Chiral aryl pyridyl alcohols as enantioselective catalysts in the addition of diethylzinc to substituted benzaldehydes

Article abstract of DOI:10.1002/jccs.200800088

Chiral (5-aryl-10,10-dimethyl-6-aza-tricyclo[7.1.1.0^2,7]undeca- 2(7),3,5-trien-8-yl)-diphenyl-methanols were prepared from highly enantiopure (1R)-(+)-α-pinene (> 97% ee), and applied in the enantioselective addition of diethylzinc to substitut

Full text of DOI:10.1002/jccs.200800088

606
Journal of the Chinese Chemical Society, 2008, 55, 606-615
Chiral Aryl Pyridyl Alcohols as Enantioselective Catalysts in the Addition
of Diethylzinc to Substituted Benzaldehydes
Tien-Chu Chang (
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, R.O.C.
) and Chinpiao Chen* (
)
Chiral (5-aryl-10,10-dimethyl-6-aza-tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-8-yl)-diphenyl-meth-
anols were prepared from highly enantiopure (1R)-(+)-a-pinene (> 97% ee), and applied in the enantio-
selective addition of diethylzinc to substituted benzaldehydes, to yield alcohols with the (S)-configuration
with an enantiomeric excess that typically ranges from 19 to 86%. Importantly, the electron-withdrawing
substituents at the meta-position of the substituted benzaldehydes exhibited high enantioselectivity dur-
ing alkylation using diethylzinc.
Keywords: Enantioselective catalysts; Diethylzinc; Benzaldehyde; Hammett substituent con-
stants.
Scheme I
INTRODUCTION
Asymmetric catalysis of organic reactions to provide
N
O
N
O
enantiomerically enriched products is extremely important
in modern synthetic and pharmaceutical chemistry.1-4 Among
asymmetric catalysis of C-C bond-forming reactions, the
enantioselective addition of diorganozinc reagents to alde-
hydes represents one of the most important and fundamen-
tal asymmetric reactions.5,6 Since the first report by Oguni,7
various chiral ligands, including a-amino alcohols,8-21
BINOL,22-26 salen,27,28 TADDOL,29 pyridyl alcohol,30-37
and their derivatives have been used in this type of reac-
tion. The chiral ligands with diol generally need a Lewis
acid such as Ti(O-i-Pr)4 to form a chiral environment to in-
duce an asymmetric addition of diethylzinc to aldehydes.
While the chiral ligands with amino alcohol or pyridyl al-
cohol form an asymmetric environment with two mole-
cules of diethylzinc, one performs as Lewis acid, and an-
other plays as a nucleophile.38-41 The interaction between
diethylzinc and an amino alcohol produces a chelated eth-
ylzinc alkoxide (A), which is in equilibrium with a dimeric
species (B).39 Only the monomer is catalytically active, and
the adjacent Zn and O ring atoms, displaying complemen-
tary Lewis acid and Lewis base characters, are believed to
respectively coordinate one molecule of aldehyde and one
molecule of diethylzinc to assemble the key species (C)
where the ethyl group transfer occurs (Scheme I).
Zn
H
PhCHO
Et2Zn
Zn
O
Zn
N
O
O
Zn
Zn
(C)
Ph
N
(B)
(A)
cation of chiral bipyridine derivatives as ligands in metal
complexes in enantioselective catalysis,42-44 the possibility
of modifying the structure of 7 by changing the pyridyl
group is of interest (Fig. 1). This substitution yields ligands
6-10.45,46 This characteristic affects the steric interactions
between the ligand and the substrate, both coordinated to
the metal, and, therefore, the stereoselectivity.
RESULTS AND DISCUSSION
Scheme II outlines the synthesis of compounds 6-10.
(1R)-(+)-a-Pinene was readily photooxygenated in the
Ph
Ph
N
N
OH
7
Fig. 1.
Given the authors’ interest in the synthesis and appli-
* Corresponding author. Tel: +886-3-8633597; Fax: +886-3-8630475; E-mail: chinpiao@mail.ndhu.edu.tw

Enantioselectivity and Hammett Constant
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 607
Scheme II
NH4OAc, AcOH
100-110oC
1. LDA, -40oC
Ph
O
I2, pyridine
O
Py+I-
Ph
OH
100-110oC
CH3
R
2. Ph2CO
R
N
N
R
R
6-10
1-5
O
N
N
N
N
N
O
N
S
N
1
3
5
4
2
10
1
9
Ph
Ph
Ph
OH
Ph
Ph
OH
8
2
11
Ph
Ph
3
4
7
Ph
OH
N
N
S
N 6 OH
N
N
O
5
N
OH
Ph
N
Ph
10
6
7
8
9
presence of acetic anhydride, pyridine, DMAP and TPP to
yield directly a,b-unsaturated ketone.47 Additionally, 2-
acetyl-aromatic compounds were heated with iodine in
pyridine at 100-110 °C for 3 h and recrystallized from etha-
nol to produce pyridinium salts.48,49 Pyridinium salts and
a,b-unsaturated ketone were then heated with ammonium
acetate in glacial acetic acid at 100-110 °C overnight to
yield the corresponding pyridines 1-5.49 Next, compounds
1-4 were treated with LDA at -40 °C, and a solution of ben-
zophenone in THF was added to generate the correspond-
ing alcohols 6-9. Additionally, compound 5 treated under
the same conditions did not yield the expected product, but
gave compound 10. Meanwhile, compound 13 was pre-
pared from compound 11 by treating it with phenylmagne-
sium bromide to generate compound 12, and then 12 was
treated with LDA and benzophenone (Scheme III).
Scheme III
Ph
Ph
1. LDA
PhMgBr
2. Ph2CO
N
OH
N
N
CO2Me
Ph
Ph
Ph
Ph
OH
OH
13
11
12
of various amounts of ligand 7 yielded enantiomeric ex-
cesses of 1-phenyl-1-propanol, as presented in Table 2. The
optimal catalytic amount was 5 mol% of ligand 7 (65% ee).
