rm, À0.21
rp, À0.83
rm, +0.56
rp, +0.66
r, 0
À1.0 (2.12)
À19.5 (1.10)
À31.5 (2.10)
À62.4 (1.41)
À12.1 (2.43)
À27.3 (1.41)
À50.2 (2.10)
À28.4 (3.74)
À2.7 (1.19)
À5.45 (0.65)
À28.3 (1.35)
À15.2 (1.52)
À5.6 (2.31)
À24.6 (3.37)
À41.7 (4.13)
À6.2 (1.15)
S22d
2
83
91
N/Aa
S22b
3
4
>99
S22c
5
m-Me
p-Me
o-Cl
44
65
92
98
7
N/Aa
S22c
6
7
S22c
8
m-Cl
p-Cl
S22c
9
S22b
10
11
12
13
14
15
16
17
o-NO2
m-NO2
p-NO2
m-NMe2
p-NMe2
m-CN
p-CN
H
3
N/Aa
N/Aa
N/Aa
N/Aa
N/Aa
N/Aa
N/Aa
N/Aa
>99
47
7
94
>99
11
91
a The configurations were not determined.
b The yields were obtained using 1mmol of substituted benzaldehydes and weighted after purified by flash chromatography.
m-CN
m-NO
2
m-Cl
110
90
100
80
60
40
20
0
o-CH3
m-OCH3
o-Cl
70
50
m-CH3
30
10
o-OCH3
o-NO2
m-NMe2
-0.4 -0.2
-10
-0.25
0
0.2
σm
0.4
0.6
0.8
0.25
0.75
1.25
1.75
2.25
σo
Figure 1. The correlation of substituent constants (rm) and the
enantiomeric excesses of the alkylation of meta-substituted benzalde-
hydes in the presence of Ti(IV)–10 complex.
Figure 3. The correlation of substituent constants (ro) and the
enantiomeric excesses of the alkylation of ortho-substituted benzalde-
hydes in the presence of Ti(IV)–10 complex.
90
weaker electron-withdrawing and electron-releasing at
the ortho-position of substituted benzaldehydes showed
higher enantioselectivity. An investigation is currently
underway exploring other asymmetric reactions to
rationalize this correlation.
p-NMe2
p-OCH3
p-CH3
70
50
p-NO2
30
10
p-CN
p-Cl
0
-10
-1
-0.5
0.5
1
4. Experimental
4.1. General
σp
Figure 2. The correlation of substituent constants (rp) and the
enantiomeric excesses of the alkylation of para-substituted benzalde-
hydes in the presence of Ti(IV)–10 complex.
All reactions were carried out in anhydrous solvents.
THF and diethyl ether were distilled from sodium–ben-
zophenone under argon. Toluene, CH3CN, CH2Cl2, and
hexane were distilled from CaH2. 1H NMR spectra were
acquired at 300 or 500MHz (indicated in each case), and
13C NMR were acquired at 75.5MHz on a Bruker
NMR spectrometer. Chemical shifts (d) are reported in
ppm relative to CDCl3 (7.26 and 77.0ppm). Mass spec-
tra (MS) were determined on a Micromass Platform II
from 3–99%. Importantly, the electron-releasing substit-
uents at the para-position of the substituted benzalde-
hydes gave high enantioselectivity during alkylation
using diethylzinc. Additionally, electron-withdrawing
substituents at the meta-position of substituted benz-
aldehydes gave high enantioselectivity. Moreover, the

Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
3565
mass spectrometer at a 70eV. High resolution mass
spectra (HRMS) were determined on a Finnigan/Ther-
mo Quest MAT 95XL mass spectrometer. Infrared spec-
tra were recorded on an ATI Mattson spectrometer. All
asymmetric reactions were carried out in dry glassware
under nitrogen using a standard glovebox. Enantiomeric
excesses were determined on a Lab Alliance Series III
high performance liquid chromatography (HPLC) with
Chiracel OD-H chiral column (Daicel Chemical Indus-
tries, LTD). Optical rotations were measured on a JAS-
CO P-1010 polarimeter at the indicated temperature
with a sodium lamp (D line, 589nm). Flash column
chromatography was performed using MN silica gel 60
(70–230mesh) purchased from Macherey-Nagel. Et2Zn
(1M) solution in hexane was purchased from Sigma–
Aldrich Co.
phere was heated at 100–110°C for 10h. After cooling
to room temperature, the reaction mixture was trans-
ferred to a 1-L Erlenmeyer flask. Ethyl acetate
(200mL) and water (200mL) were added, and the mix-
ture basified by sodium carbonate until the aqueous
solution became basic. The aqueous solution was ex-
tracted with ethyl acetate five times, and the combined
extracts dried over anhydrous magnesium sulfate. After
filtering and concentration, the resulting residue was
purified by flash column chromatography using silica
gel as the stationary phase and using ethyl acetate–hex-
ane (1:19) as the mobile phase to produce compound 3
16
(8.7g, 36.2mmol). Yield: 84%. ½aŠ ¼ þ88:6 (c 1.43,
D
CH2Cl2). 1H NMR (300MHz, CDCl3, d): 7.50 (d,
J = 1.7Hz, 1H), 7.36 (d, J = 7.7Hz, 1H), 7.20 (d,
J = 7.7Hz, 1H), 6.90 (d, J = 3.3Hz, 1H), 6.50 (d,
J = 3.3Hz, 1H), 3.15 (d, J = 2.8Hz, 2H), 2.70 (m, 2H),
2.30 (m, 1H), 1.40 (s, 3H), 1.29 (d, J = 9.4Hz, 1H),
0.67 (s, 3H). 13C NMR (75.5MHz, CDCl3, d): 156.9,
154.0, 146.8, 142.7, 140.5, 134.7, 115.5, 111.7, 107.2,
46.4, 40.2, 39.5, 36.7, 31.9, 26.0, 21.3. IR (neat): 3116,
2918, 1606, 1587, 1493, 737, 596cmÀ1. MS m/z (% rela-
tive intensity): 239 (M+, 75), 224 (53), 196 (100), 167
(30). HRMS-EI (m/z): [M]+ calcd for C16H17NO,
239.1310; found, 239.1304.
