A new chiral sulfonamide ligand based on tartaric acid: synthesis and application in the enantioselective addition of diethylzinc to aldehydes and ketones

Article abstract of DOI:10.1016/j.tetasy.2006.07.040

A new sulfonamide ligand based on l-tartaric acid was synthesized and was employed as a chiral ligand in the enantioselective addition of diethylzinc to aldehydes, giving rise to the best enantiomeric excess up to 83% with 5 mol % of catalyst loading. Moreover, the addition of diethylzinc to ketones can also be achieved with good to excellent enantioselectivities by employing 7 mol % of the catalyst under mild conditions.

Full text of DOI:10.1016/j.tetasy.2006.07.040

Tetrahedron: Asymmetry 17 (2006) 2101–2107
A new chiral sulfonamide ligand based on tartaric acid: synthesis
and application in the enantioselective addition of diethylzinc
to aldehydes and ketones
Ailing Hui, Jintang Zhang, Jinmin Fan and Zhiyong Wang*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 12 June 2006; accepted 24 July 2006
Abstract—A new sulfonamide ligand based on L-tartaric acid was synthesized and was employed as a chiral ligand in the enantioselective
addition of diethylzinc to aldehydes, giving rise to the best enantiomeric excess up to 83% with 5 mol % of catalyst loading. Moreover,
the addition of diethylzinc to ketones can also be achieved with good to excellent enantioselectivities by employing 7 mol % of the cat-
alyst under mild conditions.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tion to the enantioselective addition of diethylzinc to alde-
hydes and ketones.
Chiral alcohols are ubiquitous in the structures of natural
products and drug compounds, and are also important pre-
cursors for many other functional organic molecules. One
of the most useful methods for the asymmetric preparation
of sec-alcohols and tert-alcohols is the enantioselective
addition of dialkylzinc reagents to carbonyl compounds
with chiral ligands.1 Although many existing chiral ligands
can induce good to excellent selectivity, it is still desirable
to develop new chiral ligands for high enantioselectivity.
Due to the two stereogenic centers, tartaric acid has
attracted much attention recently. However, only a few
chiral ligands derived from tartaric acid were found to be
effective in promoting the asymmetric addition of dialkyl-
zinc reagents to aldehydes.2 To the best of our knowledge,
there is no successful example of a tartaric acid-derived
chiral ligand used for asymmetric addition of diethylzinc
to ketones until now. Since a variety of sulfonamide ligands
have been reported to be effective in the enantioselective
addition of dialkylzinc reagents to aldehydes3 or ketones,4,5
we focused our research on the synthesis of sulfonamide
ligands based on tartaric acid and their application in the
addition of diethylzinc to carbonyl compounds. Herein,
we report an efficient synthesis method for a new chiral
sulfonylamide ligand based on tartaric acid and its applica-
2. Results and discussion
2.1. Synthesis of the chiral ligand
Initially, L-tartaric acid was easily transformed into its es-
ter, which was reacted with acetone to generate 1. Subse-
quently, compound 1 was converted to amide 2 and then
reduced to amine 3. After that, diamine 3 was reacted with
camphor sulfonyl chloride to give compound 4. The final
ligand 5 was obtained by the reduction of sulfonamide 4,
as shown in Scheme 1.
2.2. Asymmetric addition of diethylzinc to aldehydes
Once ligands 4 and 5 were prepared, they were tested in a
standard enantioselective addition of diethylzinc to p-
chloro benzaldehyde with a 5 mol % of ligand loading in
toluene. The experimental results are listed in Table 1.
From Table 1 it can be seen that ligand 4 gave a poor enan-
tiomeric excess (20% ee, entry 1 in Table 1), while ligand 5
can achieve moderate enantioselectivity under the same
condition (70% ee, entry 2 in Table 1). Therefore, ligand
5 was chosen as a catalyst model for further optimizing
the conditions. When toluene was replaced with hexane
or ether, the reaction also gave high yields, but the ee val-
*
Corresponding author. Tel./fax: +86 551 3603185; e-mail: zwang3@
ustc.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.040

2102
A. Hui et al. / Tetrahedron: Asymmetry 17 (2006) 2101–2107
OH
NH3·H2O
HO
1) EtOH/H+
O
O
O
O
NH4Cl
COOH
HOOC
2) HC(OEt)3,
Me2CO, H+
H2NOC
CONH2
COOEt
EtOOC
(R,R)-(+)
2
1
ClO2S
LiAlH4
Et2O
O
O
O
O
NaBH4
EtOH
O
O
O
H2NH2C
CH2NH2
CH2Cl2/Et3N
NHR1 NHR1
3
NHR2 NHR2
4
5
R1 =
R2 =
OH
O
SO2
SO2
Scheme 1. Synthesis of the chiral ligands.