The asymmetric alkylation of benzaldehyde using diethyl-
zinc, in the presence of ligand 7 (5 mol%) in various sol-
vents at room temperature yielded the enantiomeric ex-
cesses of 1-phenyl-1-propanol, as presented in Table 3. The
optimized solvent was toluene (57% ee). Benzaldehyde
was asymmetrically alkylated using diethylzinc in toluene
at room temperature and in the presence of 5 mol% of
ligand. Table 4 summarizes the enantiomeric excesses of
1-phenyl-1-propanol. The optimized ligand was 8 (67%
The asymmetric alkylation of benzaldehyde using
diethylzinc, in the presence of ligand 7 in hexane at various
temperatures yielded the enantiomeric excesses of 1-phen-
yl-1-propanol, as presented in Table 1. The temperature
does not significantly influence the enantiomeric excesses
of 1-phenyl-1-propanol. The same reaction in the presence

608 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Chang and Chen
Table 1. Enantiomeric excesses of the alkylation of benzalde-
Table 3. Asymmetric addition of diethylzinc to benzaldehyde
hyde in the presence of 7 at various temperatures
using ligand 7 in various solvents
O
O
OH
Et2Zn, ligand 7 (5 mol%)
OH
Et2Zn
hexane
Ph
H
Ph
H
Ph
Ligand 7, 5 mol%, rt
Ph
*
Entry
Temp. (ºC)
Yield (%)
Ee (%)
Entry
Solvent
Yield (%)
Ee (%)
1
2
3
25
0
-20
68
74
70
65
66
67
1
2
3
4
5
6
Acetonitrile
Diethy ether
Dichloromethane
Toluene
Toluene/hexane
Hexane
60
88
88
88
90
85
40
55
45
57
52
55
Table 2. Enantiomeric excesses of the alkylation of benzalde-
hyde in the presence of various amounts of 7
O
Et2Zn, ligand 7
OH
*
Table 4. The asymmetric alkylation of benzaldehyde using
diethylzinc in the presence of various chiral ligands
hexane, rt
Ph
H
Ph
Entry
8 (mol%)
Time (h)
Yield (%)
Ee (%)
O
OH
*
Et2Zn, ligand, 5 mol%
toluene, rt, 5 h
1
2
3
5.0
1.0
0.5
8
8
8
68
53
63
65
62
62
Ph
H
Ph
Entry
Ligands
Yield (%)
Ee (%)
1
2
3
4
5
6
6
7
70
88
80
75
63
-
60
57
67
55
09
08
8
ee).
9
The enantioselective formation of carbon-carbon
10
13
bonds by the asymmetric addition of dialkylzinc to alde-
hydes continues to be very important in the development of
the enantioselective approach methodology.5,6 Numerous
pyridine-alcohol derivatives have been demonstrated to be
effective chiral catalysts.30-37 Therefore, following re-
search in this field,39 the authors evaluated the potential
utility of ligands 6-10 and 13 in this catalytic process. Sub-
stituted benzaldehydes were asymmetrically alkylated in
the presence of catalyst 8 as described below. Diethylzinc
was added to a solution of ligand 8 (5 mol%) and aldehyde
in toluene at room temperature and stirred for 5 h. The reac-
tion was then quenched by adding 1M HCl. Following pu-
rification by flash chromatography, the enantiomeric ex-
cess of the product was determined by HPLC, and the
yields, % ee and the specific rotation were as presented in
Table 5. Next, the absolute configurations of all products
were determined by comparing the signs of the specific ro-
tations (aD).50-53 The stereochemical outcome depends
mainly on the stereogenic centers in the 8-position of the
pyridyl-pinane-ring (ligand 8).45 In fact, the benzaldehyde
asymmetrically alkylated using diethylzinc was affected by
the aromatic groups at the 5-position of ligands (Scheme II,
Table 4). The enantioselectivities obtained using the 5-
(pyridin-4-yl)-substituted ligand 8 were in the range 19-
86% ee. Some products were in the (S)-configuration, as
determined by comparing the signs of the specific rotations
(aD) in the literature.14 The electron-releasing substituents
at the meta-position of the substituted benzaldehydes re-
duced enantioselectivity. The electron-withdrawing sub-
stituents of benzaldehydes may enhance p-p interaction be-
tween the pyridine group of ligand 8 and the aromatic ring
of benzaldehyde. Therefore, the aromatic ring of benzalde-
hydes may be fixed tightly such that the Si-face of the car-
bonyl group favors alkylation and increases enantioselec-
tivity.
The correlation of Hammett substituent constants
with enantiomeric excesses in the alkylation of meta-sub-
stituted benzaldehydes using diethylzinc was strong. Im-
portantly, the stronger electron-releasing substituents at the
meta-position corresponded to the lower enantiomeric ex-
cesses (m-OMe, m-Me, 66%), whereas the stronger elec-
tron-withdrawing substituents at the meta-position resulted
in greater enantiomeric excesses (m-Cl, 86%; m-CN, 73%)
(Fig. 4). Electron-releasing substituents at the ortho-posi-
tion increased enantiomeric excesses (o-OMe, 54%; o-Me,

Enantioselectivity and Hammett Constant
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 609
Table 5. The asymmetric alkylation of benzaldehyde using diethylzinc in the presence of
ligand 8
OH
O
Ligand 8, 5 mol%
H
+ Et2Zn
R
R
toluene, rt
[a]TD (c), CH2Cl2
[a]/T °C/c (g/mL)
Entry
R
Yield (%)
Ee (%)
Configuration
1
2
3
4
5
6
7
8
H
80
88
90
90
77
81
93
44
70
80
79
80
67
54
66
60
19
86
70
67
66
69
73
67
-18.2/24.1/1.02
-14.4/25.0/1.02
-17.7/23.5/1.10
-22.3/25.5/1.07a
+20.9/23.5/1.05b
-16.9/25.5/1.13
-19.0/24.3/1.03
+52.8/23.7/0.88b
-8.6/24.1/1.02
S
o-OCH3
m-OCH3
p-OCH3
o-Cl
m-Cl
p-Cl
o-CH3
m-CH3
p-CH3
m-CN
p-CN
S
N/Ac
S
N/Ac
S
S
N/Ac
N/Ac
N/Ac
N/Ac
N/Ac
9
10
11
12
+15.3/23.5/1.01b
-0.18/24.0/0.30
+49.8/25.5/0.65b
a The ee% and [a] were determined by the pivolate.
b The ee% and [a] were determined by the benzoates.
c The configurations were not determined.