4.2. Synthesis of bipyridyldiol 10
4.2.1. (2S,5S)-6,6-Dimethyl-2-methylene-bicyclo[3.1.1]-
heptan-3-one 1. To a solution of (2R,5R)-2,6,6-tri-
methyl-bicyclo[3.1.1]hept-2-ene (31.0mL, 183mmol),
acetic anhydride (17.9mL, 190mmol), pyridine
(7.4mL, 92mmol), DMAP (457mg, 3.7mmol), and
TPP (13mg, 21lmol) in dichloromethane (169mL)
was passed through oxygen gas and irradiated with a so-
dium lamp (400W) under a À78°C dry ice condenser.
The reaction was traced by TLC until the (2R,5R)-
2,6,6-trimethyl-bicyclo[3.1.1]hept-2-ene was completely
consumed. The reaction solution was washed with satu-
rated sodium bicarbonate solution, 1M hydrochloric
acid, aqueous solution of copper sulfate, and brine.
The organic phase then was dried over anhydrous mag-
nesium sulfate, and after filtration and concentration the
resulting brown solution was distilled at 75–78°C
(3mmHg) to produce compound 1 (13.7g, 92mmol).
4.2.4. (1S,9S)-10,10-Dimethyl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-triene-5-carboxylic acid methyl ester
4. A solution of compound 3 (8.4g, 35.2mmol) in
methanol–dichloromethane (120:240mL) was passed
through the ozone at À78°C, and the reaction traced
by TLC until compound 3 disappeared. Argon was
passed through the reaction solution another 2min.
The solvent was removed using a rotary evaporator to
give a brown residue, at which point the minimum
amount of methanol was used to dissolve the residue.
Sufficient diazomethane in ether was added to the result-
ing brown solution until nitrogen bubbling stopped.
After concentration to produce a brown residue, the
residue was purified by flash column chromatography
using silica gel as a stationary phase and using ethyl
acetate–hexane (1:9, 1:5, 1:1) as the mobile phase. After
concentration, compound 4 (3.4g, 14.7mmol) yield 42%,
16
D
1
Yield: 50%. ½aŠ ¼ À69:9 (c 1.11, CH2Cl2). H NMR
(300MHz, CDCl3, d): 5.97 (d, J = 1.6Hz, 1H), 5.0 (d,
J = 1.6Hz, 1H), 2.78–2.55 (m, 4H), 2.21–2.19 (m, 1H),
1.36 (s, 3H), 1.31–1.28 (d, J = 10.2Hz, 1H), 0.81 (s,
3H). 13C NMR (75.5MHz, CDCl3, d): 149.1, 117.4,
48.2, 42.5, 40.8, 38.5, 32.4, 30.9, 26.0, 21.5. IR (dry film):
2929, 1706, 1625cmÀ1. MS m/z (% relative intensity):
151 (M+1, 89), 150 (M+, 49), 135 (57), 107 (100).
HRMS-EI m/z: [M]+ calcd for C10H14O, 150.1044;
found, 150.1051.
and compound 5 (2.0g, 7.4mmol) yield 21% were pro-
16
duced. Compound 4: ½aŠ ¼ þ71:0 (c 1.39, CH2Cl2).
D
1H NMR (300MHz, CDCl3, d): 7.88 (d, J = 7.6Hz,
1H), 7.34 (d, J = 7.7Hz, 1H), 3.99 (s, 3H), 3.22 (d,
J = 2.8Hz, 2H), 2.86 (m, 2H), 2.40 (m, 1H), 1.41
(s, 3H), 1.28 (d, J = 9.7Hz, 1H), 0.63 (s, 3H). 13C
NMR (125.7MHz, CDCl3, d): 165.7, 157.2, 146.1,
144.7, 133.2, 122.3, 52.4, 46.3, 39.6, 39.0, 36.3, 31.1,
25.5, 20.9. IR (neat): 3613, 3461, 3421, 2925, 1737,
1720, 1575, 1427cmÀ1. MS m/z (% relative intensity):
231 (M+, 38), 188 (63), 156 (74), 128 (100). HRMS-EI
(m/z): [M]+ calcd for C14H17NO2, 231.1259; found,
231.1252.
4.2.2. 1-(2-Furan-2-yl-2-oxo-ethyl)-pyridinium; iodide
2. To a solution of 2-acetylfuran (10.0mL, 100mmol)
in pyridine (25.0mL) was added a solution of iodine
(25.4g, 100mmol) in pyridine (75.0mL), and the result-
ing solution heated at 100–110°C for 3h. The reaction
solution was left to stand overnight, filtered, washed
with ethanol, and then recrystallized twice in ethanol.
The crystal was dried under vacuum to yield compound
2 (17.7g, 56.3mmol). Yield: 56%.
