Chirality control in the enantioselective arylation of aromatic aldehydes catalyzed by cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid derived 1,3-aminoalcohols

Article abstract of DOI:10.1016/j.tetasy.2010.01.003

A series of chiral 1,3-aminoalcohols derived from cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid were synthesized and applied to the enantioselective arylation of aromatic aldehydes. The reactions exhibited good yields (up to 90%) and moderate to high

Full text of DOI:10.1016/j.tetasy.2010.01.003

Tetrahedron: Asymmetry 21 (2010) 75–80
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Tetrahedron: Asymmetry
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Chirality control in the enantioselective arylation of aromatic aldehydes
catalyzed by cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid derived
1,3-aminoalcohols
b
b
Xiang-Bo Wang a, Koichi Kodama a, Takuji Hirose a, , Xiao-Feng Yang , Guang-You Zhang
*
a School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakura, Saitama 338-8570, Japan
b Department of Chemical Engineering, University of Jinan, 106 Jiwei Road, Jinan, Shandong Province 250022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral 1,3-aminoalcohols derived from cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid
were synthesized and applied to the enantioselective arylation of aromatic aldehydes. The reactions
exhibited good yields (up to 90%) and moderate to high enantioselectivities (up to 99%). Not only the
enantioselectivity but also the stereochemistry of the product were controlled by the substituent effect
of the chiral ligands.
Received 17 November 2009
Accepted 7 January 2010
Available online 3 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
ligands with the same configuration at the stereogenic centers
effectively work to induce the opposite chirality in the product.6
Enantioselective addition of organozinc reagents to aldehydes is
one of the most extensively investigated C–C bond forming reac-
tions over the last few decades.1 A large number of chiral ligands
with various structures and reaction features have been developed
to meet the demand.2 Recently, the addition of arylzinc reagents to
obtain enantiopure diarylmethanols has gained substantial atten-
tion, because they are key structures of pharmaceutically active
compounds, such as (R)-neobenodine, (R)-orphenadrine, and
(S)-carbinoxamine.1d–f,3 In most cases, the desired enantiomer of
the product is available from one enantiomer of the ligand. How-
ever, it has also recently been reported that chirality inversion of
the product can be achieved by a change of substituent with the
same framework, that is, with the same ligand chirality.4 For exam-
ple, Szakonyi et al.4b obtained both enantiomers of the product in
the asymmetric ethylation of aromatic aldehydes by applying their
Herein, we investigated the substituent effect of chiral 1,3-amino-
alcohol ligands to change the chirality of diarylmethanols obtained
by the catalytic arylation of arylaldehydes. All optically active
1,3-aminoalcohols used in this study were prepared from the same
chiral source, cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid.
2. Results and discussion
All the enantiopure 1,3-aminoalcohols in this study were pre-
pared following our previous method.6
In order to examine the chiral induction abilities of 1,3-amino-
alcohols, we chose the aryl transfer reaction to benzaldehyde using
4-chlorophenylboronic acid and diethylzinc as a model reaction.
The reaction was conducted in the presence of 20 mol % of 1,3-ami-
noalcohols 1–7 and the results are summarized in Table 1.
The enantiomeric excess of the diarylmethanol obtained in-
creased with an increase in the number and size of N-substituents
for primary alcohols 1–4 except for 2, which holds larger N-substit-
uents but shows lower enantioselectivity than tertiary amine 1.
With a five-membered rigid cyclic structure, compound 1 showed
the best chiral induction ability (71.5% ee) compared to any other
ligand studied (Fig. 1).
The introduction of two phenyl groups in the vicinity of the
hydroxyl group of secondary amine 3 improved both the enanti-
oselectivity (41.7% ee) and the chemical yield (entries 3 vs 6).
The introduction of two 3,5-dimethoxyphenyl groups further
improved the enantioselectivity (53.5% ee) for 7, but decreased
the chemical yield dramatically compared with 3 and 6 (entries 3
and 6 vs 7). This is probably due to the increased steric hindrance
a-pinene derived 1,3-aminoalcohols. However there are as yet no
reports on chirality inversion for the asymmetric arylation of alde-
hydes caused by the substituent effects of chiral ligands. Although
both enantiomers of a target diarylmethanol can be obtained by
interchanging two reactants, boronic acids and aldehydes, as
shown by Bolm et al.,5 it is of interest to determine if a similar chi-
rality inversion is observed by changing the substituents of chiral
ligands.
In our previous work on chiral cis-(1R,2S)-2-benzamidocycloh-
exanecarboxylic acid derived 1,3-aminoalcohols as ligands for the
catalytic addition of Et2Zn to arylaldehydes, we found that some
* Corresponding author. Tel./fax: +81 48 858 3522.
