Catalytic enantioselective arylation of aryl aldehydes by chiral aminophenol ligands

Article abstract of DOI:10.1016/j.tetasy.2009.01.025

The catalytic enantioselective arylation of aryl aldehydes using boronic acids as the source of transferable aryl groups is described; the reaction is found to proceed in good yields and in good to high enantioselectivities (up to 99% ee) in the presence of a chiral aminophenol ligand.

Full text of DOI:10.1016/j.tetasy.2009.01.025

Tetrahedron: Asymmetry 20 (2009) 415–419
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Tetrahedron: Asymmetry
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Catalytic enantioselective arylation of aryl aldehydes by
chiral aminophenol ligands
b
Xiao-Feng Yang a,b, Takuji Hirose a, , Guang-You Zhang
*
a Graduate 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:
The catalytic enantioselective arylation of aryl aldehydes using boronic acids as the source of transferable
aryl groups is described; the reaction is found to proceed in good yields and in good to high enantiose-
lectivities (up to 99% ee) in the presence of a chiral aminophenol ligand.
Received 27 November 2008
Accepted 23 January 2009
Available online 26 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
t
t
1: R1 = Bu, R2 = Bu, R3 = H, R4 = H
1. Introduction
OH NHR4
: R = Pr, R = tBu, R = H, R4 = H
1
2
3
i
2
3
R3
t
t
t
: R1 = Bu, R2 = Bu, R3 = Bu, R4 = H
R1
*
Enantiopure diarylmethanols are the basis of economically and
therapeutically important medicines such as (R)-neobenodine, (R)-
orphenadrine, and (S)-carbinoxamine.1 Since the pioneering work
of Fu,2 several reports concerning the preparation of chiral diaryl-
methanols by arylzinc addition to aldehydes have been published.3
One interesting approach to the synthesis of such compounds has
been recently introduced by Bolm et al.4 It consists of using arylbo-
ronic acids as the source of the transferable aryl groups. This new
methodology offers interesting advantages over the use of Ph2Zn
itself, or over the most widely used Ph2Zn–Et2Zn mixture, because
(1) it allows for an easy preparation of several substituted arylzinc
reagents and therefore for the synthesis of a wide range of diaryl-
methanols; (2) phenylboronic acid offers an inexpensive alterna-
tive to the expensive Ph2Zn. The most interesting feature of this
methodology is that both enantiomers of a given diarylmethanol
can be easily prepared in excellent yields and high enantiomeric
excess with the same chiral ligand, just by the appropriate choice
of the reaction partners: arylboronic acid and aldehyde. However,
because ligands that effectively catalyze the asymmetric arylation
of aldehydes with high ee values are relatively rare,5 the search for
efficient chiral ligands to realize high enantioselectivity still
remains an important challenge in this area.
i
4: R1 = Pr, R2 = tBu, R3 = tBu, R4 = H
5: R1 = Me, R2 = Me, R3 = Bu, R4 = H
t
R2
: R = Bu, R = Bu, R3 = Br, R4 = H
1
2
t
t
6
t
t
7: R1 = Bu, R2 = Bu, R3
=
tBu, R4 = Me
Figure 1.
sized from the electrophilic aromatic substitution reaction of Br2
to 1.
We initiated our studies by choosing p-tolualdehyde as a model
substrate to examine the efficiency of the asymmetric arylation in
the presence of a catalytic amount (10 mol %) of these aminophe-
nol ligands using phenylboronic acid as an aryl resource. The
results are summarized in Table 1. In all entries, a small amount
of ethylation product was also formed. The results of 1–7 demon-
strated the steric and electronic effects of a variety of correspond-
ing substituents on the chiral carbon atom and 4,6-positions of
phenol. Higher yields and enantiomeric excesses were achieved
by using the chiral aminophenols 3–4 with a bulky tert-butyl group
at the 6-position of phenol (Table 1, entries 1–4). Decreasing the
substituent size on the chiral carbon from bulky tert-butyl 3 to
the smallest methyl group 5 resulted in a decrease in both yield
and ee (Table 1, entries 3–5). Replacement of the electron-donating
tert-butyl group 3 with an electron-withdrawing bromo group 6
resulted in critically diminished catalytic activity (Table 1, entries
3 and 6). Methylation of the amino group 7 provided the product
in a low yield (8%) with only 5% ee, while some N-substituted ami-
noalcohols or aminophenols are effective in the asymmetric addi-
tion of alkynylzinc reagents or diethylzinc to aldehydes.7,8
In order to optimize the reaction conditions, the effects of cata-
lyst loading, solvent, temperature, and amount of PhB(OH)2–Et2Zn
were investigated in some detail with 3 that was identified as the
most effective ligand (Table 2). The phenylation of p-tolualdehyde
In connection with our current interests in the asymmetric
addition of organozinc reagents to aldehydes,6 we herein report
the behavior of these chiral aminophenols as ligands in the enan-
tioselective arylation of aryl aldehydes.