4.2.3. (1S,9S)-5-Furan-2-yl-10,10-dimethyl-6-aza-tricy-
clo[7.1.1.02,7]undeca-2(7),3,5-triene 3. A mixture of
compound 1 (6.5g, 43.3mmol), compound 2 (17.7g,
56.3mmol), and ammonium acetate (26.7g, 346mmol)
in glacial acetic acid (60.0mL) under an argon atmos-
4.2.5. 3-((1S,9S)-10,10-Dimethyl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-trien-5-yl)-3-oxo-propionic acid methyl
16
ester 5. ½aŠ ¼ þ77:1 (c 1.48, CH2Cl2). 1H NMR
D
(300MHz, CDCl3, d): 7.81 (d, J = 7.7Hz, 1H), 7.34 (d,
J = 7.7Hz, 1H), 4.21 (d, J = 3.8Hz, 2H), 3.74 (s, 3H),

3566
Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
3.11 (d, J = 2.8Hz, 2H), 2.85 (m, 2H), 2.40 (m, 1H), 1.42
(s, 3H), 1.28 (d, J = 9.7Hz, 1H), 0.67 (s, 3H). 13C NMR
(125.7MHz, CDCl3, d): 194.4, 169.0, 156.5, 149.8, 147.1,
133.5, 119.5, 52.1, 46.7, 44.6, 39.8, 39.4, 36.3, 31.4, 25.8,
21.2. IR (neat): 3376, 2971, 2937, 2873, 2103, 1749,
1698, 1569cmÀ1. MS m/z (% relative intensity): 273
(M+, 90), 242 (40), 198 (74), 128 (100). HRMS-EI
(m/z): [M]+ calcd for C16H19NO3, 273.1364; found,
273.1356.
192.9, 157.7, 150.4, 147.6, 133.5, 119.6, 46.7, 39.7,
39.3, 36.1, 31.3, 25.7, 21.1. IR (thin film): 2967, 2932,
2807, 2682, 1708, 1574cmÀ1. MS m/z (% relative inten-
sity): 201 (M+, 24), 200 (27), 158 (100), 130 (26).
HRMS-EI (m/z): [M]+ calcd for C13H15NO, 201.1153;
found, 201.1145. The iodomethane (2.0mL, 21.7mmol)
was added to a suspension of magnesium (473mg,
19.7mmol) in sodium dried diethyl ether (50mL), and
refluxed for 5h. Freshly prepared methylmagnesium
iodide was added to a solution of (1S,9S)-10,10-dimeth-
yl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene-5-carb-
aldehyde (1.8g, 9.0mmol) in diethyl ether (50mL), and
stirred at room temperature under an argon atmosphere
for 1.5h. A saturated aqueous solution of ammonium
chloride then was added to the reaction solution, and
the organic phase separated. The aqueous solution was
extracted three times using diethyl ether, and the com-
bined organic phase dried over anhydrous magnesium
sulfate. After filtering and concentration, the residue
was purified by flash column chromatography using sil-
ica gel as the stationary phase and using ethyl acetate–
hexane (1:9, 1:5) as the mobile phase, thus producing a
diastereoisomers mixture of secondary alcohol 1-
((1S,9S)-10,10-dimethyl-6-aza-tricyclo[7.1.1.02,7]undeca-
4.2.6. 1-((1S,9S)-10,10-Dimethyl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-trien-5-yl)-ethanone 6. A solution of
compound 4 (3.2g, 13.7mmol) in THF (25mL) was
added to a mixture of lithium aluminum hydride
(623mg, 16.4mmol) in tetrahydrofuran (30mL) at room
temperature under an argon atmosphere. After stirring
at room temperature for 30min, the reaction was
quenched by adding water. The reaction mixture was fil-
tered through Celite and washed with tetrahydrofuran,
and the combined organic solution dried over anhy-
drous magnesium sulfate. After filtering and concentra-
tion, the resulting residue was purified by flash column
chromatography using silica gel as the stationary phase,
and the use of ethyl acetate–hexane (1:10, 2:5) as the
mobile phase produced a primary alcohol (1S,9S)-
(10,10-dimethyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-
2(7),3,5-trien-5-yl)-ethanol (1.5g, 7mmol). Yield: 77%.
16
D
½aŠ ¼ þ63:7 (c 0.9, CH2Cl2). 1H NMR (300MHz,
trien-5-yl)-methanol (2.0g, 9.9mmol). Yield: 72%.
CDCl3, d): 7.20 (d, J = 7.6Hz, 1H), 7.94 (m, 1H), 4.84
(m, 1H), 4.43 (m, 1H), 3.08 (d, J = 2.7Hz, 2H), 2.75
(m, 2H), 2.36 (m, 1H), 1.50 (m, 3H), 1.40 (s, 3H), 1.29
(m, 1H), 0.63 (s, 3H). 13C NMR (75.5MHz, CDCl3,
d): 159.3, 154.8, 140.9, 134.7, 116.6, 68.2, 46.0, 39.9,
39.4, 35.6, 31.8, 25.9, 23.9, 21.2. IR (neat): 3257, 2971,
2919, 2719, 1926, 1589, 1463, 1419, 1105cmÀ1. MS m/z
(% relative intensity): 217 (M+, 100), 202 (66), 174
(75), 156 (95). HRMS-EI (m/z): [M]+ calcd for
C14H19NO, 217.1466; found, 217.1458. DMSO
(1.0mL, 14.1mmol) was added dropwise to a solution
of oxalyl chloride (705L, 8.4mmol) in dichloromethane
(35mL) at À78°C under an argon atmosphere. After
stirring for 20min, a solution of 1-((1S,9S)-10,10-di-
methyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-5-
yl)-ethanol (1.5g, 7mmol) in dichloromethane (20mL)
was added. The reaction was then stirred for 40min,
and triethylamine (4.8mL, 34.4mmol) added. The reac-
tion solution was warmed to room temperature, and
stirred for 30min before adding water. The resulting
solution was extracted with dichloromethane thrice,
and the combined extracts dried over anhydrous magne-
sium sulfate. After filtering and concentration, the resi-
due was purified by flash column chromatography
using silica gel as the stationary phase and ethyl ace-
16
D
½aŠ ¼ þ65:3 (c 0.95, CH2Cl2). 1H NMR (300MHz,
CDCl3, d): 7.20 (d, J = 7.5Hz, 1H), 7.93 (d, J = 7.5Hz,
1H), 4.70 (s, 2H), 3.64 (s, 1H), 3.09 (d, J =
2.8Hz, 2H), 2.77 (m, 2H), 2.39 (m, 1H), 1.40 (s, 3H),
1.27 (d, J = 9.4Hz, 1H), 0.63 (s, 3H). 13C NMR
(125.7MHz, CDCl3, d): 155.3, 155.2, 141.3, 134.9,
118.0, 63.5, 46.0, 39.8, 39.4, 35.4, 31.8, 25.8, 21.1. IR
(neat): 3224, 2927, 2832, 1585, 1467, 1423, 1076,
1074cmÀ1. MS m/z (% relative intensity): 203 (M+,
80), 160 (100), 142 (99), 130 (76). HRMS-EI (m/z):
[M]+ calcd for C13H17NO, 203.1310; found, 203.1305.