established the optimal conditions, different aldehydes were
submitted to the addition with ligand 5. The results are pre-
sented in Table 2. As illustrated in Table 2, in all cases
tested, the reactions gave the desired products in high
yields. The addition of diethylzinc to benzaldehyde gave
the expected product with moderate enantioselectivity
(entry 1 in Table 2). Electron-withdrawing substituents at
the para-position of benzaldehyde were favorable to the
reaction yield and enantioselectivity of this addition
(entries 2 and 3 in Table 2) while electron-donating substit-
uents at the para-position of benzaldehyde disfavored the
ee value in comparison with benzaldehyde (entries 4, 5 vs
entry 1, Table 2). The ortho-substituents in benzaldehyde
gave lower ee values regardless of whether this substituent
was electron-withdrawing or electron-donating, as shown
in entries 7, 9, and 10 in Table 2. However, 2-methylbenz-
aldehyde bearing a methyl group at the ortho-position
Table 1. Enantioselective addition of diethylzinc to aldehydes under
different conditions
OH
O
L*
+ Ti(OiPr)4
H
+
Et2Zn
Cl
T (ꢁC) Time Yield eea
Cl
Entry Ligand mol % Solvent
(h)
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
Toluene
Toluene
Hexane
Et2O
20
20
20
20
20
20
20
20
20
0
1
1
2
5
10
4
85
95
93
95
—
70
96
90
82
90
84
75
95
95
20
70
64
62
—
43
58
63
64
58
41
13
60
60
THF
5
CH2Cl2
Toluene
Toluene
Toluene
Toluene
10
15
3
5
5
5
5
5
1
3
18
4
18
24
1
Toluene ꢀ20
Table 2. The addition of diethylzinc to aldehydes in the presence of ligand
5
Toluene ꢀ35
Toluene
Toluene
40
60
1
O
5 (5 mol% )
OH
Ti(OiPr)4
+
a The enantiomeric excess was determined by chiral HPLC.
+
Et2Zn
R
H
Toluene/RT
R
1.0 equiv 1.8 equiv 1.2 equiv
Entry
R
Yielda (%)
Time (h)
eeb (%)
ues decreased slightly (entries 3 and 4 in Table 1). When the
reaction was carried out in tetrahydrofuran under the same
conditions, no desired product was obtained (entry 5 in
Table 1). Neither the reaction yield nor the enantiomeric
excess can be obtained satisfactorily when the reaction
was performed in dichloromethane (entry 6 in Table 1).
The optimization for the catalyst loading showed that a
5 mol % of ligand loading was the best compromise for
reaction yield and enantioselectivity (entries 2, 7–9 in Table
1). Optimization of the reaction temperature indicated that
room temperature favored a higher enantiomeric excess.
Either elevation or decrease in reaction temperature would
lower the enantioselectivity (entries 10–14 in Table 1). The
reaction conditions in entry 2 were chosen as the optimal
conditions for this type of asymmetric addition. Having
1
2
3
4
5
6c
7
8
9
C6H5
4-FC6H4
90
93
95
81
83
97
92
96
90
95
85
95
2
1
1
12
12
2
3
2
3
2
65
75
70
60
58
63
38
81
54
63
83
31
4-ClC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
2-ClC6H4
2-MeC6H4
2-MeOC6H4
2-MeOC6H4
1-Naphthyl
Cinnamyl
10c
11
12
3
3
a Isolated yields.
b The ee values were determined by chiral OD-H column.
c 3 equiv Et2Zn was used.

A. Hui et al. / Tetrahedron: Asymmetry 17 (2006) 2101–2107
Table 3. Enantioselective addition of diethylzinc to ketones in the presence of ligand 5
2103
O
OH
5-15 mol% L*
Ti(OiPr)4
1.2 equiv
+
+
Et2Zn
R
Me
R
1.8 equiv
1.0 equiv
mol % L*
Entry
R
Solvent
T (ꢁC)
Time (h)
Yielda (%)
ee (config.)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
16d
17
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
C6H5
4-MeOC6H4
4-MeC6H4
4-PhC6H4
2-Furan
5
5
10
10
15
7
7
7
7
7
7
7
7
7
7
7
7
Toluene
Hexane
Hexane
Tol/hexc
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
Tol/hex
20
20
20
20
20
20
0
40
20
20
20
20
20
20
20
20
20
48
50
50
50
50
50
50
36
40
40
50
56
48
40
36
40
48
60
72
73
72
75
73
62
65
78
78
70
68
70
80
88
75
80
58
76
80
81
81
81
80
79
83
80
99 (S)
35
70
78
10
18
82
2-Thiophene
2-Naphthyl
a Isolated yields.
b The ee were determined by chiral HPLC using OD-H column or OJ-H column.
c Mixed solvents were used with the ratio of 1:6.
d 3 equiv Et2Zn was used in the reaction.
improved the ee value up to 81% in this addition reaction
(Table 2, entry 8). Usually it is assumed that this addition
involves a transition state, which is a titanium complex
containing the corresponding ligand and the coordinated
carbonyl compound.6 A higher electronegative substitution
at the ortho-position of benzaldehyde would have a great
influence on the coordination of the carbonyl compound
to the titanium center possibly due to the electrostatics or
a hydrogen bond between the ortho-substituent and coordi-
nated heteroatoms such as oxygen and nitrogen atoms in
this complex. Therefore, 2-chloro and 2-methoxy substitu-
tion has a electrostatic effect or an hydrogen bond with
coordinated oxygen or nitrogen in this complex besides
steric hindrance while 2-methyl substitution has only steric
hindrance, resulting in the difference of the substitution
effect on the ee value. In comparison with benzaldehyde,
sterically demanding 1-naphthaldehyde gave better enantio-
selectivity of 83% ee (Table 2, entry 11). Increasing the
amount of diethylzinc enhanced both the reaction yield
and ee value in this addition reaction (Table 2, entries 6
and 10). Cinnamaldehyde also gave the desired product
in high yield but with a poor enantioselectivity (Table 2 en-
try 12).