2. Results and discussion
Chiral aminophenol ligands 1–5 and 7 (Fig. 1) were prepared
following the procedure recently reported.6a,b Ligand 6 was synthe-
* 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 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.025

416
X.-F. Yang et al. / Tetrahedron: Asymmetry 20 (2009) 415–419
Table 1
Table 3
Catalytic phenylation of p-tolualdehyde with phenylboronic acid in the presence of
Catalytic arylation of aromatic aldehydes with aryl boronic acid by the chiral ligand 3a
10 mol % chiral aminophenol ligands 1–7a
1) toluene, 60 ºC, 12 h
2) 3 (20 mol%)
1) toluene, 60 ºC, 12 h
OH
OH
Ar1B(OH)2
B(OH)2
2) ligand (10 mol%)
+
Et2Zn
*
*
+
Ar1
Yieldb (%)
Ar2
3) Ar2CHO, -20 ºC, 72 h
Et2Zn
3) p-tolualdehyde, rt
Entry
Ar1
Ar2
eec,d (%)
Entry
Ligand
Reaction conditions
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MePh
o-MePh
o-ClPh
p-ClPh
p-ClPh
p-MePh
o-MePh
p-MePh
p-ClPh
p-BrPh
p-ClPh
p-MePh
p-C6H5Ph
p-MeOPh
m-MePh
o-ClPh
o-BrPh
o-MePh
2-Naphthyl
Ph
Ph
Ph
Ph
p-BrPh
o-MePh
p-MePh
p-ClPh
p-MePh
78
80
83
84
21
45e
65
82
80
88
82
77
68
90
92
87
84
88
86
91 (R)
90 (R)
92 (R)
75 (R)
50 (R)
85 (R)
80 (R)
89 (R)
>99 (R)
91 (R)
86 (S)
88 (S)
73 (S)
95 (S)
99 (R)
95 (R)
88 (S)
90 (R)
93 (S)
1
2
3
4
5
6
7
(S)-1
(S)-2
(S)-3
(S)-4
(ꢀ)-5
(R)-6
(R)-7
Toluene, rt, 28 h
Toluene, rt, 28 h
Toluene, rt, 8 h
Toluene, rt, 8 h
Toluene, rt, 20 h
Toluene, rt, 18 h
Toluene, rt, 48 h
80
78
91
90
88
89
8
6 (S)
6 (S)
78 (R)
48 (R)
54 (S)
10 (S)
5 (S)
a
Reactions were performed on a 0.25-mmol scale with PhB(OH)2 (2 equiv), Et2Zn
(6 equiv) (first at 60 °C for 12 h, then at rt).
b
Isolated yield.
Based on HPLC analysis using OB-H column.
Absolute configuration was determined by comparison of the HPLC elution
c
d
order with the literature data.5p
in the presence of 20 mol % of 3 gave the corresponding product in
a high yield and a high ee (Table 2, entry 2). We found that the
reaction was strongly influenced by solvent (Table 2, entries 2
and 4–6). Toluene gave the best result with 93% yield and 83% ee
(Table 2, entry 2). However, low ee values were obtained in tolu-
ene/CH2Cl2 or toluene/hexane, especially in toluene/THF (5% ee)
(Table 2, entries 4–6). Therefore, toluene was selected as the reac-
tion solvent in the following reactions. Decreasing or increasing the
amount of phenylboronic acid resulted in the formation of prod-
ucts with significantly lower enantiomeric excesses (Table 2,
entries 7 and 8). We then examined the effect of the PhB(OH)2–
Et2Zn ratio on the reaction, and found that decreasing the ratio of
PhB(OH)2–Et2Zn from 3:1 to 2:1 resulted in a decrease in the
enantioselectivity (Table 2, entry 2 vs entry 9). A further decrease
in the amount of PhB(OH)2–Et2Zn ratio to 1:1 gave no phenylation
product (Table 2, entry 10). Optimization of the reaction tempera-
ture indicated that carrying out the reaction at ꢀ20 °C favored a
higher ee (Table 2, entries 11–14). Thus, entry 14 was identified
as the optimized reaction conditions because of the highest
enantioselectivity.