E-mail address: hirose@apc.saitama-u.ac.jp (T. Hirose).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.003

76
X.-B. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 75–80
Table 1
R
Asymmetric arylation of benzaldehyde with 4-chlorophenylboronic acid in the
R
O
presence of 1–7a
R
Zn
O
Ar
Ph
Ar
O
Zn
Zn
Zn
OH
B
OH
*
N
N
1) toluene, 60 ºC, 12h
H
O
R
2) chiral ligand (20 mol%)
OH
H
Et2Zn
Ph
3) PhCHO, r.t., 48h
disfavored anti (Si)
favored anti (Re)
Cl
Cl
Entry
Chiral ligand
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
1
2
3
4
5
6
7
80.5
72.6
59.8
29.9
75.2
79.6
22.9
71.5
51.8
16.6
7.3
5.4
41.7
53.5
(S)
(S)
(S)
(S)
(R)
(R)
(R)
OH
OH
Ph
Ar
Ph
Ar
(S)
(R)
R = Et, Ar
a
b
c
Molar ratio: benzaldehyde/4-ClC6H4B(OH)2/Et2Zn/chiral ligand = 1:2:6:0.2.
Isolated yield.
Determined by HPLC analysis using a chiral column (Chiralpak AD-H; 2-PrOH/
Figure 2. Proposed transition states for arylation of benzaldehyde using 1 as a
chiral ligand.
n-hexane = 10:90; 0.5 ml/min).
d
Absolute configuration was determined by comparison of the HPLC elution
order with the literature data.7
Ph
Ph
Ph
O
Ph
O
R
R
Zn
H
R
N
Ar
Ph
O
Ar
H
Zn
Zn
Zn
OH
OH
N
H
OH
OH
NH2
Bn
O
R
Bn
H
N
N
Ph
N
H
Ph
favored anti (Si)
disfavored anti (Re)
1
2
3
4
OMe
OMe
Ph
Ph
Ph Ph
OH
Ph
OH
MeO
OH
Ph
OH
Ph
OMe
N
Ar
Ar
Ph
OH
N
H
(S)
(R)
N
H
R = Et, Ar
5
6
7
Figure 3. Proposed transition states for the arylation of benzaldehyde using 6 as a
chiral ligand.
Figure 1. Chiral ligands studied.
around the catalytic center. However, in the case of cyclic tertiary
amine 5, the introduction of two phenyl groups greatly decreased
the enantioselectivity (entries 1 vs 5).
Ph
Ph
N
Ph
O
Ph
O
R
R
Zn
H
R
N
Ar
Ph
The results summarized in Table 1 clearly show the most inter-
esting feature of the present system: both enantiomers of the prod-
uct were obtained by changing the 1,3-aminoalcohol ligands,
despite having the same chirality. Primary alcohols 1–4 gave
(S)-isomers, while tertiary alcohols 5–7 afforded (R)-isomers.
Previously, we reported that the substituent effect induces an
opposite chirality in the product of asymmetric ethylation reac-
tions to aldehydes in the presence of 1,3-aminoalcohols 1 and
3–6. Although such phenomena have been observed by several
studies, to the best of our knowledge there are still no reports on
chirality inversion caused by ligands with the same chirality in
the study of asymmetric arylation reactions.
Based on the well-known transition state models proposed by
some researchers,8 the tentative 6/4/4 tricyclo transition states
for the asymmetric arylation of aldehydes are shown in Figures
2–4 for 1, 6, and 5, respectively. In the reaction using 1 as a chiral
ligand, the anti-(Re) transition state, which leads to the formation
of the (S)-product, is favored over anti-(Si) because of the steric
repulsion difference. In the anti-(Si) form, large steric repulsion is
expected between the R group on the Zn atom and the rigid and
adjacent bulky cyclic structure of the tertiary amino group in the
six-membered Zn-chelate ring, while the anti-(Re) form has smal-
ler steric repulsion between the cyclohexane ring and the R group
O
Ar
H
Zn
Zn
Zn
O
R
Ph
comparable stability
anti (Si)
anti (Re)
Figure 4. Proposed transition states for the arylation of benzaldehyde using 5 as a
chiral ligand.
on Zn atom in the 1,3-relationship (Fig. 2). The three primary alco-
hols, 2–4 also showed (S)-selectivity but lower enantioselectivity
because of the smaller or more flexible N-substituents.