studying the effect of solvent, catalyst loading and temper-
ature (entries 1–8 in Table 3). After optimization, it was
found that hexane-toluene (mixed solvent with the ratio
6:1), 7 mol % of catalyst loading and room temperature
were the best options in all the conditions tested (Table
3, entry 6) and as a result were adopted in experimental
manipulation. Subsequently, different substrates were
tested under these conditions. All the experimental results
are listed in Table 3. From Table 3 it was found that ace-
tophenone gave the best enantioselectivity, being up to
99% with a good yield (entry 11 in Table 3). The electronic
properties of the substituents had a great influence on the
reaction yield and ee value. The electron-withdrawing
group on the aromatic ring of the substrate increased the
reaction enantiomeric excess (Table 3, entries 6, 9, and
10) while electron-donating substitution disfavored the
enantioselectivity (Table 3, entries 12–14). In addition,
heteroaromatic ketone derivatives, such as 2-acetyl furan
and 2-acetylthiophene, also gave good yields but with a
poor enantioselectivity in the presence of 3 equiv of Et2Zn
(entries 15 and 16 in Table 3). In comparison with acetoph-
enone, the more sterically demanding 2-acetylnaphthalene
gave good enantiomeric excess (entry 17), which implied
that steric hindrance in this substrate helped increase the
ee value.
2.3. Asymmetric addition of diethylzinc to ketones
On the basis of the good efficiency of ligand 5 for the asym-
metric addition of diethylzinc to aldehydes, we tried to
employ the sulfonamide 5 in the addition of diethylzinc
to ketones, in order to extend the scope of the reaction sub-
strate and to synthesize chiral building blocks containing a
quaternary stereogenic carbon center. First of all, p-chloro
acetophenone was chosen as a standard substrate for
3. Conclusion
We have described a new C2-symmetric chiral sulfonamide
ligand, which can be easily prepared from L-tartaric acid
and camphor sulfonyl chloride. This ligand has been
successfully used in the asymmetric addition of diethylzinc

2104
A. Hui et al. / Tetrahedron: Asymmetry 17 (2006) 2101–2107
to aldehydes and ketones in the presence of titanium tetra-
isopropoxide under mild conditions, affording the corre-
sponding chiral alcohols in high yields with good ee
values. Further investigation on the scope of the reaction
and the mechanism of the catalytic species is currently in
progress.
Calcd for C27H48N2O8S2: C, 54.70; H, 8.16; N, 4.73.
Found: C, 54.58; H, 8.12; N, 4.71.
4.3. General procedure for enantioselective addition of
diethylzinc to aldehydes
Ligand 5 (15 mg, 0.025 mmol, 0.05 equiv) and Ti(OiPr)4
(175 mg, 0.6 mmol, 1.2 equiv) were dissolved in toluene
(2 ml) or other solvents under nitrogen. The resulting mix-
ture was stirred for 10 min at room temperature (20 ꢁC).
Diethylzinc solution (0.6 ml, 0.9 mmol, 1.5 M in hexane,
1.8 equiv) was added to the above flask and the color of
the solution became orange-green. After 2 min, the corre-
sponding aldehyde (0.5 mmol, 1 equiv, diluted with 0.5 ml
toluene or dissolved in 0.5 ml toluene) was added at this
temperature. The reaction was stirred for the appointed
time indicated in Table 1 or 2 until it was quenched with
diluted hydrochloric acid. The resulting mixture was fil-
tered through silica gel, extracted with ethyl acetate
(3 · 10 ml), and the organic layer dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography col-
umn to afford the expected sec-alcohol. The enantiomeric
excess was determined by chiral HPLC.
4. Experimental
4.1. General
Unless other indicated, all reactions using diethylzinc and
Ti(OiPr)4 were carried out in dry glassware under nitrogen.
Hexane, tetrahydrofuran, ethyl ether, and toluene were
freshly distilled from sodium and benzophenone. Dichloro-
methane was freshly distilled from CaH2. Titanium tetra-
isopropoxide was freshly distilled under reduced pressure.
˚
Triethylamine was distilled and stored in 4 A MS. Ethyl
zinc solution was 1.5 M in hexane and used directly. Reac-
tions were monitored by thin-layer chromatography (TLC)
analysis. 1H NMR and 13C NMR spectra were recorded on
a Bruker AC-300 FT (1H: 300 MHz, 13C: 75.46 MHz) or
AC-400 FT (1H: 400 MHz, 13C: 100 MHz) using TMS as
internal reference. The chemical shifts (d) and coupling
constants (J) were expressed in parts per million and hertz,
respectively. IR spectra were recorded on a Perkin–Elmer
2000 FTIR. High resolution mass spectra were obtained
on GCT-TOF spectrometer. Optical rotations were
measured on a WZZ-2 polarimeter. Chiral HPLC was per-
formed in an Agilent 1100 series instrument equipped with
a diode array detector. Chiralcel OD-H column and
Chiralcel OJ-H column were purchased from Daicel chem-
ical industries with 0.46 cm B · 25 cm. Retention times (t)
for HPLC are given in minutes.
4.3.1. 1-Phenyl-1-propanol (entry 1 in Table 2). Colorless
25
oil, ½aꢁD ¼ ꢀ32:5 (c 1.0, CHCl3); IR 3383, 3029, 2965,
1
2933 cmꢀ1; H NMR 0.91 (3H, t, J = 7.4 Hz), 1.70–1.87
(3H, m and s overlap), 4.59 (1H, t, J = 6.4 Hz), 7.25–7.36
(5H, m) ppm; 13C NMR 10.1, 31.8, 75.8, 126.0, 127.3,
128.3, 144.7 ppm; HRMS calcd for C9H12O 136.0888,
found 136.0884; HPLC (chiralcel OD-H):, n-hex-
ane/iPrOH = 97:3 (v/v), flow rate = 0.5 ml/min, 25 ꢁC,
254 nm, t1 = 20.2 min, t2 = 22.9 min.