DMSO (1.4mL, 19.7mmol) was added dropwise to a
solution of oxalyl chloride (988lL, 11.8mmol) in
dichloromethane (50mL) at À78°C under an argon
atmosphere. After stirring for 20min, a solution of
(1S,9S)-(10,10-dimethyl-6-aza-tricyclo[7.1.1.02,7]undeca-
2(7),3,5-trien-5-yl)-methanol (2.0g, 9.9mmol) in dichlo-
romethane (20mL) added. The reaction solution was
then stirred for 40min, and triethylamine (6.75mL,
48.4mmol) was added. Subsequently, the reaction solu-
tion was warmed to room temperature, stirred at
room temperature for 30min, and then water added.
The resulting solution was extracted three times with
dichloromethane, and the combined extracts dried over
anhydrous magnesium sulfate. After filtering and con-
centration, the residue was purified by flash column
chromatography using silica gel as the stationary phase
and using ethyl acetate–hexane (1:9) as the mobile phase
to produce an aldehyde, (1S,9S)-10,10-dimethyl-6-aza-
tate–hexane (1:9) as the mobile phase to produce com-
16
D
pound 6 (1.5g, 7mmol). Yield: 100%. ½aŠ ¼ þ73:0 (c
1
1.4, CH2Cl2). H NMR (300MHz, CDCl3, d): 7.77 (d,
J = 7.6Hz, 1H), 7.32 (d, J = 7.7Hz, 1H), 3.15 (d,
J = 2.8Hz, 2H), 2.85 (m, 5H), 2.40 (m, 1H), 1.42
(s, 3H), 1.29 (d, J = 9.6Hz, 1H), 0.64 (s, 3H). 13C
NMR (125.7MHz, CDCl3, d): 199.7, 156.3, 150.9,
146.4, 133.5, 119.1, 46.6, 39.8, 39.3, 36.3, 31.4, 25.9,
25.8, 21.1. IR (neat): 3367, 2927, 1695, 1571cmÀ1. MS
m/z (% relative intensity): 215 (M+, 46), 200 (43), 172
(100), 130 (23). HRMS-EI (m/z): [M]+ calcd for
C14H17NO, 215.1310; found, 215.1312.
tricyclo[7.1.1.02,7]undeca-2(7),3,5-triene-5-carbaldehyde
16
D
(1.8g, 9mmol). Yield: 91%. ½aŠ ¼ þ73:0 (c 1.4,
1
CH2Cl2). H NMR (300MHz, CDCl3, d): 10.0 (s, 1H),
7.77 (d, J = 7.6Hz, 1H), 7.38 (d, J = 7.6Hz, 1H), 3.21
(d, J = 2.8Hz, 2H), 2.89 (t, J = 5.6Hz, 1H), 2.75 (m,
1H), 2.44 (m, 1H), 1.43 (s, 3H), 1.31 (d, J = 9.7Hz,
1H), 0.65 (s, 3H). 13C NMR (125.7MHz, CDCl3, d):

Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
3567
4.2.7. 1-((1S,9S)-10,10-Dimethyl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-trien-5-yl)-ethanone 6. A solution of
compound 5 (1.9g, 6.8mmol) in concd sulfuric acid
(1mL), glacial acetic acid (10mL), and water (3mL)
was refluxed for 13h. The reaction solution was cooled
in an ice bath and basified by adding 2M sodium
hydroxide aqueous solution until the solution became
basic. The resultant solution was extracted three times
with diethyl ether, and the combined extracts dried over
anhydrous magnesium sulfate. After filtering and con-
centration, the residue was purified by flash column
chromatography using silica gel as the stationary phase
and ethyl acetate–hexane (1:19) as the mobile phase to
produce compound 6 (1.3g, 6.0mmol). Yield: 88%.
which the reaction temperature was raised to room
temperature, and the solution stirred for 30min. The
solution then turned a yellowish green color. n-
Butyllithium (1.67mL, 2.7mmol, 1.6M in hexane) was
then added to this solution and stirred at room temper-
ature for 30min until it turned a darkish blue. A solu-
tion of benzophenone (486mg, 2.7mmol) in diethyl
ether (10mL) was added at À78°C, and the reaction
temperature was raised to room temperature, and stirred
for 3h until the solution turned orange. The reaction
was quenched by adding water. The reaction mixture
was then extracted three times with diethyl ether. The
combined extracts then were dried over anhydrous mag-
nesium sulfate. After filtering and concentration, the res-
idue was purified by flash column chromatography
using silica gel as the stationary phase and ethyl ace-
tate–hexane (1:49, 1:19) as the mobile phase, thus pro-
ducing compound 9 (1.15g, 2.2mmol) yield 82%, and
4.2.8. (1S,9S,10S,90S)-10,10,100,100-Tetramethyl-[5,50]bi[6-
aza-tricyclo[7.1.1.02,7]undecyl]-2(7),3,5,20,40,60-hexane 8.