Both improved enantioselectivity and the chirality inversion of
6 can be similarly explained by the substituent effect in the pro-
posed transition states. It is obvious that the anti-(Re) form should
have much larger steric repulsion with the R group on the Zn atom
in the 1,3-relationship compared with the transition states of 1,
while the anti-(Si) form avoids such a repulsion to afford the
(R)-product (Fig. 3).
The additional 1,3-repulsion between the bulky phenyl groups
and the R group on Zn atom make the anti-(Re) form of tertiary
alcohol 6 less favored than that of primary alcohol 3. Therefore,

X.-B. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 75–80
77
Table 3
the introduction of substituents in the vicinity of the hydroxyl
group can substantially alter the enantioselectivity.
Asymmetric arylation of aldehydes in the presence of 1 and 6a
The situation is different, however, for the tertiary amine 5
(Fig. 4); both transition states have comparable steric repulsions.
The anti-(Si) form appears to be slightly favored compared with
the anti-(Re) form, resulting in low enantioselectivity (entry 5).
In order to optimize the reaction conditions, tertiary amine 1
was used in the model reaction and the results are summarized
in Table 2. It was shown that the reaction temperature has a large
effect on the enantioselectivity, and the best result was obtained at
room temperature (71.5% ee; entry 2). However, only a small effect
on conversion was observed (entries 1–3); therefore, the following
reactions were performed at room temperature.
1) toluene, 60 ºC, 12h
OH
OH
*
2) chiral ligand (30 mol%)
B
Et2Zn
Ar1
Ar2
Ar1
OH
3) Ar 2CHO, r.t., 48h
Entry Chiral ligand
Ar1
Ar2
Yieldb (%) eec (%) Config.d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1
1
1
1
1
1
1
1
1
1
1
1
1
6
6
6
6
6
6
6
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
Ph
84.6
78.6
70.9
60.9
75.8
63.5
59.4
68.5
53.2
>99
(S)
(S)
—
(R)
(S)
(R)
4-MePh
3-MePh
2-MePh
4-MeOPh 78.6
4-BrPh 90.0
2-Thienyl 56.4
e
e
5.2
—
In accordance with reports in the literature,3,5–8b,11–17 toluene
and n-hexane were chosen and the effects on enantioselectivity
and conversion were studied (entries 2, 4, and 5). Toluene afforded
a better chemical yield and enantioselectivity than the less polar
toluene/n-hexane mixture and n-hexane, perhaps due to the higher
solubility of boronic acid in toluene.
The investigation of ligand loading showed that enantioselectiv-
ity and chemical yield gradually improved by increasing the
amount of 1 (entries 2, 6, and 7). Ligand loading less than
20 mol % greatly decreased the enantioselectivity of asymmetric
arylation reactions (entries 2 vs 6).
2-MePh 4-MePh
4-MePh 2-MePh
4-MePh 4-MeOPh 38.5
4-MePh 4-ClPh
Ph
60.3
59.0
84.5
80.6
57.1
60.1
49.5
61.2
50.2
57.2
74.5
53.5
34.4
51.4
46.3
(S)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
68.8
44.5
83.5
74.1
78.8
82.7
27.6
4-MePh
4-ClPh
Ph
4-MePh
4-BrPh
Ph
4-ClPh
4-ClPh
4-ClPh
4-MePh 2-MePh
4-MePh 4-MeOPh 52.0
4-MePh 4-ClPh
Ph 4-ClPh
67.6
75.9
It has been reported that enantioselectivity is improved by the
addition of a catalytic amount of DiMPEG or MPEG.5,9 However,
the addition of MPEG to the present system led to similar enanti-
oselectivity and chemical yield (entries 2 vs 8). The addition of
Et3N and DMAP showed that the basic additives could not improve
either the enantioselectivity or the chemical yield (entries 2, 9 and
10). Possible coordination of the nitrogen atoms of the additives to
Zn atoms has a negative effect on the transition states.10
Under the optimized conditions, asymmetric arylation reactions
of other aromatic aldehydes with arylboronic acids were conducted
to further investigate the ligand effect on the chiral induction using
30 mol % of 1 and 6. As seen in Table 3, all substrates afforded the
corresponding diarylmethanols. As is widely known,5 both enantio-
mers of the desired products can be obtained using the same catalyst
by the reverse combination of arylboronic acid and aromatic alde-
hyde. For example, the reaction of 4-chlorophenylboronic acid with
benzaldehyde gave (S)-(4-chlorophenyl)phenylmethanol (75.8% ee,
a
b
c
Molar ratio: Ar2CHO/Ar1B(OH)2/Et2Zn/chiral ligand = 1:2:6:0.3.
Isolated yield.