4.3.2. 1-(4-Fluorophenyl)propan-1-ol (entry 2 in Table
25
4.2. Preparation of chiral ligand
2). Colorless oil, ½aꢁD ¼ ꢀ28:0 (c 1.0, CHCl3); IR 3383,
2967, 1605 cmꢀ1 1H NMR 0.90 (3H, t, J = 7.4 Hz),
;
The syntheses of compounds 1–5 are already described in
1.67–1.85 (2H, m), 1.94 (1H, s), 4.58 (1H, t, J = 6.6 Hz),
6.99–7.05 (2H, m), 7.28–7.32 (2H, m) ppm; 13C NMR
10.0, 31.9, 75.3, 115.0, 115.2, 127.6, 127.7, 140.4, 140.4,
160.5, 163.8 ppm; HRMS calcd for C9H11FO 154.0794
found 154.0796; HPLC (chiralcel OD-H column): hex-
the literature.7
Spectral and physical data for compound 4: Yellowish solid,
25
yield: 90%; mp = 126–127 ꢁC; ½aꢁD ¼ þ25:0 (c 0.8, CHCl3);
IR 3449, 3287, 2957, 1745, 1146 cmꢀ1
;
1H NMR
ane/iPrOH = 99.5:0.5;
t1 = 68.3 min, t2 = 71.6 min.
0.4 ml/min,
25 ꢁC,
270 nm,
(300 MHz, CDCl3) 0.91 (6H, s), 1.02 (6H, s), 1.44–1.50
(6H and 2H, s and m overlap), 1.90–2.22 (10H, m), 2.30–
2.40 (2H, m), 2.95 (2H, d, J = 15.0 Hz), 3.38–3.49 (2H
and 4H overlap, d and m, J = 15.0 Hz), 4.18 (2H, m),
5.53–5.55 (2H, m) ppm; 13C NMR (75.5 Hz, CDCl3)
20.0, 20.4, 27.0, 27.6, 43.3, 43.4, 43.7, 49.3, 50.3, 59.6,
76.2, 78.0, 109.8, 217.1 ppm.
4.3.3. 1-(4-Chlorophenyl)-1-propanol (entry 3 in Table
25
2). Colorless oil, ½aꢁD ¼ ꢀ18:0 (c 1.0, benzene); IR 3374,
2966, 2933, 2877 cmꢀ1
;
1H NMR 0.90 (3H, t,
J = 7.4 Hz), 1.69–1.81 (2H, m), 1.84 (1H, s), 4.58 (1H, t,
1
J = 6.4 Hz), 7.25–7.33 (4H, m) ppm; H NMR 10.0, 31.9,
75.1, 127.4, 128.4, 133.0, 143.1 ppm; HRMS calcd for
C9H11ClO 170.0498, found 170.0493; HPLC (chiralcel
OD-H): hexane/iPrOH = 99:1, flow rate = 0.5 ml/min,
25 ꢁC, 254 nm; t1 = 38.2 min, t2 = 40.3 min.
Spectral and physical data for compound 5: white foam
25
solid, yield: 40%; mp = 83–84 ꢁC; ½aꢁD ¼ ꢀ42:6 (c 0.5,
1
CHCl3); IR 3450, 2920, 1140 cmꢀ1; H NMR (400 MHz,
CDCl3) 0.84 (6H, s), 1.07 (6H, s), 1.11–1.16 (2H, m), 1.42
(6H, s), 1.44–1.48 (2H, m), 1.72–1.82 (10H, m), 2.50 (2H,
br), 2.94 (2H, d, J = 13.8 Hz), 3.43 (4H, m), 3.53 (2H, d,
J = 13.8 Hz), 4.01 (2H, m), 4.06–4.09 (2H, q), 4.92 (2H,
m) ppm; 13C NMR (100 MHz, CDCl3) 20.0, 20.7, 27.2,
27.5, 30.5, 39.3, 44.3, 44.5, 48.9, 50.5, 52.8, 76.5, 77.1,
109.9 ppm; m/z (HPLC–ESI/MS) 591 (MꢀH)ꢀ. Anal.
4.3.4. 1-(4-Methylphenyl)-1-propanol (entry 4 in Table
25
2). Colorless oil, ½aꢁD ¼ ꢀ25:0 (c 1.0, benzene); IR 3381,
2966, 2933, 2875 cmꢀ1
;
1H NMR 0.90 (3H, t,
J = 7.4 Hz), 1.70–1.84 (3H, m and s overlap), 2.34 (3H,
s), 4.55 (1H, t, J = 6.6 Hz), 7.13–7.25 (4H, m) ppm; 13C
NMR 10.1, 21.0, 31.7, 75.7, 126.0, 128.9, 136.8,

A. Hui et al. / Tetrahedron: Asymmetry 17 (2006) 2101–2107
2105
141.8 ppm; HRMS calcd for C10H14O 150.1045, found
150.1048; HPLC (chiralcel OD-H): n-hexane/iPrOH =
99.5:0.5, flow rate = 0.4 ml/min, 25 ꢁC, 254 nm, t1 =
67.1 min, t2 = 70.1 min.