a
Reactions were performed on a 0.25-mmol scale with PhB(OH)2 (2 equiv), Et2Zn
(6 equiv) (first at 60 °C for 12 h, then at ꢀ20 °C).
b
Isolated yield.
Based on HPLC analysis.
Absolute configuration was determined by comparison of the HPLC elution
c
d
order with the literature data.3c,5f,g,m,n,p,q
e
About 30% of the corresponding ethyl addition product was formed.
With the above optimal results, ligand 3 was further used in the
asymmetric phenylation of other aromatic aldehydes, a series of
substrates with different steric and electronic properties (Table 3,
entries 1–10). Fortunately, 3 gave good enantioselectivities (90–
92% ee) for p-substituted aryl aldehydes except for p-phenylbenz-
aldehyde (75% ee) and p-methoxybenzaldehyde (50% ee). The ee
decreases in the order of Me > Ph > MeO for the substrates with
electron-donating groups in the para-position. These results sug-
gest that the substrate with stronger electron-donating group in
Table 2
Catalytic phenylation of p-tolualdehyde with phenylboronic acida
1) toluene,
2) 3
60 ºC, 12 h
OH
B(OH)2
+
Et2Zn
3) p-tolualdehyde
Entry
Ligand 3 (equiv)
PhB(OH)2 (equiv)/Et2Zn (equiv)
Reaction conditions
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
0.1
0.2
0.5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
2/6
2/6
2/6
2/6
2/6
2/6
1/3
2.5/7.5
2/4
2/2
2/6
2/6
2/6
2/6
Toluene, rt, 8 h
Toluene, rt, 8 h
Toluene, rt, 8 h
Toluene/CH2Cl2, rt, 28 h
Toluene/THF, rt, 72 h
Toluene/hexane, rt, 30 h
Toluene, rt, 72 h
Toluene, rt, 24 h
Toluene, rt, 72 h
Toluene, rt, 72 h
Toluene, 10 °C, 32 h
Toluene, 0 °C, 36 h
Toluene, ꢀ5 °C, 36 h
Toluene, ꢀ20 °C, 72 h
91
93
92
79
10
68
16
88
56
—
78 (R)
83 (R)
84 (R)
58 (R)
5 (R)
60 (R)
66 (R)
72 (R)
53 (R)
—
86
85
85
83
85 (R)
85 (R)
88 (R)
92 (R)
a
Reactions were performed on a 0.25-mmol scale.
Isolated yield.
b
c
Based on HPLC analysis using OB-H column.
d
Absolute configuration was determined by comparison of the HPLC elution order with the literature data.5p

X.-F. Yang et al. / Tetrahedron: Asymmetry 20 (2009) 415–419
417
the para-position of aryl aldehydes affords lower enantioselectivi-
ties. On the other hand, only 20% chemical yield was obtained for
p-methoxybenzaldehyde. This aldehyde remained unreacted after
the reaction time, so that the reaction is apparently retarded by
this functional group but the effect is not clear at present, which
is different from the literature.4,5a–n,p The presence of groups at
the ortho-position shows some differences in enantioselection.