Based on HPLC analysis.
d
Absolute configuration assigned by comparison of the known elution order with
data from reports in the literature.5,7,8b,11,12b,15,17
e
Not determined.
entry 1), while that of phenylboronic acid and 4-chlorobenzalde-
hyde gave the corresponding (R)-isomer (61.2% ee, entry 13). Unfor-
tunately, the present system was not effective for a heteroaromatic
aldehyde (entry 7), as the enantioselectivity was very low in contrast
to the systems by Bolm et al.11 As commented by Noyori et al.,1d the
possible heteroatom coordination to the Zn atom disturbed the tran-
sition states of the present ligands.
The substituent effect on chirality inversion (Table 1) was
reconfirmed for all the other aromatic aldehydes studied; when 1
Table 2
Optimization of the arylation of benzaldehyde with 4-chlorophenylboronic acid using 1a
OH
OH
*
1) solvent, 60 ºC, 12h
2) 1
3) PhCHO, temp., 48h
B
OH
Et2Zn
Cl
Cl
Entry
Chiral ligand loading (mol %)
Solvent (toluene/n-hexane)
Temp (°C)
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
20
20
20
20
20
10
30
20
20
20
1:0
1:0
1:0
1:1
0:1
1:0
1:0
1:0
1:0
1:0
0
rt
45
rt
rt
rt
rt
rt
rt
rt
71.3
80.5
85.5
75.9
55.5
73.8
84.6
82.9
37.8
51.8
67.9
71.5
12.8
68.7
59.3
54.9
75.8
71.1
44.3
63.3
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
6
7
8e
9f
10g
a
b
c
d
e
f
Molar ratio: benzaldehyde/4-ClC6H4B(OH)2/Et2Zn = 1:2:6.
Isolated yield.
Determined by HPLC analysis using a chiral column (Chiralpak AD-H; 2-PrOH/n-hexane = 10:90; 0.5 ml/min).
Absolute configuration was determined by comparison of the HPLC elution order with data from reports in the literature.7,12b
MPEG (mw = 2000 g/mol, 10 mol %) was added.
Et3N (10 mol %) was added.
DMAP (10 mol %) was added.
g

78
X.-B. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 75–80
and 6 were used in the asymmetric arylation, the opposite enanti-
omers of each target product were obtained, respectively (e.g.,
entries 1 vs 14, 2 vs 15, 6 vs 16, 9–11 vs 17–19). The use of the sub-
stituent effect to switch the product chirality is important for chiral
ligand design from certain natural chiral sources.
100 MHz): d 67.9, 64.0, 52.2, 36.2, 28.1, 25.8, 25.7, 23.0, 20.7; IR
(neat) m: 3437, 3393, 3318, 2934, 2856, 2778, 2708, 1654, 1445,
1408, 1126, 1107, 1036, 953, 915, 888 cmꢁ1; HRMS (ESI+) calcd
for C11H22NO 184.1696 (M+H+), found 184.1673.
For the reaction of p-substituted benzaldehydes with (4-chloro-
phenyl)boronic acid, the enantioselectivities decreased in the order
of Br > H > Me > OMe for the para-substituents of benzaldehyde
(entries 1, 2, 5 and 6). This result suggests that introduction of a
stronger electron-donating group onto benzaldehyde lowers the
enantioselectivity. In addition, when comparing the enantioselec-
tivities of the products from p-substituted phenylboronic acids
and arylaldehydes, (4-chlorophenyl)boronic acid afforded better
results than phenylboronic acid and (4-methylphenyl)boronic acid
(e.g., entries 2 vs 12, 5 vs 10). The improved enantioselectivity can
be attributed to the enhanced reactivity of the arylboronic acid by
the electron-withdrawing substituent. In fact, the reaction of
(4-chlorophenyl)boronic acid and 4-bromobenzaldehyde afforded
excellent chemical yield and selectivity (>99% ee, entry 6).
From the slightly higher enantioselectivity observed for the
reaction of 2-methylbenzaldehyde (entry 4) compared with those
of 3- and 4-methylbenzaldehydes (entries 2 and 3), a positional ef-
fect of the substituent was suggested for ligand 1. Considering the
anti-6/4/4 tricyclo transition states, the ortho-substituent will lead
directly to an increase in steric repulsion with the alkyl group on
Zn atom for the anti-(Si) form compared with the anti-(Re) form
(Fig. 2). The high enantioselectivity of entry 9 (80.6% ee) appears
to come from the same substituent effect of the ortho-methyl
group, despite its electron-donating property.