A solution of iodine (4.95g, 19.5mmol) in pyridine
(15mL) was added to a solution of compound 6
(2.75g, 12.8mmol) in pyridine (4.0mL), and the result-
ing solution heated at 100–110°C for 16h, after which
iodine (1.00g, 3.95mmol) was added and the solution
stirred for 3h. The reaction solution was stored at
À20°C for 4h, after which the solvent was removed,
and the remaining solid dried under vacuum to produce
compound 7, which was not further purified before the
next reaction. A mixture of compound 1 (2.82g,
18.8mmol), compound 7 (11.69g, 27.8mmol), and
ammonium acetate (11.59g, 150.4mmol) in glacial acetic
acid (25mL) under an argon atmosphere was heated at
100–110°C for 15h. After cooling to room temperature,
the reaction mixture was transferred to a 500-mL
Erlenmeyer flask, at which point water (100mL) was
added, and the mixture basified by sodium carbonate
until it became basic. The aqueous solution was ex-
tracted three times with ethyl acetate and the combined
extracts dried over anhydrous magnesium sulfate. After
filtering and concentration, the resulting residue was
purified by flash column chromatography using silica
gel as the stationary phase and ethyl acetate–hexane
compound 10 (153mg, 216lmol) yield 8%. Compound
16
D
10: ½aŠ ¼ À427:5 (c 0.32, CH2Cl2). 1H NMR
(300MHz, CDCl3, d): 9.65 (s, 1H), 7.99 (d, J = 7.8Hz,
2H), 7.37–7.1 (m, 22H), 4.47 (s, 2H), 2.61 (d,
J = 5.4Hz, 4H), 2.13 (m, 2H), 1.41 (s, 6H), 1.28 (d,
J = 8.9Hz, 2H), 0.88 (s, 6H). 13C NMR (75.4MHz,
CDCl3, d): 156.9, 150.6, 147.0, 145.8, 144.2, 135.1,
128.2, 128.1, 127.8, 127.2, 118.3, 81.9, 60.4, 48.0, 45.8,
42.9, 41.5, 29.7, 28.8, 26.3, 21.2, 21.1, 14.2. IR (KBr):
3451, 2954, 2927, 2864, 1943, 1446, 1423, 699cmÀ1
.
MS m/z (% relative intensity): 708 (M+, 0.04), 526 (4),
344 (51), 329 (16), 301 (15). HRMS-EI (m/z): [M]+ calcd
for C50H48N2O2, 708.3715; found, 708.3730. Anal.
Calcd for C50H48N2O2: C, 84.71; H, 6.82; N, 3.95.
Found: C, 83.71; H, 6.62; N, 3.79.
4.2.10. (1S,8R,9S,10S,90S)-Diphenyl-(10,10,100,100-tetra-
methyl-[5,50]bi[6-aza-tricyclo[7.1.1.02,7]undecyl]-2(7),3,5,
16
20,40,60-hexaen-8-yl)-methanol 9. ½aŠ ¼ À235:3 (c
D
0.7, CH2Cl2). 1H NMR (300MHz, CDCl3, d): 10.23
(d, J = 12.0Hz, 1H), 8.19 (d, J = 7.5Hz, 1H), 8.00 (d,
J = 7.8Hz, 1H), 7.4–6.0 (m, 12H), 4.44 (s, 1H), 3.19
(d, J = 2.4Hz, 2H), 2.82–2.35 (m, 4H), 2.61 (m, 1H),
2.04 (m, 1H), 1.44 (s, 3H), 1.39 (s, 3H), 1.32 (m, 2H),
0.87 (s, 1H), 0.73 (s, 1H). 13C NMR (125.7MHz, CDCl3,
d): 156.6, 156.3, 151.8, 146.9, 145.9, 145.8, 143.8, 142.6,
134.8, 129.0, 128.1, 127.8, 127.0, 126.4, 125.2, 118.6,
117.8, 47.7, 46.3, 45.7, 42.9, 41.4, 40.0, 39.5, 36.4, 31.8,
30.9, 29.6, 28.6, 26.3, 25.9, 21.4, 21.2, 21.1. IR (KBr):
3205, 2976, 2944, 1732, 1463, 1446, 1419, 772,
701cmÀ1. MS m/z (% relative intensity): 526 (M+, 15),
508 (44), 344 (100), 329 (41), 301 (27). HRMS-EI
(m/z): [M]+ calcd for C37H38N2O, 526.2984; found,
526.2992.
(1:19, 1:9) as the mobile phase to produce compound 8
16
(1.94g, 5.7mmol). Yield: 39%. ½aŠ ¼ þ123:7 (c 0.5,
D
CH2Cl2). 1H NMR (300MHz, CDCl3, d): 8.00 (d,
J = 7.7Hz, 2H), 7.30 (d, J = 7.7Hz, 2H), 3.18 (d,
J = 2.6Hz, 4H), 2.81 (m, 4H), 2.40 (m, 2H), 1.41 (s,
6H), 1.31 (m, 2H), 0.67 (s, 6H). 13C NMR (75.5MHz,
CDCl3, d): 156.2, 152.6, 142.3, 143.4, 118.5, 46.3, 40.0,
39.4, 36.3, 31.8, 25.9, 21.2. IR (neat): 2918, 2357, 2331,
1557, 1432, 1419cmÀ1. MS m/z (% relative intensity):
344 (M+, 100), 329 (27), 301 (24), 257 (15). HRMS-EI
(m/z): [M]+ calcd for C24H28N2, 344.2252; found,
344.2250.
4.2.9.