67%), while electron-withdrawing substituents at that posi-
tion reduced enantiomeric excesses (m-Cl, 19%) (Fig. 5).
Fig. 3 is the Hammett plot of the substituents on the para-
position.
the enantiomeric excess of 1-phenyl-1-propanol was very
low (8%). The steric energy was calculated using the MM2
program (CS Chem3D Pro). Calculation results indicate
that intermediate (E) has a lower steric energy (49.322
kcal/mol) than intermediate (F) (54.283 kcal/mol). Inter-
mediate (E) is more stable than intermediate (F), and the re-
action center might shift far away from the stereogenic cen-
ters and can not induce high enantioselectivity. This result
may similarly prove that ligand 10 is responsible for an
extremely low enantioselectivity (Fig. 2).
The unexpected ligand 10 was synthesized and ap-
plied in the asymmetric addition of dialkylzinc to benz-
aldehyde. The enantiomeric excess of the resulting 1-phen-
yl-1-propanol was very low (9%). The stereochemical out-
come depends mainly on the stereogenic centers in the 8-
position of the pyridyl-pinane-ring. In ligand 10, the reac-
tion center may shift toward the thioenyl group that is far
away from the stereogenic centers and can not cause high
enantioselectivity. Meanwhile, ligand 13 was used in the
asymmetric addition of dialkylzinc to benzaldehyde, and
In summary, a class of chelating ligands 7-10 and 13
Ph
Ph
Ph
Ph
N
OH
N
O
Zn
Zn
Ph
Ph
Ph
Ph
O
OH
(E)
(F)
Fig. 3. The correlation of substituent constants (sp)
and the enantiomeric excesses of the alkylation
of para-substituted benzaldehydes in the pres-
ence of ligand 8.
MM2 steric energy:
54.283 kcal/mol
MM2 steric energy:
49.322 kcal/mol
Fig. 2.

610 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Chang and Chen
dride. 1H NMR spectra were acquired at 300 or 500 MHz
(indicated in each case), and 13C NMR were acquired at
125.7 MHz on a Bruker NMR spectrometer. Chemical
shifts (d) are reported in ppm relative to CDCl3 (7.26 and
77.0 ppm). Mass spectra (MS) were determined on a
Micromass Platform II mass spectrometer at a 70 eV. High
resolution mass spectra (HRMS) were determined on a
Finnigan/Thermo Quest MAT 95XL mass spectrometer. In-
frared spectra were recorded on a JASCO FT/IR 410 spec-
trometer. All asymmetric reactions were carried out in dry
glassware under nitrogen using a standard glovebox. En-
antiomeric excesses were determined on a Lab Alliance Se-
ries III high performance liquid chromatograph (HPLC)
with a Chiracel OD-H chiral column (Daicel Chemical In-
dustries, LTD). Optical rotations were measured on a
JASCO P-1010 polarimeter at the indicated temperature
with a sodium lamp (D line, 589 nm). Flash column chro-
matography was performed using MN silica gel 60 (70-230
mesh) purchased from Macherey-Nagel. Diethylzinc (1 M)
solution in hexane was purchased from Sigma-Aldrich Co.
General procedure for the preparation of 10,10-di-
methyl-5-aryl-6-azatricyclo[7.1.1.02,7]undeca-2(7),3,5-
triene (1-5)
Fig. 4. The correlation of substituent constants (sm)
and the enantiomeric excesses of the alkylation
of meta-substituted benzaldehydes in the pres-
ence of ligand 8.
Fig. 5. The correlation of substituent constants (so)
and the enantiomeric excesses of the alkylation
of ortho-substituted benzaldehydes in the pres-
ence of ligand 8.
The general procedure is demonstrated by the prepa-
ration of compound 4. Amixture of pyridinium salt (1.26 g,
4.0 mmol), pinenone (0.66 g, 4.0 mmol), and ammonium
acetate (2.46 g, 32.0 mmol) in glacial acetic acid (5.5 mL)
under argon atmosphere was heated at 100-110 °C for 10 h.
After cooling to room temperature, the reaction mixture
was diluted with water, and the aqueous solution was basified
by sodium carbonate until the aqueous solution become ba-
sic. The aqueous phase was extracted with ethyl acetate
three times, and the combined extracts were dried over an-
hydrous magnesium sulfate. After filtering and concentra-
tion, the resulting residue was purified by flash column
chromatography using silica gel (The silica gel was deacti-
vated by ammonia gas.) as the stationary phase and using
ethyl acetate-hexane (1:19) as the mobile phase producing
compound 4.
was prepared. Their catalytic activity in the asymmetric ad-
dition of diethylzinc to substituted benzaldehydes was
demonstrated. These ligands were prepared from highly
enantiopure (1R)-(+)-a-pinene (> 97% ee). Bipyridyl alco-
hol 8 acts as an interesting chiral catalyst in the enantio-
selective addition of diethylzinc to various substituted ben-
zaldehydes, yielding alcohols with the (S)-configuration
and an enantiomeric excess that ranged generally from 19
to 86%. Importantly, the electron-withdrawing substituents
at the meta-position of the substituted benzaldehydes ex-
hibited high enantioselectivity during alkylation using di-
ethylzinc. Other asymmetric reactions are currently being
examined to rationalize this correlation.