4.1.2. (1R,2S)-2-Piperidin-10-ylcyclohexylmethanol 2
Light yellow liquid. ½a D26
ꢀ
¼ þ16:5 (c 0.40, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 4.22–4.17 (m, 1H), 3.49–3.46 (m, 1H), 2.85–
2.40 (br, 1H), 2.50–2.39 (m, 5H), 1.93–1.74 (m, 2H), 1.70–1.15
(m, 13H); 13C NMR (CDCl3, 100 MHz): d 66.8, 63.9, 51.7, 34.9,
28.7, 26.3, 26.2, 24.4, 23.8, 21.0; IR (neat) m: 3334, 3220, 2934,
2862, 2791, 1655, 1638, 1449, 1104, 1077, 1038, 987, 961,
874 cmꢁ1; HRMS (ESI+) calcd for C12H23NO 197.1774 (M+), found
197.1218.
4.1.3. (1R,2S)-2-Benzylaminocyclohexylmethanol 3
White solid. Mp 68–68.5 °C, ½a D25
ꢀ
¼ ꢁ24:0 (c 1.0, MeOH); 1H
NMR (CDCl3, 400 MHz): d 7.35–7.14 (m, 5H), 6.25–5.65 (br, 1H),
3.94–3.87 (m, 1H), 3.82 (d, J = 8.90 Hz, 2H), 3.73–3.71 (m, 1H),
3.00–2.98 (m, 1H), 1.91–1.90 (m, 2H), 1.65–1.36 (m, 7H); 13C
NMR (CDCl3, 100 MHz): d 149.7, 128.6, 128.3, 127.2, 66.4, 58.7,
51.7, 39.0, 27.8, 25.9, 23.5, 22.6; IR (KBr)
m: 3297, 3198, 3065,
3027, 2925, 2844, 1499, 1483, 1462, 1448, 1370, 1348, 1333,
1203, 1188, 1143, 1105, 1080, 1065, 1033, 966, 914, 899, 864,
840, 805, 748, 696 cmꢁ1
; HRMS (ESI+) calcd for C14H22NO
220.1696 (M+H+), found 220.1615.
4.1.4. (1R,2S)-2-Aminocyclohexylmethanol 4
White solid. Mp 60–62 °C, ½a D19
ꢀ
¼ þ16:9 (c 1.1, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 3.81–3.70 (m, 2H), 3.27–3.25 (m, 1H), 3.21–
2.85 (br, 3H), 1.73–1.70 (m, 1H), 1.60–1.44 (m, 7H), 1.36–1.28
(m, 1H); 13C NMR (CDCl3, 100 MHz): d 66.3, 51.0, 41.1, 33.0, 24.6,
3. Conclusion
The enantioselective arylation of aromatic aldehydes was
explored in the presence of optically active 1,3-aminoalcohols
derived from cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid.
The results demonstrated that substituents in the vicinity of the
hydroxyl group have a crucial effect on chirality control. Both
enantiomers of the product could be obtained using the same chi-
rality ligands with different substituents. The chirality inversion
ability of the substituent effect of 1,3-aminoalcohols was con-
firmed for all aromatic aldehydes studied. The present study will
help to design new chiral ligands derived from natural sources,
such as amino acids.
24.2, 21.3; IR (KBr) m: 3445, 3335, 2934, 2846, 1488, 1386, 1355,
1335, 1303, 1105, 1092, 1059, 1047, 1026 cmꢁ1; HRMS (ESI+) calcd
for C7H16NO (M+H+) 130.1226, found 130.1278.
4.1.5. (1R,2S)-2-Pyrrolidin-10-ylcyclohexyldiphenylmethanol 5
White solid. Mp 143–145 °C, ½a D27
ꢀ
¼ þ4:4 (c 0.34, CHCl3); 1H
NMR: (CDCl3, 400 MHz): d 9.31–8.65 (br, 1H), 7.66–7.64 (m, 2H),
7.54–7.52 (m, 2H), 7.30–7.23 (m, 4H), 7.14–7.08 (m, 2H), 3.19 (s,
1H), 2.92–2.18 (m, 4H), 1.93–1.83 (m, 2H), 1.69–1.49 (m, 8H),
1.43–1.37 (m, 2H); 13C NMR (CDCl3, 100 MHz): d 149.3, 147.1,
128.1, 128.0, 125.8, 125.7, 125.5, 125.0, 80.6, 63.7, 54.1, 51.9,
48.0, 29.7, 26.4, 24.4, 22.6; IR (KBr) m: 3426, 3055, 3032, 2952,
4. Experimental
4.1. General
2916, 2840, 1460, 1447, 1434, 1399, 1343, 1253, 1179, 1143,
1066, 1032, 994, 908, 855, 768, 752, 707 cmꢁ1; HRMS (ESI+) calcd
for C23H30NO 336.2322 (M+H+), found 336.2583.