2964, 1600 cmꢀ1
1.59–1.74 (3H,
;
1H NMR 0.97 (3H, t, J = 7.4 Hz),
and overlap), 4.21 (1H, q,
m
s
J = 6.5 Hz), 6.21 (1H, dd, J = 6.7, 15.9 Hz), 6.57 (1H, d,
J = 15.9 Hz), 7.21–7.39 (5H, m) ppm; 13C NMR 9.8,
30.3, 74.4, 126.5, 127.6, 128.6, 130.4, 132.4, 136.9 ppm;
HRMS calcd for C11H14O 162.1045 found 162.1052;
HPLC (chiralcel OD-H column): hexane/iPrOH = 91:9,
flow rate = 0.5 ml/min, 260 nm, 25 ꢁC, t1 = 16.1 min,
t2 = 24.1 min.
4.3.5. 1-(4-Methoxyphenyl)-1-propanol (entry 5 in Table
25
2). Colorless oil, ½aꢁD ¼ ꢀ21:0 (c 1.0, benzene); IR 3405,
2963, 2934 cmꢀ1 1H NMR 0.89 (3H, t, J = 7.4 Hz),
;
1.69–1.84 (3H, m and s overlap), 3.80 (3H, s), 4.54 (1H,
t, J = 6.7 Hz), 6.86–6.89 (2H, m), 7.25–7.27 (2H, m) ppm;
13C NMR 10.1, 31.7, 55.2, 75.4, 113.7, 127.2, 136.9,
158.8 ppm; HRMS calcd for C10H14O2 166.0994, found
166.0996; HPLC (chiralcel OD-H): n-hexane/iPrOH =
97:3, flow rate = 0.5 ml/min, 25 ꢁC, 270 nm, t1 = 28.5
min, t2 = 31.9 min.
4.4. General procedure for enantioselective addition of
diethylzinc to ketones
Ligand 5 (21 mg, 0.035 mmol, 0.07 equiv) and Ti(OiPr)4
(175 mg, 0.6 mmol, 1.2 equiv) were dissolved in hexane
(2.5 ml) under nitrogen. The resulting mixture was stirred
for 2 min at room temperature (20 ꢁC). A diethylzinc solu-
tion (0.6 ml, 0.9 mmol, 1.5 M in hexane) was added to the
above flask causing the color of the solution to turn
orange-green. After 2 min, the corresponding ketone
(0.5 mmol, 1 equiv, dissolved in 0.5 ml toluene or diluted
with 0.5 ml toluene) was added at this temperature. The
reaction was stirred for the appointed time mentioned in
Table 3 until it was quenched with diluted hydrochloric
acid. The resulting mixture was filtered through silica gel,
extracted with ethyl acetate (3 · 10 ml) and the organic
layer was dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue purified
by flash chromatography column to afford the expected
tert-alcohol. The enantiomeric excess was determined by
chiral HPLC.
4.3.6. 1-(2-Chlorophenyl)-1-propanol (entry 7 in Table
25
2). Colorless oil, ½aꢁD ¼ ꢀ17:5 (c 2.0, CHCl3); IR 3383,
3068, 2967, 2934 cmꢀ1
;
1H NMR 0.96 (3H, t, J =
7.4 Hz), 1.65–1.83 (2H, m), 1.93 (1H, s), 5.03 (1H, dd,
J = 4.9, 7.5 Hz), 7.15–7.50 (4H, m) ppm; 13C NMR 10.0,
30.5, 71.9, 127.0, 127.3, 128.3, 129.3, 132.0, 142.1 ppm;
HRMS calcd for C9H11ClO 170.0498, found 170.0492;
HPLC (chiralcel OD-H): n-hexane/iPrOH = 99:1, flow
rate = 0.5 ml/min, 25 ꢁC, 270 nm, t1 = 30.5 min, t2 =
31.5 min.
4.3.7. 1-o-Tolylpropan-1-ol (entry 8 in Table 2). Colorless
25
oil, ½aꢁD ¼ ꢀ43:0 (c 0.5, benzene); IR 3357, 2964,
1
1460 cmꢀ1; H NMR 0.98 (3H, t, J = 7.4 Hz), 1.72–1.81
(3H, m and s overlap), 2.34 (3H, s), 4.87 (1H, t,
J = 6.3 Hz), 7.12–7.26 (3H, m), 7.44–7.47 (1H, m) ppm;
13C NMR 10.3, 19.0, 30.9, 71.8, 125.3, 126.1, 127.0,
130.2, 134.5, 142.8 ppm; HRMS calcd for C10H14O
150.1045, found 150.1040; HPLC (chiralcel OD-H col-
umn): hexane/iPrOH = 98:2, flow rate = 0.3 ml/min;
254 nm, 25 ꢁC, t1 = 40.5 min, t2 = 44.0 min.
4.4.1. 2-Phenyl-butan-2-ol (entry 11 in Table 3). Colorless
25
oil, ½aꢁD ¼ ꢀ15:7 (c 0.70, acetone); IR 3399, 2967,
1
1645 cmꢀ1; H NMR 0.80 (3H, t, J = 7.4 Hz), 1.55 (3H,
s), 1.68 (1H, s), 1.80–1.88 (2H, m), 7.23–7.44 (5H, m)
ppm; 13C NMR 8.4, 29.5, 36.7, 74.9, 125.0, 126.5, 128.1,
147.9 ppm; HRMS calcd for C10H14O 150.1045, found
150.1046; HPLC (chiralcel OD-H column): hexane/isopro-
panol = 99:1, flow rate = 0.3 ml/min, 254 nm, 25 ꢁC,
t1 = 45.3 min, t2 = 49.3 min.