10,10-Dimethyl-5-phenyl-6-aza-tricyclo[7.1.1.02,7]un-
deca-2(7),3,5-triene (1)
Yield: 56%. [a] D22. 4 +100.0° (c 1.06, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 7.98 (dd, J = 7.1, 1.5 Hz, 2H), 7.48-
7.28 (m, 5H), 3.21 (d, J = 2.8 Hz, 2H), 2.81 (t, J = 5.6 Hz,
1H), 2.72-2.69 (m, 1H), 2.41-2.40 (m, 1H), 1.43 (s, 3H),
1.33 (d, J = 9.5 Hz, 1H), 0.70 (s, 3H). IR (KBr, thin film):
3057, 2981, 1567, 1439, 1234, 1024, 834, 779, 740, 695
EXPERIMENTAL SECTION
General Chemical Procedures
All reactions were carried out in anhydrous solvents.
Tetrahydrofuran and diethyl ether were distilled from so-
dium-benzophenone under argon. Toluene, acetonitrile, di-
chloromethane, and hexane were distilled from calcium hy-

Enantioselectivity and Hammett Constant
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 611
cm-1. MS-FAB m/z: 250 (M++1, 100), 234 (12), 220 (13),
206 (23), 194 (15), 133 (34).
1.1 Hz, 1H), 7.36-7.31 (m, 2H), 7.20 (d, J = 7.8 Hz, 1H),
7.10 (dd, J = 5.0, 3.7 Hz, 1H), 3.15 (d, J = 2.8 Hz, 2H),
2.77-2.64 (m, 2H), 2.40-2.36 (m, 1H), 1.40 (s, 3H), 1.30 (d,
J = 9.4 Hz, 1H), 0.68 (s, 3H). 13C NMR (CDCl3, 75 MHz,
d): 156.8, 150.0, 145.6, 140.4, 133.6, 128.0, 126.4, 123.6,
115.6, 46.3, 40.2, 39.5, 36.6, 32.1, 26.1, 21.4. IR (KBr, thin
film): 3046, 2925, 1571, 1421, 1222, 1111, 943, 817, 707
cm-1. MS-FAB m/z: 256 (M++1, 64), 241 (18), 133 (30), 75
(100), 57 (63). HRMS-FAB (m/z): [M + H]+ calcd for
C16H18NS, 256.1160; found, 256.1155.
10,10-Dimethyl-5-pyridin-2-yl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-triene (2)
Yield: 84%. [a] D20 +102.8° (c 2.65, CHCl3). 1H NMR
(300 MHz, CDCl3, d): 8.67 (m, 1H), 8.36 (d, J = 8.0 Hz,
1H), 8.05 (d, J = 7.8 Hz, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H),
7.34 (d, J = 7.8 Hz, 1H), 7.28-7.26 (m, 1H), 3.20 (d, J = 2.8
Hz, 2H), 2.83 (t, J = 5.6 Hz, 1H), 2.74-2.67 (m, 1H), 2.42-
2.38 (m, 1H), 1.42 (s, 3H), 1.33 (d, J = 9.5 Hz, 1H), 0.68 (s,
3H). IR (KBr, thin film): 3057, 2985, 2918, 1557, 1432,
1108, 944, 861, 796, 754, 609 cm-1. MS-FAB m/z: 251
(M++1, 100), 235 (10), 221 (12), 207 (20), 195 (20), 133
(79).
General procedure for the preparation of (10,10-di-
methyl-5-aryl-6-azatricyclo[7.1.1.02,7]undeca-2(7),3,5-
trien-8-yl)-diphenyl-methanol (6-10)
The general procedure is demonstrated by the prepa-
ration of compound 9. n-Butyllithium (0.60 mL, 1.0 mmol,
1.6 M in hexane) was added to a solution of diisopropyl-
amine (0.13 mL, 1.0 mmol) in tetrahydrofuran (0.6 mL) at
0 °C and stirred for 15 min to give a LDA solution. The
LDA solution was cooled to -40 °C, and then was added to
a solution of compound 4 (204.0 mg, 0.9 mmol) in tetrahy-
drofuran (4.3 mL) by canula, and stirred at -40 °C for 2 h.
Then the reaction temperature was decreased to -78 °C, and
a solution of benzophenone (155 mg, 0.9 mmol) in tetrahy-
drofuran (4.0 mL) was added. The reaction temperature
was increased to room temperature and stirred overnight.
The reaction was quenched by adding water, and the reac-
tion mixture was extracted with ethyl acetate. The com-
bined extracts then were dried over anhydrous magnesium
sulfate. After filtering and concentration, the residue was
purified by flash column chromatography using silica gel
as the stationary phase and ethyl acetate-hexane (1:49) as
the mobile phase, thus producing compound 9 (65.0 mg,
0.15 mmol).
10,10-Dimethyl-5-pyridin-4-yl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-triene (3)
Yield: 60%. mp: 69-70 °C. [a] 1D8.9 +104.5° (c 1.01,
CH2Cl2). 1H NMR (300 MHz, CDCl3, d): 8.69 (dd, J = 4.6,
1.6 Hz, 2H), 7.88 (dd, J = 4.5, 1.6 Hz, 2H), 7.50 (d, J = 7.8
Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 3.19 (d, J = 2.8 Hz, 2H),
2.84-2.69 (m, 2H), 2.43-2.39 (m, 1H), 1.43 (s, 3H), 1.32 (d,
J = 9.6 Hz, 1H), 0.68 (s, 3H). 13C NMR (CDCl3, 75 MHz,
d): 157.3, 151.3, 150.1, 164.6, 142.3, 133.5, 120.5, 120.3,
117.7, 117.4, 46.1, 40.0, 39.3, 36.5, 31.7, 25.8, 21.1. IR
(KBr, thin film): 3068, 2932, 1597, 1441, 1236, 1065,
1022, 814, 598 cm-1. MS-FAB m/z: 251 (M++1, 100), 235
(13), 221 (17), 207 (23), 195 (17), 133 (42), 77 (7). HRMS-
FAB (m/z): [M + H]+ calcd for C17H19N2, 251.1548; found,
251.1548.