For example, o-tolualdehyde undergoes smooth aryl addition,
delivering the corresponding diarylmethanol in over 99% ee, while
the o-chloro and o-bromo derivatives resulted in much lower
enantioselectivities (entries 7–9). These results suggest that the
enantioselectivity of phenylzinc species to ortho-substituted alde-
hydes is affected not only by steric effect, but also by the electronic
effect. In the next step, we investigated the aryl transfer to benzal-
dehyde with substituted phenylboronic acid (Table 3, entries
11–14). In order to examine if different aryl groups could be trans-
ferred to aldehydes with the same stereoselectivity, the aryl trans-
fer reaction of some substituted arylboronic acids with
benzaldehyde was studied; good to high yields and enantiomeric
excesses were obtained (entries 11–14). For example, the aryl
transfer reaction from p-chlorophenylboronic acid to benzalde-
hyde occurred with 90% yield and 95% ee (entry 14). The aryl trans-
noted in all the examples studied (Table 2; Table 3, entries
1–10). Comparison of the absolute configuration of the addition
products for the phenylation of arylaldehydes with that obtained
in ethylation and phenylethynylation of arylaldehydes enabled us
to ascertain that the present phenyl transfer process was mecha-
nistically similar to ethyl or phenylethynyl transfer process, that
is, the Re face of arylaldehydes was attacked by a phenyl group,
an ethyl group, and a phenylethynyl group, respectively (Fig. 2).6a,b
3. Conclusions
In conclusion, an efficient and catalytic asymmetric synthesis of
diarylmethanols by the aminophenol 3 has been demonstrated.
This method provides a direct and convenient way to synthesize
functionalized diarylmethanols with good to high enantioselectiv-
ities from the combination of readily available arylboronic acids
and aryl aldehydes.
4. Experimental
The 1H NMR spectra were recorded on Bruker AC300 or DPX400
MHz in Molecular Analysis and Life Science Center (Saitama Uni-
versity). The chemical shifts were reported in ppm downfield from
Me4Si in CDCl3 solution, and the coupling constants were given in
Hz. IR spectra were recorded on JASCO FT/IR 400. Enantiomeric ex-
cess determination was carried out using a set of JASCO LC 900 ser-
ies with chiral columns. Optical rotations were measured with a
JASCO DIP-370 polarimeter. Melting points were determined with
a Mitamura Riken Kogyo MEL-TEMP instrument, and are reported
uncorrected. All reagents that are commercially available were
purchased at the highest quality and were purified by distillation
when necessary. Hexane and toluene were distilled and stored
over sodium wire before use.
fer
reaction
of
substituted
phenylboronic
acid
(p-
chlorophenylboronic acid) with substituted benzaldehyde (p-bro-
mobenzaldehyde) also afforded the corresponding product with
enantioselectivities of up to 99% (Table 3, entry 15).
So far, the substrate scope of the aryl transfer reaction seems to
be rather limited,5 that is, phenyl-transfer to aromatic aldehydes
(substituted benzaldehydes) or aryl-transfer to benzaldehyde has
usually been investigated, affording arylphenylmethanols. To the
best of our knowledge, only two examples have been reported
regarding the synthesis of diarylmethanols with two differently
substituted aryl groups by organozinc reagents.5d,m,n In order to
further examine the generality of this methodology and the appli-
cability of the approach to more functionalized diarylmethanols, a
series of reverse combinations of the reaction of arylaldehydes
with arylboronic acid were tested, and the results are summarized
in Table 3 (Table 3, entries 16–19). As seen in Table 3, just by the
appropriate choice of the reaction partners, both enantiomers of
a given diarylmethanol can be easily obtained in good yields with
high enantioselectivities by means of the same ligand 3 (entries
16–19). On the other hand, the enantioselectivity of the reactions
of p-chlorophenylboronic acid with substituted benzaldehydes is
subject to an electronic effect. The substrate with an electron-
withdrawing group (p-bromobenzaldehyde) afforded higher
enantioselectivity than that with an electron-donating group
(p-tolualdehyde) (Table 3, entries 14, 15, and 19).