(1S,8R,9S,10S,80R,90S)-[80-(Hydroxy-diphenyl-
4.3. Typical procedure for the enantioselective addition
of diethylzinc to aldehydes catalyzed by the complex
of Ti–ligand 10
methyl)-10,10,100,100-tetramethyl-[5,50]bi[6-aza-tricyclo-
[7.1.1.02,7]undecyl]-2(7),3,5,20,40,60-hexaen-8-yl]-diphen-
yl-methanol 10. n-Butyllithium (1.67mL, 2.7mmol,
1.6M in hexane) was added to a solution of compound
8 (920mg, 2.7mmol) in diethyl ether (15mL), and stirred
at 0°C for 30min to give a solution, which turned a
darkish blue. After further stirring at room temperature
for 1h, a solution of benzophenone (486mg, 2.7mmol)
in diethyl ether (10mL) was added at À78°C, after
Ti(O-i-Pr)4 (22lL, 75lmol) was added to a solution of
ligand 10 (1.8mg, 2.5lmol) in toluene (1mL) and stirred
at room temperature for 10min; then a solution of
Et2Zn (75lL, 1M in hexane) was added and stirred
for 10min, after which aldehydes (0.05mmol) were
added and stirred at room temperature for 30h. The

3568
Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
reaction was quenched by adding 1M HCl (0.5mL), and
the reaction mixture extracted three times with diethyl
ether. The combined extracts were then dried over anhy-
drous magnesium sulfate. After filtering and concentra-
tion, the residue was purified by flash column
chromatography using silica gel as the stationary phase
and ethyl acetate–hexane (1:19) as the mobile phase,
thus producing products. The enantiomeric excess of
the products were determined by HPLC (Chiralcel
OD-H column, flow rate 0.25mL/min, and KR100-
5CHI-DMB column, flow rate 0.5mL/min, 10% 2-pro-
panol in hexane, 254nm UV detector). The data are
shown in Table 3. The yields were obtained using
1mmol of substituted benzaldehydes and weighted after
being purified by flash chromatography.
7.45 (d, J = 7.2Hz, 1H), 7.23–7.14 (m, 3H), 4.89–4.85
(m, 1H), 2.34 (s, 3H), 1.81–1.72 (m, 3H), 1.01–0.96 (t,
J = 7.4Hz, 3H). 13C NMR (125.7MHz, CDCl3, d):
142.6, 134.5, 130.2, 127.0, 126.1, 125.1, 71.9, 30.8,
19.0, 10.2. IR (KBr): 3367, 2963, 2931, 2873, 1458,
970, 750, 727cmÀ1. MS m/z: 150 (M+, 7), 121 (100), 93
(45), 77 (24). HRMS-EI (m/z): [M]+ calcd for
C10H14O, 150.1044; found, 150.1051.
16
D
4.3.6. 1-m-Tolyl-propan-1-ol. Yield: 78%. ½aŠ ¼ À12:1
1
(c 2.43, CHCl3). H NMR (300MHz, CDCl3, d): 7.24–
7.08 (m, 4H), 4.59–4.54 (m, 1H), 2.36 (s, 3H), 2.04–
1.72 (m, 3H), 0.94–0.90 (t, J = 7.4Hz, 3H). 13C NMR
(125.7MHz, CDCl3, d): 144.5, 138.0, 128.2, 126.6,
123.0, 76.0, 31.7, 21.4, 10.1. IR (KBr): 3358, 2963,
2929, 2873, 1612, 1455, 785, 702cmÀ1. MS m/z: 150
(M+, 10), 121 (100), 93 (62), 77 (61). HRMS-EI (m/z):
[M]+ calcd for C10H14O, 150.1044; found, 150.1042.
16
D
4.3.1. 1-Phenyl-propan-1-ol. Yield: 67%. ½aŠ ¼ À40:7
1
(c 1.95, CHCl3). H NMR (300MHz, CDCl3, d): 7.38–
7.34 (m, 4H), 4.63–4.57 (m, 1H), 1.83–1.73 (m, 3H),
0.92 (t, J = 7.4Hz, 3H). 13C NMR (125.7MHz, CDCl3,
d): 144.5, 128.2, 127.3, 125.9, 75.8, 31.7, 10.0. IR (KBr):
3354, 3083, 3061, 3029, 2927, 2874, 1490, 1450, 760, 742,
698cmÀ1. MS m/z: 134 (M+, 9), 107 (100), 79 (51), 69
(12). HRMS-EI (m/z): [M]+ calcd for C9H12O,
136.0888; found, 136.0884.
16
D
4.3.7. 1-p-Tolyl-propan-1-ol. Yield: 82%. ½aŠ ¼ À27:3
1
(c 1.41, CHCl3). H NMR (300MHz, CDCl3, d): 7.25–
7.22 (d, J = 8.1Hz, 2H), 7.17–7.14 (d, J = 7.9Hz, 2H),
4.59–4.54 (m, 1H), 2.55 (s, 3H), 1.87–1.71 (m, 3H),
0.93–0.88 (t, J = 7.4Hz, 3H). 13C NMR (125.7MHz,
CDCl3, d): 141.5, 137.1, 129.0, 125.9, 75.8, 31.7, 21.0,
10.1. IR (KBr): 3362, 2963, 2927, 2873, 1509, 1455,
815, 539cmÀ1. MS m/z: 150 (M+, 9), 121 (100), 93
(35), 77 (23). HRMS-EI (m/z): [M]+ calcd for
C10H14O, 150.1044; found, 150.1039.
4.3.2. 1-(2-Methoxy-phenyl)-propan-1-ol. Yield: 79%.
16
D
½aŠ ¼ À1:0 (c 2.12, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.31–7.21 (m, 2H), 6.98–6.87 (m, 2H),
4.81–4.75 (m, 1H), 3.85 (s, 3H), 2.53 (d, J = 6.3Hz,
1H), 1.87–1.77 (m, 2H), 0.95 (t, J = 7.3Hz, 3H). 13C
NMR (125.7MHz, CDCl3, d): 156.4, 132.2, 128.0,
126.9, 120.5, 110.3, 72.1, 55.1, 30.0, 10.3. IR (KBr):
3389, 2963, 2931, 1598, 1580, 1490, 1458, 1238, 1091,
754cmÀ1. MS m/z: 166 (M+, 4), 137 (100), 121 (9), 107
(35), 77 (10). HRMS-EI (m/z): [M]+ calcd for
C10H14O2, 166.0993; found, 166.0991.