5-Furan-2-yl-10,10-dimethyl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-triene (4)
Yield: 76%. [a] D20 +97.0° (c 0.95, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 7.50 (d, J = 1.1 Hz, 1H), 7.39 (d, J =
7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 3.3 Hz,
1H), 6.50 (dd, J = 3.4, 1.8 Hz, 1H), 3.17 (d, J = 2.8 Hz, 2H),
2.78-2.65 (m, 2H), 2.40-2.36 (m, 1H), 1.40 (s, 3H), 1.30 (d,
J = 9.5 Hz, 1H), 0.67 (s, 3H). 13C NMR (CDCl3, 75 MHz,
d): 157.0, 154.1, 146.8, 142.7, 140.6, 133.5, 115.5, 111.8,
107.3, 46.5, 40.2, 39.6, 36.7, 32.0, 26.1, 21.3. IR (KBr, thin
film): 3043, 2922, 1589, 1447, 1243, 1085, 1005, 811, 734,
595 cm-1. MS-FAB m/z: 240 (M++1, 100), 218 (16), 133
(46), 75 (23). HRMS-FAB (m/z): [M + H]+ calcd for
C16H18NO, 240.1388; found, 240.1389.
(10,10-Dimethyl-5-phenyl-6-aza-tricyclo[7.1.1.02,7]un-
deca-2(7),3,5-trien-8-yl)-diphenyl-methanol (6)
Yield: 40%. mp: 148-149 °C. [a] 2D3.5 -446.4° (c 1.09,
CH2Cl2). 1H NMR (300 MHz, CDCl3, d): 10.15 (br, 1H),
8.04 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.55 (m,
10H), 7.10 (s, 5H), 4.47 (s, 1H), 2.66 (t, J = 6.0 Hz, 1H),
2.57 (t, J = 5.3 Hz, 1H), 1.40 (s, 3H), 1.29 (t, J = 7.2 Hz,
1H), 0.90 (s, 3H). IR (KBr, thin film): 3118, 3060, 2956,
1585, 1475, 1027, 767, 719, 698 cm-1. MS-FAB m/z: 432
(M++1, 8), 414 (5), 372 (4), 354 (4), 248 (23), 234 (29), 220
(17), 206 (39), 167 (100), 105 (67), 77 (63).
10,10-Dimethyl-5-thiophen-2-yl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-triene (5)
Yield: 54%. mp: 80-81 °C. [a] 2D3 +104.0° (c 1.03,
CH2Cl2). 1H NMR (300 MHz, CDCl3, d): 7.53 (dd, J = 3.7,
(10,10-Dimethyl-5-pyridin-2-yl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-trien-8-yl)-diphenyl-methanol (7)
Yield: 69%. mp: 99-100 °C. [a] 2D5.5 -403.0° (c 1.05,

612 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Chang and Chen
1
CH2Cl2). H NMR (300 MHz, CDCl3, d): 9.90 (br, 1H),
2.37-2.34 (m, 1H), 1.40 (s, 3H), 1.28 (d, J = 3.8 Hz, 1H),
0.66 (s, 3H). 13C NMR (CDCl3, 75 MHz, d): 156.9, 153.2,
149.9, 146.6, 145.3, 140.6, 133.6, 128.1, 127.8, 127.7,
127.5, 127.1, 123.1, 115.6, 80.2, 46.4, 40.3, 39.6, 36.6,
32.1, 26.2, 21.5. IR (KBr, thin film): 3447, 2923, 1573,
1444, 1012, 808, 758, 700, 646 cm-1. MS-FAB m/z: 439
(M++1, 100), 420 (43), 241 (22), 207 (31), 167 (33), 149
(42), 133 (45), 115 (61). HRMS-FAB (m/z): [M + H]+ calcd
for C29H28NOS, 438.1892; found, 438.1891.
8.70 (d, 1H), 8.28 (dd, J = 13.5, 8.0 Hz, 2H), 7.78 (t, J = 7.7
Hz, 1H), 7.47-7.30 (m, 7H), 7.10 (s, 5H), 4.48 (s, 1H),
2.64-2.57 (m, 2H), 2.11-2.04 (m, 1H), 1.40 (s, 3H), 1.28 (t,
J = 7.3 Hz, 1H), 0.9 (s, 3H). IR (KBr, thin film): 3150,
3058, 2925, 1578, 1431, 1025, 788, 700 cm-1. MS-FAB
m/z: 433 (M++1, 8), 415 (6), 249 (32), 235 (41), 221 (26),
207 (52), 167 (100), 105 (82), 77 (70).
(10,10-Dimethyl-5-pyridin-4-yl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-trien-8-yl)-diphenyl-methanol (8)
Yield: 63%. mp: 196-197 °C. [a] 2D5.5 -409.0° (c 1.02,
General procedure for the preparation of [8-(hy-
droxy-diphenyl-methyl)-10,10-dimethyl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl]-diphenyl-methanol
(12-13)
1
CH2Cl2). H NMR (300 MHz, CDCl3, d): 9.37 (br, 1H),
8.70 (d, J = 6.0 Hz, 2H), 7.83 (dd, J = 4.6, 1.4 Hz, 2H), 7.61
(d, J = 7.8 Hz, 1H), 7.46-7.31 (m, 6H), 7.11 (s, 5H), 4.48 (s,
1H), 2.62 (d, J = 5.6 Hz, 2H), 2.15-2.08 (m, 1H), 1.40 (s,
3H), 1.26 (s, 1H), 0.88 (s, 3H). 13C NMR (CDCl3, 75 MHz,
d): 158.1, 150.6, 149.6, 146.8, 145.7, 145.3, 144.7, 134.9,
128.3, 128.1, 127.8, 127.2, 127.1, 126.6, 120.5, 118.4,
81.9, 48.2, 45.8, 42.9, 41.6, 28.8, 26.3, 21.3. IR (KBr, thin
film): 3219, 3059, 2925, 1600, 1548, 1444, 1031, 819, 700
cm-1. MS-FAB m/z: 433 (M++1, 15), 415 (6), 251 (40), 235
(38), 221 (21), 207 (44), 167 (89), 133 (42), 105 (100), 77
(79). HRMS-FAB (m/z): [M + H]+ calcd for C30H29N2O,
433.2280; found, 433.2280.