4.1. (R)-2-(1-Amino-2,2-dimethylpropyl)-6-bromo-4-tert-
butylphenol 6
To a solution of (R)-1 (149.0 mg, 0.632 mmol) in glacial acetic
acid (10 ml) was added Br2 (50 ll) at 10–20 °C, and the mixture
was stirred for 12 h. At 0 °C, an aqueous Na2CO3 solution was
added to bring the solution to pH 8–9, and the mixture was ex-
tracted with ethyl acetate (5 ml ꢁ 3). The organic layer was dried
with anhydrous Na2SO4, and the solvent was removed. The crude
product was purified by silica gel TLC (hexane/ethyl acetate = 2:1)
to give (R)-6 (103.0 mg, 0.328 mmol, 51.6%) as a white solid. (R)-6,
½
a 2D0
ꢂ
¼ ꢀ14:1 (c 1.0, MeOH). Mp: 137.8–139.2 °C. 1H NMR
(400 MHz, CDCl3, d ppm): 7.41 (d, 1H, J = 2.4 Hz, ArH), 6.84 (d,
1H, J = 2.4 Hz, ArH), 3.85 (s, 1H, (CH3)3CCHAr), 1.26 (s, 9H,
(CH3)3CAr), 0.97 (s, 9H, (CH3)3CCHAr). 13C NMR (100 MHz, CDCl3):
d 152.5, 141.6, 128.7, 127.2, 124.2, 110.9, 66.7, 36.2, 33.9, 31.4,
26.7. IR (KBr) 3482, 3014, 2964, 1644, 1595, 1407, 1323, 1270,
1140, 808, 776 cmꢀ1. Anal. Calcd for C15H24BrNO: C, 57.33; H,
7.70; N, 4.46. Found: C, 57.56; H, 7.81; N, 4.42.
The (R)-configuration for the arylphenyl addition products, the
same as the addition of diethylzinc to arylaldehydes and the addi-
tion of phenylacetylene to arylaldehydes catalyzed by 3,6a,b was
tBu
tBu
tBu
4.2. Catalytic enantioselective arylation of aromatic aldehydes
O
H
Zn
R
N
H
R
Diethylzinc (1.5 mmol, 1.0 M in hexane) was added to a solu-
tion of arylboronic acid (0.5 mmol) in toluene (1.5 ml) under nitro-
gen atmosphere. After stirring for 12 h at 60 °C, the mixture was
cooled to room temperature, and chiral ligand 3 (20 mol %) was
added. After stirring for additional 30 min, the mixture was cooled
to ꢀ20 °C, and aldehyde (0.25 mmol) was subsequently added un-
der nitrogen atmosphere. After 72 h at ꢀ20 °C, the reaction was
quenched with 1 N HCl aq. The mixture was extracted twice with
ethyl acetate. The combined organic layer was washed with brine,
Zn
H
Ph
H
O
R = Et, Ph
anti (Re)
Figure 2.

418
X.-F. Yang et al. / Tetrahedron: Asymmetry 20 (2009) 415–419
dried with anhydrous Na2SO4, filtered, and the solvent was re-
moved. Purification of the residue by silica gel TLC afforded the
pure diarylmethanol. Enantiomeric excess of the product was
determined by chiral HPLC on a Chiralcel OB-H, OJ, AD-H, or OD-
H column.
d 142.9, 141.4, 135.4, 130.5, 128.5, 127.6, 127.5, 127.1, 126.3,
126.1, 73.4, 19.4.
4.2.9. (R)-Naphthalen-2-yl-phenyl-methanol5g
88% isolated yield. 91% ee determined by HPLC analysis (Chiral-
cel OD-H column, 10% IPA in hexane, 0.5 ml/min, 254 nm UV
4.2.1. (R)-(p-Tolyl)phenylmethanol5p
detector).
Retention
time:
t = 44.23 min
((S)-isomer:
83% isolated yield. 92% ee determined by HPLC analysis (Chiral-
cel OB-H column, 10% IPA in hexane, 0.5 ml/min, 254 nm UV detec-
tor). Retention time: t = 28.51 min ((S)-isomer: t = 47.31 min). 1H
NMR (400 MHz, CDCl3): d 7.36–7.23 (m, 7H), 7.12–7.11 (m, 2H),
5.36 (s, 1H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3): d 142.6,
139.4, 139.3, 137.1, 129.1, 128.3, 127.3, 127.2, 127.1, 79.7, 21.2.
t = 37.27 min). 1H NMR (300 MHz, CDCl3): d 7.80–7.69 (m, 4H),
7.41–7.32 (m, 5H), 7.27–7.16 (m, 3H), 5.90 (s, 1H), 2.37 (s, 1H).