All the asymmetric arylation reactions of diethylzinc and aryl-
boronic acid to aldehydes were carried out under a nitrogen atmo-
sphere in anhydrous solvents. NMR spectra were recorded at
400 MHz (1H NMR) and 100 MHz (13C NMR) on a Bruker DPX400
spectrometer (Molecular Analysis and Life Science Center, Saitama
University) using CDCl3 as solvent. Optical rotations were mea-
sured with a JASCO DIP-370 polarimeter. Melting points were
obtained using a Mitamura Riken Kogyo MEL-TEMP instrument
and uncorrected. IR spectra were recorded on a JASCO FT/IR 400.
Enantiomeric excess was determined using a set of JASCO LC 900
series with Chiralpak AD-H, Chiralcel OD, OD-3 or OB-H columns
(Daicel Chemical Industries, Ltd).
4.1.6. (1R,2S)-2-Benzylaminocyclohexyldiphenylmethanol 6
Colorless viscous liquid. ½a D26
ꢀ
¼ þ85:6 (c 2.6, MeOH); 1H NMR
(CDCl3, 400 MHz): d 8.54–8.25 (br, 1H), 7.67–7.65 (m, 2H), 7.55–
7.52 (m, 2H), 7.34–7.24 (m, 9H), 7.16–7.09 (m, 2H), 3.59 (d,
J = 12.21 Hz, 1H), 3.24 (d, J = 12.10 Hz, 1H), 3.15–2.94 (m, 1H),
2.48–2.44 (m, 1H), 1.92–1.89 (m, 1H), 1.76–1.68 (m, 1H), 1.67–
1.46 (m, 4H), 1.44–1.22 (m, 3H); 13C NMR (CDCl3, 100 MHz): d
149.1, 146.9, 139.3, 128.6, 128.3, 128.2, 128.0, 127.4, 125.9,
125.8, 125.5, 125.2, 80.6, 54.1, 52.0, 47.3, 28.5, 25.8, 21.6, 20.2;
IR (neat)
m: 3317, 3060, 2926, 2852, 1597, 1491, 1468, 1450,
1432, 1381, 1210, 1176, 1136, 1067, 1032, 992, 881, 747,
698 cmꢁ1; HRMS (ESI+) calcd for C26H30NO 372.2322 (M+H+),
found 372.2896.
4.1.1. (1R,2S)-2-Pyrrolidin-10-ylcyclohexylmethanol 1
Light yellow liquid. ½a D26
ꢀ
¼ þ21:4 (c 0.39, CHCl3); 1H NMR
4.1.7. (1R,2S)-(2-Benzylaminocyclohexyl)bis(3,5-dimethoxy-
(CDCl3, 400 MHz): d 4.20–4.10 (m, 1H), 3.48–3.44 (m, 1H), 2.87–
2.58 (m, 2H), 2.57–2.39 (m, 2H), 2.38–2.31 (m, 2H), 1.76–1.59
(m, 7H), 1.49–1.46 (m, 1H), 1.38–1.15 (m, 4H); 13C NMR (CDCl3,
phenyl)-methanol 7
Colorless viscous liquid. ½a D25
ꢀ
¼ þ64:7 (c 4.0, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 8.60–8.32 (br, 1H), 7.51–7.22 (m, 5H), 6.98–

X.-B. Wang et al. / Tetrahedron: Asymmetry 21 (2010) 75–80
79
6.69 (m, 4H), 6.51–6.23 (m, 2H), 3.76 (s, 12H), 3.62 (d, J = 12.24 Hz,
1H), 3.30 (d, J = 12.04 Hz, 1H), 3.19–2.99 (m, 1H), 2.48–2.30 (m,
1H), 2.02–1.87 (m, 1H), 1.86–1.28 (m, 8H); 13C NMR (CDCl3,
100 MHz): d 160.6, 160.4, 151.7, 149.3, 139.2, 128.6, 128.3, 127.4,
104.1, 103.7, 97.8, 80.8, 55.3, 55.2, 54.2, 47.3, 28.5, 25.8, 21.7,
4.2.5. (S)-(4-Bromophenyl)(40-chlorophenyl)methanol7
White solid. 82.7% isolated yield. 74.5% ee determined by HPLC
analysis (Chiralpak AD-H column, IPA/n-hexane = 1:99, 0.5 ml/min,
230 nm). Retention time: t = 183.7 min ((R)-isomer: t = 179.1 min).