(5-Furan-2-yl-10,10-dimethyl-6-aza-tricyclo[7.1.1.02,7]-
undeca-2(7),3,5-trien-8-yl)-diphenyl-methanol (9)
Yield: 18%. mp: 123-124 °C. [a] 2D5.5 -151.1° (c 1.5,
CH2Cl2). 1H NMR (300 MHz, CDCl3, d): 10.07 (br, 1H),
7.53-7.31 (m, 7H), 7.22 (d, J = 7.9 Hz, 1H), 7.11 (s, 5H),
7.06 (d, J = 3.0 Hz, 1H), 6.55 (dd, J = 3.3, 1.7 Hz, 1H), 4.42
(s, 1H), 2.64 (t, J = 5.8 Hz, 1H), 2.54 (t, J = 5.5 Hz, 1H),
2.10 (m, 1H), 1.39 (s, 3H), 1.26 (s, 1H), 0.89 (s, 3H). 13C
NMR (CDCl3, 75 MHz, d): 157.3, 153.1, 146.7, 145.8,
144.5, 143.1, 142.2, 134.5, 128.4, 128.2, 128.0, 127.1,
127.0, 126.4, 115.8, 112.2, 108.1, 81.9, 47.9, 45.8, 42.9,
41.5, 29.0, 26.4, 21.3. IR (KBr, thin film): 3428, 3150,
3059, 2923, 1590, 1493, 1445, 1249, 1014, 767, 700, 634
cm-1. MS-FAB m/z: 422 (M++1, 7), 404 (2), 238 (5), 224
(6), 167 (46), 75 (100). HRMS-FAB (m/z): [M + H]+ calcd
for C29H28NO2, 422.2120; found, 422.2120.
(10,10-Dimethyl-6-aza-tricyclo[7.1.1.02,7]undeca-
2(7),3,5-trien-5-yl)-diphenyl-methanol (12)
To a suspension mixture of magnesium (534 mg, 22.0
mmol) in tetrahydrofuran (40 mL) was slowly added bro-
mobenzene (2.32 mL, 22.0 mmol), and stirred at room tem-
perature for 1 h to produce a phenylmagnesium bromide
solution. This freshly prepared Grignard reagent was added
to a solution of 11 (2.31 g, 10.0 mmol) in tetrahydrofuran
(15 mL) by syringe and stirred at room temperature. The re-
action was monitored by TLC. When the starting material
11 was entirely consumed, water was added to quench the
reaction, and the reaction mixture was extracted with ethyl
acetate. The combined extracts then were dried over anhy-
drous magnesium sulfate. After filtering and concentra-
tion, the residue was purified by flash column chromatog-
raphy using silica gel as the stationary phase and ethyl ace-
tate-hexane (1:19) as the mobile phase, thus producing
compound 12 (2.78 g, 7.8 mmol). Yield: 78%. mp: 135-136
1
°C. [a] 2D5.5 +37.2° (c 1.55, CH2Cl2). H NMR (300 MHz,
CDCl3, d): 7.35-7.24 (m, 10H), 7.17 (d, J = 7.8 Hz, 1H),
6.77 (d, J = 7.8 Hz, 1H), 3.12 (d, J = 2.8 Hz, 2H), 2.79 (t, J =
5.6 Hz, 1H), 2.72 (m, 1H), 2.39 (m, 1H), 1.41 (s, 3H), 1.30
(d, J = 9.5 Hz, 1H), 0.64 (s, 3H). 13C NMR (CDCl3, 75
MHz, d): 159.4, 154.6, 146.4, 146.3, 140.3, 133.1, 127.8,
127.4, 126.7, 119.3, 80.1, 45.6, 39.7, 39.1, 35.7, 31.5, 25.7,
21.0. IR (KBr, thin film): 3424, 3083, 3059, 3021, 2922,
1580, 1444, 1366, 1167, 1039, 842, 759, 698 cm-1. MS-
FAB m/s: 356 (M++1, 7), 338 (63), 322 (9), 294 (26), 241
(23), 149 (21), 132 (25), 105 (16), 75 (100).
(10,10-Dimethyl-5-thiophen-2-yl-6-aza-tricyclo-
[7.1.1.02,7]undeca-2(7),3,5-trien-8-yl)-diphenylmethanol
(10)
[8-(Hydroxy-diphenyl-methyl)-10,10-dimethyl-6-aza-
tricyclo[7.1.1.02,7]undeca-2(7),3,5-trien-5-yl]-diphenyl-
methanol (13)
o
Yield: 86%. mp: 70-71 C. [a] 2D3.5 +70.9° (c 1.00,
1
CH2Cl2). H NMR (300 MHz, CDCl3, d): 7.45-7.29 (m,
13H), 7.18 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 3.8 Hz, 1H),
3.10 (d, J = 2.8 Hz, 2H), 3.00 (s, 3H), 2.76-2.65 (m, 2H),
n-Butyllithium (5.1 mL, 10.3 mmol, 2.0 M in hexane)
was added to a solution of diisopropylamine (1.45 mL, 10.3

Enantioselectivity and Hammett Constant
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 613
mmol) in tetrahydrofuran (5.6 mL) at 0 °C and stirred for
15 min to give a LDA solution. The LDA solution was
cooled to -40 °C, and then was added to a solution of com-
pound 12 (1.66 g, 4.7 mmol) in tetrahydrofuran (20 mL) by
canula, and stirred at -40 °C for 2 h. Then the reaction tem-
perature was decreased to -78 °C, and a solution of benzo-
phenone (852 mg, 4.7 mmol) in tetrahydrofuran (16.0 mL)
was added. The reaction temperature was increased to
room temperature and stirred overnight. The reaction was
quenched by adding water, and the reaction mixture was
extracted with ethyl acetate. The combined extracts then
were dried over anhydrous magnesium sulfate. After filter-
ing and concentration, the residue was purified by flash
column chromatography using silica gel as the stationary
phase and ethyl acetate-hexane (1:24, 1:49) as the mobile
phase, thus producing compound 13 (300.0 mg, 0.56 mmol).