4.2.10. (R)-(4-Biphenyl)phenylmethanol3c
84% isolated yield. 75% ee determined by HPLC analysis (Chiral-
cel OB-H column, 10% IPA in hexane, 1.0 ml/min, 254 nm UV detec-
tor). Retention time: t = 30.49 min ((S)-isomer: t = 10.49 min). 1H
NMR (300 MHz, CDCl3): d 7.52–7.46 (m, 4H), 7.37–7.14 (m, 10H),
5.80 (s, 1H), 2.27 (s, 1H).
4.2.2. (R)-(p-Chlorophenyl)phenylmethanol5q
80% isolated yield. 90% ee determined by HPLC analysis (Chiral-
cel AD-H column, 10% IPA in hexane, 0.5 ml/min, 254 nm UV detec-
tor). Retention time: t = 16.82 min ((S)-isomer: t = 18.40 min). 1H
NMR (300 MHz, CDCl3): d 7.35–7.20 (m, 9H), 5.80 (s, 1H), 2.37 (s,
1H).
4.2.11. (R)-(2-Tolyl)-(40-tolyl)methanol5m,n
87% isolated yield. 95% ee determined by HPLC analysis (Chiral-
cel OD-H column, 1% IPA in hexane, 1.0 ml/min, 254 nm UV detec-
tor). Retention time: t = 47.95 min ((S)-isomer: t = 53.69 min). 1H
NMR (300 MHz, CDCl3): d 7.54–7.51 (m, 1H), 7.24–7.10 (m, 7H),
5.96 (s, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 2.12 (s, 1H).
4.2.3. (R)-(p-Methoxyphenyl)phenylmethanol5f
21% isolated yield. 50% ee determined by HPLC analysis (Chiral-
cel OJ column, 10% IPA in hexane, 1.0 ml/min, 254 nm UV detector).
Retention time: t = 39.03 min ((S)-isomer: t = 46.10 min). 1H NMR
(400 MHz, CDCl3): d 7.38–7.26 (m, 7H), 6.88–6.85 (m, 2H), 5.81
(s, 1H), 3.79 (s, 1H), 2.20 (s, 1H). 13C NMR (100 MHz, CDCl3): d
159.1, 144.0, 136.2, 128.5, 127.9, 127.4, 127.2, 126.4, 113.9,
113.8, 75.7, 55.3.
4.2.12. (R)-(4-Chlorophenyl)-(40-tolyl)methanol5m,n
88% isolated yield. 90% ee determined by HPLC analysis (Chiral-
cel OD-H column, 2% IPA in hexane, 1.0 ml/min, 254 nm UV detec-
tor). Retention time: t = 80.10 min ((S)-isomer: t = 63.56 min). 1H
NMR (300 MHz, CDCl3): d 7.29–7.20 (m, 7H), 7.15–7.13 (m, 1H),
5.78 (s, 1H), 2.32 (s, 3H), 2.20 (s, 1H).
4.2.4. (R)-(p-Bromophenyl)phenylmethanol5g
78% isolated yield. 91% ee determined by HPLC analysis (Chiral-
cel OB-H column, 10% IPA in hexane, 1.0 ml/min, 254 nm UV detec-
tor). Retention time: t = 20.21 min ((S)-isomer: t = 41.94 min). 1H
NMR (400 MHz, CDCl3): d 7.46–7.44 (m, 2H), 7.35–7.25 (m, 7H),
5.79 (s, 1H), 2.25 (s, 1H). 13C NMR (100 MHz, CDCl3): d 143.4,
142.7, 131.6, 131.5, 128.7, 128.2, 127.9, 126.5, 121.4, 75.7.
4.2.13. (R)-(4-Bromophenyl)-(40-chlorophenyl)methanol
92% isolated yield. 99% ee determined by HPLC analysis (Chi-
ralcel AD-H column, 2% IPA in hexane, 0.5 ml/min, 254 nm UV
detector). Retention time: t = 68.96 min ((S)-isomer: t =
70.63 min). 1H NMR (400 MHz, CDCl3): d 7.39–7.37 (m, 2H),
7.24–7.12 (m, 6H), 5.68 (s, 1H), 2.25 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 142.3, 141.7, 133.6, 131.7, 131.5, 128.7,
128.2, 127.9, 127.7, 121.7, 74.9.