4.3.8. 1-(2-Methoxyphenyl)-1-propanol (entry 9 in Table
25
2). Colorless oil, ½aꢁD ¼ ꢀ36:0 (c 1.0, toluene); IR 3406,
1
2964 cmꢀ1; H NMR 0.95 (3H, t, J = 7.4 Hz), 1.77–1.86
(2H, m), 2.40 (1H, br), 3.84 (3H, s), 4.78 (1H, t,
J = 6.6 Hz), 6.86–6.95 (2H, m), 7.23–7.30 (2H, m) ppm;
13C NMR 10.4, 30.2, 55.3, 72.1, 110.5, 120.7, 127.0,
128.2, 132.6, 156.6 ppm; HRMS calcd for C10H14O2
166.0994, found 166.0997; HPLC (chiralcel OD-H): n-hex-
ane/iPrOH = 98:2, flow rate = 0.5 ml/min, 254 nm, 25 ꢁC,
t1 = 26.9 min, t2 = 28.9 min.
4.4.2. 2-(4-Chloro-phenyl)-butan-2-ol (entry 6 in Table
25
3). Colorless oil, ½aꢁD ¼ ꢀ14:1 (c 1.5, MeOH); IR 3411,
2972, 1648, 1164 cmꢀ1
;
1H NMR 0.79 (3H, t,
J = 7.4 Hz), 1.53 (3H, s), 1.69 (1H, s), 1.77–1.83 (2H, m),
7.28–7.38 (4H, m) ppm; 13C NMR 8.3, 29.6, 36.7, 74.7,
126.6, 128.2, 132.3, 146.4 ppm; HRMS calcd for
C10H13ClO 184.0655, found 184.0658; HPLC (chiralcel
OJ-H column): hexane/isopropanol = 99:1, flow rate =
0.3 ml/min, 254 nm, 25 ꢁC, t1 = 55.5 min, t2 = 66.2 min.
4.3.9. 1-(1-Hydroxypropyl) naphthalene (entry 11 in Table
25
2). Yellow oil, ½aꢁD ¼ ꢀ53:5 (c 0.5, CHCl3); IR 3384,
3052, 2966, 2929 cmꢀ1
;
1H NMR 1.03 (3H, t,
J = 7.1 Hz), 1.85 (1H, s), 1.88–2.07 (2H, m), 5.40 (1H,
dd, J = 5.1, 7.4 Hz), 7.47–8.10 (7H, m) ppm; 13C NMR
10.5, 31.1, 72.5, 123.0, 123.3, 125.4, 125.5, 125.9, 127.8,
128.9, 130.6, 133.9, 140.3 ppm; HRMS calcd for C13H14O
186.1045, found 186.1054; HPLC (chiralcel OD-H): n-hex-
ane/iPrOH = 91:9, flow rate = 0.5 ml/min, 254 nm, 25 ꢁC,
t1 = 16.3 min, t2 = 27.8 min.
4.4.3. 2-(4-Fluoro-phenyl)-butan-2-ol (entry 9 in Table
25
3). Colorless oil, ½aꢁD ¼ ꢀ6:5 (c 3.0, MeOH); IR 3418,
2973, 1603, 1161 cmꢀ1
;
1H NMR 0.79 (3H, t,
J = 7.4 Hz), 1.53 (3H, s), 167 (1H, s), 1.77–1.86 (2H, m),
6.98–7.03 (2H, m), 7.37–7.41 (2H, m) ppm; 13C NMR
8.3, 29.6, 36.9, 74.7, 114.6, 114.9, 126.7, 126.8, 143.6,
143.6, 160.0, 163.3 ppm; HRMS calcd for C10H13FO
168.0950, found 168.0948; HPLC (chiralcel OJ-H column):
hexane/isopropanol = 99:1, flow rate = 0.3 ml/min, 270 nm,
25 ꢁC, t1 = 44.0 min, t2 = 48.9 min.
4.3.10. (E)-1-Phenylpent-1-en-3-ol (entry 11 in Table
25
2). Yellow oil, ½aꢁD ¼ ꢀ2:4 (c 3.0, CHCl3); IR 3374,

2106
A. Hui et al. / Tetrahedron: Asymmetry 17 (2006) 2101–2107
1
4.4.4. 2-(4-Bromo-phenyl)-butan-2-ol (entry 10 in Table
2971, 1130 cmꢀ1; H NMR 0.81 (3H, t, J = 7.4 Hz), 1.64
(3H, s), 1.75 (1H, s), 1.84–2.00 (2H, m), 7.25–7.54 (3H,
m), 7.80–7.90 (4H, m) ppm; 13C NMR 8.4, 29.5, 36.5,
75.0, 123.3, 123.9, 125.6, 126.0, 127.4, 127.8, 128.2, 132.3,
132.2, 145.2 ppm; HRMS calcd for C14H16O 200.1201,
found 200.1200; HPLC (chiralcel OD-H column): hex-
ane/isopropanol = 98:2, flow rate = 0.4 ml/min, 270 nm,
25 ꢁC, t1 = 52.1 min, t2 = 61.9 min.
25
3). Colorless oil, ½aꢁD ¼ ꢀ10:0 (c 2.0, MeOH); IR 3416,
1
2971, 1164 cmꢀ1; H NMR 0.79 (3H, t, J = 7.4 Hz), 1.52
(1H, s), 1.66 (1H, s), 1.76–1.85 (2H, m), 7.29–7.32 (2H,
m), 7.44–7.47 (2H, m) ppm; 13C NMR 8.3, 29.5, 36.6,
74.7, 120.4, 126.9, 131.1, 146.9 ppm; HRMS calcd for
C10H13BrO 228.0150 found 228.0152; HPLC (chiralcel
OJ-H column): hexane/isopropanol = 99:1, flow rate =
0.3 ml/min, 270 nm, 25 ꢁC, t1 = 65.8 min, t2 = 85.1 min.