Mp 95.5–97.0 °C (74.5% ee). 1H NMR (CDCl3, 400 MHz): d 7.46–7.44
(m, 2H), 7.31–7.15 (m, 6H), 5.74 (s, 1H), 2.44 (s, 1H). 13C NMR
(CDCl3, 100 MHz): d 142.4, 141.8, 133.6, 131.7, 131.5, 128.8,
128.2, 127.9, 127.7, 121.7, 75.0.
20.2; IR (neat)
m: 3437, 3079, 3002, 2934, 2841, 1595, 1509,
1458, 1425, 1335, 1308, 1287, 1204, 1154, 1063, 925, 832, 740,
697 cmꢁ1; HRMS (ESI+) calcd for C30H37NO5 491.2666 (M+), found
491.2994.
4.2.6. (S)-(2-Methylphenyl)(40-methylphenyl)methanol7,8b
Pale yellow oil. 60.3% isolated yield. 84.5% ee determined by
HPLC analysis (Chiralcel OD and OD-3 columns, IPA/n-hex-
ane = 2:98, 0.5 ml/min, 254 nm). Retention time (Chiralcel OD):
t = 41.1 min ((R)-isomer: t = 36.2 min). Retention time (Chiralcel
OD-3): t = 55.0 min ((R)-isomer: t = 48.0 min). 1H NMR (CDCl3,
400 MHz): d 7.55–7.53 (m, 1H), 7.25–7.12 (m, 7H), 5.96 (s, 1H),
2.32 (s, 3H), 2.23 (s, 3H), 2.12 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d 141.49, 139.87, 137.23, 135.19, 130.41, 129.10, 127.34, 127.02,
126.01, 73.1, 21.0, 19.3.
4.2. General procedure for the enantioselective arylation of
aromatic aldehydes
Diethylzinc (0.9 mmol, 1.0 M in n-hexane) was added to a solu-
tion of arylboronic acid (0.3 mmol) in toluene (1.5 ml) under a
nitrogen atmosphere. After stirring for 12 h at 60 °C, the mixture
was cooled to room temperature, and the chiral ligand (30 mol %,
in 0.5 ml toluene) was added. After stirring for additional 30 min,
aldehyde (0.15 mmol, in 0.5 ml toluene) was added under a nitro-
gen atmosphere. After stirring for 48 h at room temperature, the
reaction was quenched with 1 M HCl aq. The mixture was
extracted twice with ethyl acetate. The combined organic layer
was washed with brine, dried with anhydrous Na2SO4, then filtered
and the solvent was removed. After the crude product was purified
by silica gel TLC, pure diarylmethanol was obtained. The absolute
configuration and the enantiomeric excess were determined by
the chiral HPLC analysis.
4.2.7. (R)-(4-Chlorophenyl)(20-Methylphenyl)methanol11,15
Pale yellow oil. 60.9% isolated yield. 68.5% ee determined by
HPLC analysis (Chiralcel OD column, IPA/n-hexane = 1:99, 1.0 ml/
min, 254 nm). Retention time: t = 48.4 min ((S)-isomer:
t = 54.7 min). 1H NMR (CDCl3, 400 MHz): d 7.46–7.42 (m, 1H),
7.32–7.13 (m, 7H), 5.97 (s, 1H), 2.24 (s, 3H), 2.16 (s, 1H). 13C
NMR (CDCl3, 100 MHz): d 141.4, 141.1, 135.4, 133.3, 130.7, 128.6,
128.4, 127.8, 126.4, 126.3, 72.8, 19.4.
4.2.1. (S)-(4-Chlorophenyl)phenylmethanol2b,7,12b,16
White solid. 84.6% isolated yield. 75.8% ee determined by HPLC
analysis (Chiralpak AD-H column, IPA/n-hexane = 10:90, 0.5 ml/
min, 254 nm). Retention time: t = 18.0 min ((R)-isomer: t =
16.6 min). Mp 53.5–55.2 °C (69.0% ee). 1H NMR (400 MHz, CDCl3):
d 7.35–7.26 (m, 9H), 5.81 (s, 1H), 2.26 (s, 1H). 13C NMR (100 MHz,
CDCl3): d 143.4, 142.1, 133.2, 128.6, 128.5, 128.3, 127.8, 125.9,
75.5.
4.2.8. (4-Chlorophenyl)(30-methylphenyl)methanol
Pale yellow oil. 70.9% isolated yield. 59.4% ee determined by
HPLC analysis (Chiralcel OD column, IPA/n-hexane = 1:99, 1.0 ml/
min, 230 nm). Retention time: tmajor = 49.2 min, tminor = 42.9 min.