Yield: 18%. mp: 80 °C. [a] 1D9 -186.4° (c 0.55, CH2Cl2). 1H
NMR (300 MHz, CDCl3, d): 7.37-7.09 (m, 22H), 4.40 (s,
1H), 2.61 (t, J = 5.6 Hz, 1H), 2.35 (m, 1H), 2.18-2.14 (m,
1-m-Tolyl-propan-1-ol
Yield: 70%. [a] D24.1 -8.6° (c 1.02, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J =
8.6 Hz, 2H), 4.48 (t, J = 6.7 Hz, 1H), 3.74 (s, 3H), 2.03 (br,
1H), 1.85-1.63 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3, 75 MHz, d): 144.6, 138.1, 128.3, 128.2, 126.7,
123.1, 76.1, 31.9, 21.5, 10.2. IR (KBr, thin film): 3365,
3026, 2927, 2873, 2964, 1608, 1459, 1159, 1043, 784, 703
cm-1. MS-FAB m/z: 166 (M+, 8), 149 (77), 137 (34), 121
(13), 43 (100).
1-(3-Chloro-phenyl)-propan-1-ol
Yield: 81%. [a] D25.5 -16.9° (c 1.13, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 3.75-7.20 (m, 4H), 4.61 (t, J = 6.4
Hz, 1H), 1.98 (br, 1H), 1.83-1.71 (m, 2H), 0.95 (t, J = 7.4
Hz, 3H). 13C NMR (CDCl3, 75 MHz, d): 146.7, 134.3,
129.7, 127.6, 126.2, 124.2, 75.3, 31.9, 10.0. IR (KBr, thin
film): 3357, 3064, 2965, 1575, 1432, 1199, 1085, 782, 698
cm-1. MS-FAB m/s: 153 (M+-17, 42), 149 (52), 133 (82), 57
(100), 43 (70).
1H), 1.35 (s, 3H), 1.28 (d, J = 9.5 Hz, 1H), 0.84 (s, 3H). 13
C
1-(4-Chloro-phenyl)-propan-1-ol
Yield: 93%. [a] D24. 3 -19.0° (c 1.03, CH2Cl2). 1H NMR
NMR (CDCl3, 75 MHz, d): 160.3, 160.6, 147.1, 145.8,
145.5, 145.0, 142.4, 133.9, 128.4, 128.0, 127.9, 127.8,
127.4, 127.2, 127.1, 126.7, 126.5, 126.2, 119.4, 81.3, 81.2,
48.9, 45.7, 42.7, 41.8, 28.6, 26.2, 21.2. IR (KBr, thin film):
3433, 3087, 3056, 3028, 2930, 1735, 1574, 1445, 1242,
1041, 851, 763, 699 cm-1. MS-FAB m/s: 538 (M++1, 15),
520 (5), 502 (12), 460 (7), 235 (85), 167 (100). HRMS-EI
(m/z): [M]+ calcd for C38H35NO2, 537.2668; found, 537.2667.
General procedure for the enantioselective addition
of diethylzinc to aldehydes catalyzed by chiral
ligands
(300 MHz, CDCl3, d): 7.33-7.26 (m, 4H), 4,61 (t, J = 6.5
Hz, 1H), 1.85-1.72 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13
C
NMR (CDCl3, 75 MHz, d): 143.0, 133.1, 128.5, 127.4,
75.3, 32.0, 10.0. IR (KBr, thin film): 3357, 3047, 3026,
2931, 2877, 2965, 1490, 1091, 1012, 825, 526 cm-1. MS-
FAB m/s: 153 (M+-17, 13), 149 (43), 133 (93), 69 (100), 57
(84), 43 (82).
1-(2-Methoxy-phenyl)-propan-1-ol
Yield: 88%. [a] D25 -14.4° (c 1.02, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 7.31-7.21 (m, 2H), 6.98-6.87 (m,
2H), 4.81 (t, J = 6.7 Hz, 1H), 3.87 (s, 3H), 2.54 (br, 1H),
1.89-1.70 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR
(CDCl3, 75 MHz, d): 156.6, 132.4, 128.2, 127.1, 120.7,
110.5, 72.3, 55.3, 30.2, 10.5. IR (KBr, thin film): 3419,
3050, 2964, 1600, 1490, 1238, 1089, 1045, 754 cm-1. MS-
FAB m/s: 167 (M++1, 5), 149 (100), 137 (39), 121 (32), 43
(27).
Aldehyde (0.5 mmol) was added to a solution of lig-
ands (5.0 mol%) in solvent (1.0 mL) at room temperature,
and then a solution of diethylzinc (1.0 mL, 1 M in hexane)
was added and stirred for 5 h. The reaction was quenched
by adding 1N HCl (5.0 mL), and the reaction mixture was
extracted three times with dichloromethane. The combined
extracts then were dried over anhydrous magnesium sul-
fate. After filtering and concentration, the residue was puri-
fied by flash column chromatography using silica gel as the
stationary phase and ethyl acetate-hexane as the mobile
phase, thus producing products. The enantiomeric excess
of products were determined by HPLC (Chiralcel OD-H
column, flow rate 0.25 mL/min, and KR100-5CHI-DMB
column, flow rate 0.5 mL/min, 10% 2-propanol in hexane,
254 nm UV detector).