4.3.8. 1-(2-Chloro-phenyl)-propan-1-ol. Yield: 85%.
16
D
½aŠ ¼ À50:2 (c 2.10, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.56–7.53 (d, J = 7.6Hz, 1H), 7.34–7.19 (m,
3H), 5.10–5.04 (m, 1H), 1.92–1.90 (d, J = 3.8Hz, 1H),
1.84–1.74 (m, 2H), 1.02–0.97 (t, J = 7.4Hz, 3H). 13C
NMR (125.7MHz, CDCl3, d): 141.9, 131.8, 129.2,
128.2, 127.0, 126.9, 71.7, 30.3, 9.9. IR (KBr): 3353,
3066, 2963, 2927, 1463, 1095, 754cmÀ1. MS m/z: 170
(M+, 5), 141 (100), 113 (10), 105 (12), 77 (60). HRMS-
EI (m/z): [M]+ calcd for C9H11ClO, 170.0498; found,
170.0500.
4.3.3. 1-(3-Methoxy-phenyl)-propan-1-ol. Yield: 75%.
16
D
½aŠ ¼ À19:5 (c 1.10, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.34–7.24 (m, 1H), 1.98 (m, 2H), 6.83–6.80
(d, J = 8.0Hz, 1H), 4.61–4.55 (m, 1H), 3.82 (s, 3H),
1.87–1.70 (m, 3H), 0.95–0.90 (t, J = 7.4Hz, 3H). 13C
NMR (125.7MHz, CDCl3, d): 159.6, 146.3, 129.3,
118.2, 112.8, 111.3, 75.8, 55.1, 31.7, 10.0. IR (KBr):
3390, 2963, 2932, 2874, 2838, 1606, 1463, 1321, 1259,
1160, 782, 698cmÀ1. MS m/z: 166 (M+, 33), 137 (95),
109 (100), 94 (32), 77 (33). HRMS-EI (m/z): [M]+ calcd
for C10H14O2, 166.0993; found, 166.0998.
4.3.9. 1-(3-Chloro-phenyl)-propan-1-ol. Yield: 96%.
16
D
½aŠ ¼ À28:4 (c 3.74, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.35 (s, 1H), 7.30–7.19 (m, 3H), 4.62–4.56
(m, 1H), 1.85 (d, J = 3.5Hz, 1H), 1.83–1.71 (m, 2H),
0.94–0.89 (t, J = 7.4Hz, 3H). 13C NMR (125.7MHz,
CDCl3, d): 146.6, 134.2, 129.6, 127.5, 126.1, 124.0,
75.2, 31.8, 9.9. IR (KBr): 3348, 2967, 2931, 2873, 1575,
1431, 786, 696cmÀ1. MS m/z: 170 (M+, 12), 143 (29),
141 (100), 113 (18), 77 (36). HRMS-EI (m/z): [M]+ calcd
for C9H11ClO, 170.0498; found, 170.0498.
4.3.4. 1-(4-Methoxy-phenyl)-propan-1-ol. Yield: 70%.
16
D
½aŠ ¼ À31:5 (c 2.10, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.29–7.25 (d, J = 8.5Hz, 2H), 6.90–6.87 (d,
J = 8.7Hz, 2H), 4.56–4.53 (m, 1H), 3.81 (s, 3H), 1.85–
1.69 (m, 3H), 0.92–0.87 (t, J = 7.4Hz, 3H). 13C NMR
(125.7MHz, CDCl3, d): 158.8, 136.7, 127.1, 113.4, 75.4,
55.1, 31.1, 10.1. IR (KBr): 3389, 2963, 2931, 1612,
1512, 1247, 1032, 831cmÀ1. MS m/z: 166 (M+, 8), 137
(100), 109 (18), 94 (13), 77 (15). HRMS-EI (m/z): [M]+
calcd for C10H14O2, 166.0993; found, 166.0995.
4.3.10. 1-(4-Chloro-phenyl)-propan-1-ol. Yield: 54%.
16
D
½aŠ ¼ À2:7 (c 1.19, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.33–7.28 (m, 4H), 4.62–4.57 (m, 1H),
1.82–1.71 (m, 2H), 0.93–0.90 (t, J = 7.4Hz, 3H). 13C
NMR (125.7MHz, CDCl3, d): 142.9, 133.0, 128.4,
127.3, 75.2, 31.9, 9.9. IR (KBr): 3348, 2963, 2927,
2873, 1593, 1490, 1090, 1010, 821cmÀ1. MS m/z:
170 (M+, 7), 141 (100), 113 (12), 77 (60). HRMS-EI
(m/z): [M]+ calcd for C9H11ClO, 170.0498; found,
170.0494.
16
4.3.5. 1-o-Tolyl-propan-1-ol. Yield: 72%. ½aŠ ¼ À62:4
D
1
(c 1.41, CHCl3). H NMR (300MHz, CDCl3, d): 7.47–

Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
3569
4.3.11. 1-(2-Nitro-phenyl)-propan-1-ol. Yield: 12%.
(m, 1H), 1.96–1.95 (d, J = 3.4Hz, 1H), 1.80–1.74 (m,
2H), 0.95–0.90 (t, J = 7.3Hz, 3H). 13C NMR
(125.7MHz, CDCl3, d): 146.0, 145.0, 130.3, 129.6,
127.1, 125.4, 118.8, 112.3, 74.7, 32.0, 9.7. IR (KBr):
3425, 2967, 2927, 2362, 2229, 1676, 773, 689cmÀ1. MS
m/z: 161 (M+, 4), 132 (100), 104 (37), 77 (23).