4.4.5. 2-(4-Methoxy-phenyl)-butan-2-ol (entry 12 in Table 3).
Acknowledgment
25
Colorless oil, ½aꢁD ¼ ꢀ5:7 (c 3.0, CHCl3); IR 3448, 2971,
1
1611 cmꢀ1; H NMR 0.79 (3H, t, J = 7.4 Hz), 1.53 (3H,
We are grateful to National Nature Science Foundation of
China (No. 20472078 and 30572234) for their support of
this study.
s), 1.65 (1H, s), 1.77–1.86 (2H, m), 3.80 (3H, s), 6.85–6.89
(2H, m), 7.32–7.37 (2H, m) ppm; 13C NMR 8.5, 29.6,
36.8, 55.3, 74.7, 113.5, 126.2, 140.1, 158.3 ppm; HRMS
calcd for C11H16O2 180.1150, found 180.1153; HPLC (chi-
ralcel OD-H column): hexane/isopropanol = 99:1, flow rate =
0.4 ml/min, 225 nm, 25 ꢁC, t1 = 46.6 min, t2 = 54.7 min.
References
1. (a) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757–824; (b) Pu, L.
4.4.6. 2-p-Tolyl-butan-2-ol (entry 13 in Table 3). Colorless
´
Tetrahedron 2003, 59, 9873–9886; (c) Ramon, D. J.; Yus, M.
25
oil, ½aꢁD ¼ ꢀ2:1 (c 3.0, EtOH); IR 3454, 2972, 1729 cmꢀ1
;
Angew. Chem., Int. Ed. 2004, 43, 284–287; (d) Betancort, J. M.;
Garcıa, C.; Walsh, P. J. Synlett 2004, 749–760.
1H NMR 0.78 (3H, t, J = 7.5 Hz), 1.51 (3H, s), 1.64 (1H,
s), 1.81 (2H, q, J = 7.5 Hz), 2.32 (3H, s), 7.13 (2H,
J = 7.9 Hz), 7.30 (2H, J = 8.0 Hz); 13C NMR 8.4, 21.0,
29.6, 36.7, 74.9, 124.9, 128.9, 136.0, 145.0 ppm; HRMS
calcd for C11H16O 164.1201 found 164.1200; HPLC (chiral
OD-H column): hexane/isopropanol = 99.5:0.5, flow rate =
0.4 ml/min, 270 nm, 25 ꢁC, t1 = 38.7 min, t2 = 41.7 min.
´
2. (a) Schmidt, B.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1991, 30, 99–101; (b) Schmidt, B.; Seebach, D. Angew. Chem.,
Int. Ed. 1991, 30, 1321–1323; (c) Seebach, D.; Plattner, D. A.;
Beck, A. K.; Wang, Y. M.; Hunziker, D. Helv. Chim. Acta
1992, 75, 2171–2209; (d) Weber, B.; Seebach, D. Tetrahedron
1994, 50, 7473–7484; (e) Seebach, D.; Beck, A. K.; Schmidt, B.;
Wang, Y. M. Tetrahedron 1994, 50, 4363–4384; (f) Ito, Y. N.;
´ˇ
Ariza, X.; Beck, A. K.; Bohac, A.; Ganter, C.; Gawley, R. E.;
4.4.7. 2-Biphenyl-4-yl-butan-2-ol (entry 14 in Table
Kuhnle, F. N. M.; Tuleja, J.; Wang, Y. M.; Seebach, D. Helv.
¨
25
Chim. Acta 1994, 77, 2071–2110; (g) Shao, M. Y.; Gau, H. M.
Organometallics 1998, 17, 4822–4827; (h) Seebach, D.; Pichota,
A.; Beck, A. K.; Pinkerton, A. B.; Litz, T.; Karjalainen, J.;
Gramlich, V. Org. Lett. 1999, 1, 55–58; (i) Qian, C. T.; Gao, F.
F.; Sun, J. Tetrahedron: Asymmetry 2000, 11, 1733–1740.
3. (a) Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett.
1989, 30, 1657–1660; (b) Takahashi, H.; Kawakita, T.;
Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett.
1989, 30, 7095–7098; (c) Takahashi, H.; Kawakita, T.; Ohno,
M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992, 48, 5691–
5700; (d) Knochel, P. Synlett 1995, 393–403; (e) Pritchett, S.;
Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J. Am. Chem.
Soc. 1998, 120, 6423–6424; (f) Balsells, J.; Betancort, J. M.;
Walsh, P. J. Angew. Chem., Int. Ed. 2000, 39, 3428–3430; (g)
Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 3250–
3251; (h) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122,
1802–1803; (i) Hwang, C.-D.; Uang, B.-J. Tetrahedron:
Asymmetry 1998, 9, 3979–3984; (j) Paquette, L. A.; Zhou, R.