1-(3-Methoxy-phenyl)-propan-1-ol
Yield: 90%. [a] D23.5 -17.7° (c 1.10, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 7.29 (t, J = 8.1 Hz, 1H), 6.93-6.91
(m, 2H), 6.83 (dd, J = 8.1, 2.5 Hz, 1H), 4.60 (t, J = 6.5 Hz,
1H), 3.82 (s, 3H), 1.87 (m, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C
NMR (CDCl3, 75 MHz, d): 159.8, 146.4, 129.4, 118.3,
113.0, 111.5, 76.0, 55.2, 31.9, 11.2. IR (KBr, thin film):
3376, 3055, 2964, 1602, 1455, 1261, 1157, 1043, 858, 782,

614 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Chang and Chen
700 cm-1. MS-FAB m/s: 166 (M+, 18), 149 (100), 137 (23),
121 (17), 109 (9).
1-(4-Methoxy-phenyl)-propan-1-ol
J = 7.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz, d): 166.0,
137.7, 137.6, 132.8, 130.7, 129.6, 129.1, 128.3, 126.5,
77.9, 43.7, 29.5, 21.1, 10.0. IR (KBr): 3060, 3030, 2969,
1718, 1450, 1270, 1176, 1110, 1025, 813, 709 cm-1. MS-
FAB m/z: 254 (M+, 2), 225 (4), 132 (67), 105 (100), 77
(13).
Yield: 90%. [a] D25.5 -22.3° (c 1.07, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 7.29 (d, J = 8.6 Hz, 2H), 6.90 (d, J =
8.6 Hz, 2H), 4.57 (t, J = 6.6 Hz, 1H), 3.80 (s, 3H), 1.87-1.67
(m, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3, 75
MHz, d): 159.0, 136.8, 127.2, 113.8, 75.7, 55.3, 31.8, 10.2.
IR (KBr, thin film): 3394, 3064, 2962, 1612, 1511, 1247,
1037, 829 cm-1. MS-FAB m/s: 166 (M+, 41), 149 (100), 132
(50), 121 (50), 109 (38).
Benzoic acid 1-(2-chloro-phenyl)-propyl ester
Yield: 50%. [a] D23.5 +20.9° (c 1.05, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 8.13-8.10 (m, 2H), 7.58-7.56 (m,
1H), 7.49-7.46 (m, 3H), 7.37-7.36 (m, 1H), 7.25-7.23 (m,
2H), 6.35 (t, J = 6.4 Hz, 1H), 2.08-1.98 (m, 2H), 1.06 (t, J =
7.4 Hz, 3H). 13C NMR (CDCl3, 75 MHz, d): 165.7, 138.7,
133.1, 132.3, 130.3, 129.7, 128.7, 128.5, 127.1, 127.0,
74.5, 43.7, 28.6, 9.9. IR (KBr): 3064, 3032, 2971, 1722,
1600, 1452, 1268, 1108, 944, 754, 711 cm-1. MS-FAB m/z:
275 (M+ + 1, 4), 239 (12), 153 (49), 125 (72), 105 (100), 77
(55).
2,2-Dimethyl-propionic acid 1-(3-cyano-phenyl)-propyl
ester
1
Yield: 73%. [a] D24 -0.18° (c 0.3, CH2Cl2). H NMR
(300 MHz, CDCl3, d): 7.59-7.44 (m, 4H), 5.64 (dd, J = 5.9,
7.5 Hz, 1H), 1.95-1.78 (m, 2H), 1.22 (s, 9H), 0.93 (t, J = 7.4
Hz, 3H). 13C NMR (CDCl3, 75 MHz, d): 177.6, 142.7,
131.4, 130.7, 129.8, 129.3, 118.7, 112.7, 75.8, 38.9, 29.5,
27.1, 9.7. IR (KBr, thin film): 3068, 2971, 2937, 2873,
1729, 1481, 1396, 1280, 1151, 894, 802, 694, 491 cm-1.
MS-FAB m/z: 244 (M+ + 1, 12), 144 (26), 85 (100), 57 (36).
Benzoic acid 1-(4-cyano-phenyl)-propyl ester
Yield: 52%. [a] D25.5 +49.8° (c 0.65, CH2Cl2). 1H NMR
(300 MHz, CDCl3, d): 8.10 (m, 2H), 7.66-7.44 (m, 7H),
5.94 (t, J = 6.3 Hz, 1H), 2.06-1.95 (m, 2H), 1.01 (t, J = 7.4
Hz, 3H). 13C NMR (CDCl3, 75 MHz, d): 165.8, 146.1,
133.7, 133.3, 132.4, 130.2, 129.9, 129.7, 128.5, 127.1,
118.7, 111.7, 29.7, 29.5, 9.8. IR (KBr): 3064, 2971, 1722,
1452, 1270, 1110, 842, 711, 561 cm-1. MS-FAB m/z: 264
(M+ + 1, 12), 144 (26), 132 (39), 116 (34), 105 (100), 77
(36).
ACKNOWLEDGEMENT
The authors thank Ms. Hsu, L. M. at the Instruments
Center, National Chung Hsing University, and Ms. Lin, S.
C. at the Instrument Center, National Tsing Hwa University
for their help in obtaining HRMS spectra. We would also
like to thank the National Science Council of the Republic
of China for financially supporting this research under con-
tract NSC 94-2113-M-259-006.
Received February 27, 2007.
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Yield: 67%. [a] D23.7 +52.8° (c 0.88, CH2Cl2). 1H NMR
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3H), 7.33 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 5.91
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