4.2.5. (R)-(m-Tolyl)phenylmethanol5g
45% isolated yield. 85% ee determined by HPLC analysis (Chiral-
cel OJ column, 10% IPA in hexane, 1.0 ml/min, 254 nm UV detector).
Retention time: t = 20.72 min ((S)-isomer: t = 30.37 min). 1H NMR
(400 MHz, CDCl3): d 7.37–7.20 (m, 9H), 5.81 (s, 1H), 2.33 (s, 3H),
2.18 (s, 1H).
References
1. (a) Harms, A. F.; Nauta, W. T. J. Med. Pharm. Chem. 1960, 2, 57–77; (b) Sperber,
N.; Papa, D.; Schwenk, E.; Sherlock, M. J. Am. Chem. Soc. 1949, 71, 887–890.
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2532–2543.
4.2.6. (R)-(o-Chlorophenyl)phenylmethanol5p
65% isolated yield. 80% ee determined by HPLC analysis (Chiral-
cel OB-H column, 10% IPA in hexane, 0.5 ml/min, 254 nm UV detec-
tor). Retention time: t = 29.71 min ((S)-isomer: t = 42.99 min). 1H
NMR (400 MHz, CDCl3): d 7.32–7.16 (m, 9H), 6.23 (s, 1H), 2.45 (s,
1H).
4. Bolm, C.; Rudolph, J. J. Am. Chem. Soc. 2002, 124, 14850–14851.
5. (a) Rudolph, J.; Schmidt, F.; Bolm, C. Synthesis 2005, 840–842; (b) Ozcubukcu, S.;
Schmidt, F.; Bolm, C. Org. Lett. 2005, 7, 1407–1409; (c) Park, J. K.; Lee, H. G.;
Bolm, C.; Kim, B. M. Chem.-Eur. J. 2005, 11, 945–950; (d) Rudolph, J.; Loumann,
M.; Bolm, C.; Dahmen, S. Adv. Synth. Catal. 2005, 347, 1361–1368; (e) Wu, X.; Liu,
X.; Zhao, G. Tetrahedron: Asymmetry 2005, 16, 2299–2305; (f) Liu, X.; Wu, X.;
Chai, Z.; Wu, Y.; Zhao, G.; Zhu, S. J. Org. Chem. 2005, 70, 7432–7435; (g) Ji, J.-X.;
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Chem. Commun. 2005, 2512–2514; (i) Braga, A. L.; Lüdtke, D. S.; Schneider, P. H.;
Vargas, F.; Schneider, A.; Wessjohann, L. A.; Paixão, M. W. Tetrahedron Lett. 2005,
46, 7827–7830; (j) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71, 833–
835; (k) Dahmen, S.; Lormann, M. Org. Lett. 2005, 7, 4597–4600; (l) Ito, K.;
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4.2.7. (R)-(o-Bromophenyl)phenylmethanol5g
82% isolated yield. 89% ee determined by HPLC analysis (Chiral-
cel OD-H column, 10% IPA in hexane, 0.5 ml/min, 254 nm UV
detector).
Retention
time:
t = 18.89 min
((S)-isomer:
t = 24.22 min). 1H NMR (300 MHz, CDCl3): d 7.59–7.48 (m, 2H),
7.40–7.23 (m, 6H), 7.16–7.10 (m, 1H), 6.17 (s, 1H), 2.62 (s, 1H).
4.2.8. (R)-(o-Tolyl)phenylmethanol5g
80% isolated yield. 99% ee determined by HPLC analysis (Chiral-
cel OB-H column, 10% IPA in hexane, 0.5 ml/min, 254 nm UV detec-
tor). Retention time: t = 36.31 min ((S)-isomer: t = 54.21 min). 1H
NMR (400 MHz, CDCl3): d 7.52–7.50 (m, 1H), 7.33–7.13 (m, 8H),
5.99 (s, 1H), 2.24 (s, 3H), 2.21 (s, 1H). 13C NMR (100 MHz, CDCl3):

X.-F. Yang et al. / Tetrahedron: Asymmetry 20 (2009) 415–419
419
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G.-Y. Tetrahedron: Asymmetry 2007, 18, 2668–2673; (c) Yang, X.-F.; Hirose, T.;
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