1H NMR (CDCl3, 400 MHz): d 7.33–7.21 (m, 5H), 7.15–7.08 (m,
3H), 5.77 (s, 1H), 2.33 (s, 3H), 2.25 (s, 1H). 13C NMR (CDCl3,
100 MHz): d 143.3, 142.2, 138.3, 133.1, 128.6, 128.5, 127.8, 127.1,
123.5, 75.6, 21.4.
4.2.2. (R)-(4-Methylphenyl)phenylmethanol2b,7,16
White solid. 44.5% isolated yield. 49.5% ee determined by HPLC
analysis (Chiralcel OB-H column, IPA/n-hexane = 10:90, 0.5 ml/
min, 254 nm). Retention time: t = 29.3 min ((S)-isomer: t = 44.9
min). Mp 57.5–59.0 °C (44.9% ee). 1H NMR (CDCl3, 400 MHz): d
7.42–7.26 (m, 4H), 7.25–7.22 (m, 3H), 7.17–7.12 (m, 2H), 5.83 (s,
1H), 2.33 (s, 3H), 2.17 (s, 1H). 13C NMR (CDCl3, 100 MHz): d
143.9, 140.9, 137.2, 129.1, 128.4, 127.4, 126.4, 126.4, 76.0, 21.0.
4.2.9. (R)-(4-Methoxyphenyl)(40-methylphenyl)methanol11
White solid. 38.5% isolated yield. 57.1% ee determined by HPLC
analysis (Chiralcel OD-H column, IPA/n-hexane = 5:95, 0.5 ml/min,
210 nm). Retention time: t = 38.4 min ((S)-isomer: t = 42.6 min).
Mp 75.2–77.0 °C (57.1% ee). 1H NMR (CDCl3, 400 MHz): d 7.29–
7.24 (m, 4H), 7.15–7.13 (m, 2H), 6.87–6.85 (m, 2H), 5.78 (s, 1H),
3.79 (s, 3H), 2.33 (s, 3H), 2.14 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d 156.5, 138.7, 134.7, 133.9, 126.7, 125.3, 123.9, 111.4, 70.1, 52.8,
18.6.
4.2.3. (S)-(4-Chlorophenyl)(40-methylphenyl)methanol8b
White solid. 78.6% isolated yield. 63.5% ee determined by HPLC
analysis (Chiralcel OD and OD-3 columns, IPA/n-hexane = 2:98,
1.0 ml/min, 230 nm). Retention time (Chiralcel OD): t = 56.7 min
((R)-isomer: t = 52.2 min). Retention time (Chiralcel OD-3):
t = 67.9 min ((R)-isomer: t = 63.9 min). Mp 64.0–66.0 °C (63.5%
ee). 1H NMR (CDCl3, 400 MHz): d 7.31–7.14 (m, 8H), 5.79 (s, 1H),
2.33 (s, 3H), 2.20 (s, 1H). 13C NMR (CDCl3, 100 MHz): d 142.3,
140.5, 137.6, 133.1, 129.3, 128.5, 127.7, 126.4, 75.4, 21.0.
4.2.10. (4-Chlorophenyl)(20-thienyl)methanol17
Pale yellow oil. 56.4% isolated yield. 5.2% ee determined by
HPLC analysis (Chiralpak AD-H column, IPA/n-hexane = 2:98,
1.0 ml/min, 254 nm). Retention time: tmajor = 31.8 min, tmi-
nor = 36.0 min. 1H NMR (CDCl3, 400 MHz): d 7.40–7.27 (m, 5H),
6.96–6.89 (m, 2H), 6.05 (s, 1H), 2.40 (s, 1H). 13C NMR (CDCl3,
100 MHz): d 147.6, 141.5, 133.7, 128.6, 127.6, 126.7, 125.7, 125.0,
71.6.
4.2.4. (S)-(4-Chlorophenyl)(40-methoxyphenyl)methanol8b
White solid. 78.6% isolated yield. 53.2% ee determined by HPLC
analysis (Chiralcel OD and OD-3 columns, IPA/n-hexane = 2:98,
0.5 ml/min, 230 nm). Retention time (Chiralcel OD): t = 89.3 min
((R)-isomer: t = 97.7 min). Retention time (Chiralcel OD-3):
t = 100.0 min ((R)-isomer: t = 108.6 min). Mp 65.4–67.0 °C (53.2%
ee). 1H NMR (CDCl3, 400 MHz): d 7.30–7.23 (m, 6H), 6.87–6.85
(m, 2H), 3.79 (d, J = 5.70 Hz, 3H), 2.27 (s, 1H). 13C NMR (CDCl3,
100 MHz): d 159.3, 142.5, 135.8, 133.1, 128.5, 127.9, 127.8, 127.2,
114.0, 113.8, 75.2, 55.3.
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