16
D
½aŠ ¼ À5:5 (c 0.65, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.91–7.88 (d, J = 8.1Hz, 1H), 7.81–7.78 (d,
J = 7.8Hz, 1H), 7.66–7.39 (m, 2H), 5.18–5.16 (m, 1H),
2.26 (d, J = 3.8Hz, 1H), 1.82–1.80 (m, 2H), 1.07–1.02
(t, J = 7.3Hz, 3H). 13C NMR (125.7MHz, CDCl3, d):
148.0, 139.8, 133.3, 128.0, 124.3, 70.6, 31.0, 10.4. IR
(KBr): 3390, 2967, 2923, 1952, 1730, 1525, 1348, 973,
742cmÀ1. MS m/z: 152 (100), 136 (6), 107 (21), 77
(35). HRMS-EI (m/z): [M]+ calcd for C9H11NO3,
181.0738; found, 181.0735.
4.3.17. 4-(1-Hydroxy-propyl)-benzonitrile. Yield: 94%.
16
D
½aŠ ¼ À6:2 (c 1.15, CHCl3). 1H NMR (300MHz,
CDCl3, d): 7.65–7.46 (d, J = 7.2Hz, 2H), 7.44–7.41 (d,
J = 6.8Hz, 2H), 4.69 (s, 1H), 2.00 (s, 1H), 1.81–1.71
(m, 2H), 0.95–0.90 (t, J = 7.4Hz, 3H). 13C NMR
(125.7MHz, CDCl3, d): 150.0, 132.0, 126.5, 118.8,
110.7, 74.8, 31.9, 9.7. IR (KBr): 3433, 2969, 2933,
2229, 1930, 1610, 1412, 1097, 980, 845cmÀ1. MS m/z:
161 (M+, 4), 132 (100), 104 (36), 77 (17).
4.3.12. 1-(3-Nitro-phenyl)-propan-1-ol. Yield: 21%.
16
D
½aŠ ¼ À28:3 (c 1.35, CHCl3). 1H NMR (300MHz,
CDCl3, d): 8.23 (s, 1H), 8.15–8.11 (d, J = 8.1Hz, 1H),
7.70–7.68 (d, J = 7.6Hz, 1H), 7.55–7.49 (m, 1H), 4.77–
4.73 (m, 1H), 2.04 (s, 1H), 1.84–1.79 (m, 2H), 0.97–
0.93 (t, J = 7.3Hz, 3H). 13C NMR (125.7MHz, CDCl3,
d): 148.3, 146.6, 132.0, 129.2, 122.3, 120.9, 74.7, 32.1,
29.6, 9.7. IR (KBr): 3394, 2967, 2927, 2873, 1529,
1351, 1095, 736, 691cmÀ1. MS m/z: 181 (M+, 1), 152
(100), 105 (7), 77 (5). HRMS-EI (m/z): [M]+ calcd for
C9H11NO3, 181.0738; found, 181.0742.
Acknowledgements
The authors thank Ms. L. M. Hsu, at the Instruments
Center, National Chung Hsing University, and Ms. H.
C. Tan, at Instrument Center, National Tsing Hwa Uni-
versity for their help in obtaining HRMSand 13C NMR
spectra, and the National Science Council of the Repub-
lic of China for financially supporting this research
under contract NSC 92-2113-M-259-006.
4.3.13. 1-(4-Nitro-phenyl)-propan-1-ol. Yield: 24%.
16
D
½aŠ ¼ À15:2 (c 1.52, CHCl3). 1H NMR (300MHz,
CDCl3, d): 8.22–8.19 (d, J = 8.7Hz, 2H), 7.53–7.50 (d,
J = 8.7Hz, 2H), 4.78–4.73 (m, 1H), 1.97 (s, 1H), 1.84–
1.74 (m, 2H), 0.97–0.92 (t, J = 7.4Hz, 3H). 13C NMR
(125.7MHz, CDCl3, d): 151.9, 147.1, 126.6, 123.6,
74.8, 32.1, 29.6, 9.7. IR (KBr): 3385, 2966, 2931, 2455,
1921, 1679, 1517, 1344, 853, 754cmÀ1. MS m/z: 181
(M+, 0.1), 176 (4), 166 (22), 141 (100), 123 (33), 113
(33), 112 (83), 85 (79), 77 (6). HRMS-EI (m/z): [M]+
calcd for C9H11NO3, 181.0738; found, 181.0743.
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D
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16
D
28%. ½aŠ ¼ À24:6 (c 1.15, CHCl3). 1H NMR
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6.74–6.71 (d, J = 8.6Hz, 2H), 4.52–4.47 (t, J = 6.7Hz,
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Y.-J. Chen et al. / Tetrahedron: Asymmetry 15 (2004) 3561–3571
3571
Y.-C., ; Chen, J.; Cheung, K. K. J. Am. Chem. Soc. 1998,
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obtained by comparing the literature; (b) Soai, K.;
Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.
1987, 109, 7111–7115; (c) Kang, S.-W.; Ko, D.-H.; Kim,
K. H.; Ha, D.-C. Org. Lett. 2003, 5, 4517–4519; (d)
22. (a) The ortho-substituent constants were reported by
Charton, M. Org. Bio. Chem. 1969, 91, 6649–6654; The
para- and meta-substituent constants obtained from
Johnson, C. D. The Hammett Equation; University
Press: Cambridge, 1973, p 3. The configurations were
ˇ
ˇ
ˇ
Vyskocil, S.; Jaracz, S.; Smrcina, M.; Stıcha, M.; Hanus,
V.; Polasek, M.; Koovsky, P. J. Org. Chem. 1998, 63,
ˇ
´
ˇ
´ˇ
´
7727–7737.