J. J. Org. Chem. 1999, 64, 7929–7934; (k) Zhang, X. M.; Guo,
C. Tetrahedron Lett. 1995, 36, 4947–4950; (l) Qiu, J.; Guo, C.;
Zhang, X. M. J. Org. Chem. 1997, 62, 2665–2668; (m) Guo, C.;
Qiu, J.; Zhang, X. M.; Verdugo, D.; Larter, M. L.; Christie,
R.; Kenney, P.; Walsh, P. J. Tetrahedron 1997, 53, 4145–4158;
(n) Ho, D. E.; Betancort, J. M.; Woodmansee, D. H.; Larter,
M. L.; Walsh, P. J. Tetrahedron Lett. 1997, 38, 3867–3870; (o)
3). Colorless oil, ½aꢁD ¼ ꢀ17:0 (c 1.5, acetone); IR 3422,
1
2971, 1163 cmꢀ1; H NMR 0.84 (3H, t, J = 7.5 Hz), 1.56
(3H, s), 1.66 (1H, s), 1.83–1.89 (2H, m), 7.24–7.58 (9H,
m) ppm; 13C NMR 8.4, 29.5, 36.7, 74.8, 125.5, 126.8,
127.0, 127.2, 128.8, 139.3, 140.9, 147.0 ppm; HRMS calcd
for C16H18O 226.1358, found 226.1351; HPLC (chiralcel
OD-H column): hexane/isopropanol = 98:2, flow rate =
0.4 ml/min, 270 nm, 25 ꢁC, t1 = 32.6 min, t2 = 43.0 min.
4.4.8. 2-Furan-2-yl-butan-2-ol (entry 15 in Table 3). Yellow
25
oil, ½aꢁD ¼ ꢀ0:5 (c 5.0, acetone); IR 3405, 2973, 1160 cmꢀ1
;
1H NMR 0.79 (3H, t, J = 7.4 Hz), 1.43 (3H, s), 1.55 (1H, s),
1.70–1.87 (2H, m), 6.18 (1H, d, J = 3.7 Hz), 6.30 (1H, dd,
J = 1.8, 3.7 Hz), 7.34 (1H, d, J = 1.8 Hz) ppm; 13C NMR
8.5, 25.8, 34.4, 71.9, 104.6, 109.9, 141.4, 159.5 ppm; HRMS
calcd for C8H12O2 140.0837, found 140.0838; HPLC (chi-
ralcel OD-H column): hexane/isopropanol = 98:2, flow rate =
0.3 ml/min, 220 nm, 25 ꢁC, t1 = 30.1 min, t2 = 32.1 min.
4.4.9. 2-Thiophen-2-yl-butan-2-ol (entry 16 in Table
25
3). Yellow oil, ½aꢁD ¼ ꢀ1:8 (c 3.0, acetone); IR 3406,
1
2972, 1160 cmꢀ1; H NMR 0.90 (3H, t, J = 7.5 Hz), 1.60
(3H, s), 1.70 (1H, s), 1.78–1.91 (2H, m), 6.85–6.95 (2H,
m), 7.15–7.20 (1H, m) ppm; 13C NMR 8.5, 29.6, 37.4,
74.1, 122.3, 123.7, 126.6, 153.2 ppm; HRMS calcd for
C8H12OS 156.0609, found 156.0608; HPLC (chiralcel
OD-H column): hexane/isopropanol = 98:2, flow rate =
0.4 ml/min, 254 nm, 25 ꢁC, t1 = 26.6 min, t2 = 29.4 min.
´
Prieto, O.; Ramon, D. J.; Yus, M. Tetrahedron: Asymmetry
´
2000, 11, 1629–1644; (p) Ramon, D. J.; Yus, M. Tetrahedron:
Asymmetry 1997, 8, 2479–2496.
´
4. (a) Ramon, D. J.; Yus, M. Tetrahedron Lett. 1998, 39, 1239–
´
1242; (b) Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651–
5666.
´
5. (a) Garcıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem.
4.4.10. 2-Naphthalen-2-yl-butan-2-ol (entry 17 in Table
3). Colorless oil, ½aꢁD ¼ ꢀ11:5 (c 2.0, MeOH); IR 3424,
´
Soc. 2002, 124, 10970–10971; (b) Yus, M.; Ramon, D. J.;
25
Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291–2293; (c)

A. Hui et al. / Tetrahedron: Asymmetry 17 (2006) 2101–2107
2107
´
Yus, M.; Ramon, D. J.; Prieto, O. Eur. J. Org. Chem. 2003,
Ostwald, R.; Chavant, P. Y.; Stadtmuller, H.; Knochel, P. J.
Org. Chem. 1994, 59, 4143–4153; (c) Pritchett, S.; Woodman-
see, D. H.; Gantzel, P.; Walsh, P. J. J. Am. Chem. Soc. 1998,
120, 6423–6424; (d) Paquette, L. A.; Zhou, R. J. J. Org. Chem.
1999, 64, 7929–7934.
´
2745–2748; (d) Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron:
Asymmetry 2003, 14, 1103–1114; (e) de Parrodi, C. A.; Walsh,
P. J. Synlett 2004, 2417–2420; (f) Forrat, V. J.; Ramon, D. J.;
Yus, M. Tetrahedron: Asymmetry 2005, 16, 3341–3344;
´
´
(g) Jeon, S. J.; Li, H. M.; Garcıa, C.; LaRochelle, L. K.;
7. (a) Jiao, P.; Xu, J. X.; Zhang, Q. H.; Choi, M. C. K.; Chan, A.
S. C. Tetrahedron: Asymmetry 2001, 12, 3081–3083; (b) Li, C.
M.A. Thesis, Dalian Institute of Chemical Physics, 2000; (c)
Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 3250–
Walsh, P. J. J. Org. Chem. 2005, 70, 448–455; (h) Jeon, S. J.;
Li, H. M.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416–
16425.
´
6. (a) Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi,
S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095–7098; (b)
3251; (d) Garcıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am.
Chem. Soc. 2002, 124, 10970–10971.