Enantioselective addition of thiophenylboronic acids to aldehydes using ZnEt2/Schiff-base catalytic system

Article abstract of DOI:10.1016/j.tetasy.2009.02.059

Using Schiff-base amino alcohols as catalysts which were readily derived from natural amino acids in three steps, a series of valuable optically active thiophenyl methanols (4a-4n) were first obtained in good yields and high enantioselectivities (up to 96% ee) through the asymmetric addition of thiophenylboronic acid to aldehydes in the presence of ZnEt₂ in toluene. Crown Copyright

Full text of DOI:10.1016/j.tetasy.2009.02.059

Tetrahedron: Asymmetry 20 (2009) 616–620
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective addition of thiophenylboronic acids to aldehydes using
ZnEt /Schiff-base catalytic system
2
a,b
a
b
a
a,b,*
Xiaodong Liu , Li Qiu , Liang Hong , Wenjing Yan , Rui Wang
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
State Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou 730000, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Using Schiff-base amino alcohols as catalysts which were readily derived from natural amino acids in
three steps, a series of valuable optically active thiophenyl methanols (4a–4n) were first obtained in good
yields and high enantioselectivities (up to 96% ee) through the asymmetric addition of thiophenylboronic
Received 20 January 2009
Accepted 17 February 2009
Available online 22 April 2009
2
acid to aldehydes in the presence of ZnEt in toluene.
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1
. Introduction
2. Result and discussion
Catalytic asymmetric arylation of aldehydes has been widely
2
Based on the previous study of the ZnEt catalytic system in our
9
studied as one of the most important methods for the synthesis
group, we examined a series of ligands derived from natural
amino acids to catalyze the asymmetric addition of thiophenylbo-
ronic acid to aldehydes. As a model reaction, we studied the
reactivity of 2-chlorobenzaldehyde 3a with 2.5 equiv of 2-thi-
1
of enantiopure diaryl methanols, which are important intermedi-
ates for the synthesis of biologically and pharmaceutically active
2
compounds. Among these studies, the enantioselective addition
1
0
of aryl organometallic reagents to aldehydes remains an inten-
ophenylboronic acid 2 in the presence of 10 mol % ligand at room
3
9e
sively studied area. Since the pioneering work of Fu in 1997,
temperature in toluene (Table 1). Fortunately, the oxazolidine A,
1
1
9b
Pu’s group and Bolm’s group had developed a way of highly enan-
Schiff-base amino alcohol B1 , and camphorsulfonamide C were
useful ligands in this reaction (Fig. 1). The best enantioselectivity of
66% ee was obtained when Schiff-base amino alcohol B1 was used
(Table 1, entry 2). To the best of our knowledge, the use of Schiff-
base amino alcohols chiral ligands in the enantioselective thio-
phenyl transfer to aldehydes has not yet been reported.
2
a,4
tioselective phenyl transfer with diphenylzinc, respectively.
Be-
cause of the advantageous features of organoboronic acids such as
low toxicity and easy manipulation, they had been used as high
5
efficient aryl transfer reagents in the enantioselective addition.
So recently, a series of ligands had been used to catalyze this type
of reaction together with palladium or zinc reagents.6
After having identified an efficient catalyst B1, our focus was to
optimize the reaction conditions. By increasing the amount of li-
gand, we found that 20 mol % of B1 gave a higher ee value of
84%, but a further increase of B1 amount in the reaction did not
lead to a further improvement of ee value (Table 1, entries 4 and
5). The reaction gave a slightly higher ee when the reaction tem-
perature was decreased from 20 to ꢀ40 °C, but a longer reaction
time was needed and the yield decreased to 51%. According to
the results reported by Bolm et al. in 2004, simple PEG ethers
had beneficial effects on the catalyzed enantioselective pro-
Besides the phenyl addition products, the enantiopure thio-
phene methanols, which are important intermediates in manufac-
turing dyes, aroma compounds, and pharmaceuticals, also would
be a series of valuable compounds to make.7 However, only one
example using thiophenylboronic acid as a substrate to prepare
chiral thiophene methanol has been reported in 2007 by Bolm’s
5
f
group, in which they used a complicated ferrocene as catalyst.
As we know, this catalyst was synthesized from ferrocenecarbox-
ylic acid in more than five steps.8 Therefore it is still desirable to
develop or find more efficient systems for the asymmetric addition
of thiophenylboronic acid to a variety of aldehydes. Herein, we re-
port the new application result of a series of ligands for the cata-
lytic, enantioselective thiophenyl transfer reaction in the
5
b
cesses. In our case, when 10 mol % DIMPEG and IMPEG were used
as the additive, respectively, both of them could improve the ee
values (Table 1, entries 9 and 10) and a better enantioselective ex-
cess of 91% was obtained when 10 mol % IMPEG was used.
presence of ZnEt
2
.
After the identification of the Schiff-base amino alcohol B1 as
the most efficient ligand among A, B1, and C, a series of similar
Schiff-base amino alcohols were also screened to identify the most
efficient one in this series and the result is shown in Table 2. This
series of Schiff-base amino alcohols B2, B3, B4, B5, and B6 were
*
Corresponding author. Tel.: +86 931 891 1255; fax: +86 931 891 2567.
E-mail address: wangrui@lzu.edu.cn (R. Wang).
0
957-4166/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.059

X. Liu et al. / Tetrahedron: Asymmetry 20 (2009) 616–620
617
attaching a bulky substituent at the R1 position led to a dramatic
decrease in enantioselectivity, such as B4 gave only 40% ee. How-
ever, slightly increased ee values were observed when a bulky sub-
Table 1
a
Asymmetric aryl transfer to 2-chlorobenzaldehyde using 2-thiophenylboronic acid
OH
B
OH
*
1
) toluene, 70 oC, 6 h
2) ligand
2
S
S
stituent was attached at the R position. Both B5 and B6 proved to
OH
+ ZnEt2
3
) 2-ClC H4CHO 3a
be most reactive and selective ligands for this thiophenyl transfer
reaction (Table 2, entries 4 and 5). It was proposed that the strong
steric-hindrance effect provided by both of isopropyl and anthryl/
naphthyl made B5 and B6 to show a higher catalyst effect. Since li-
gand B5 gave the highest ee value of 92% together with highest
overall yield, catalyst B5 was chosen for the thiophenylboronic
acid to aldehydes addition.
Having optimized the reaction conditions, a variety of alde-
hydes were investigated to explore the substrate scope. As shown
in Table 3, most of them were proved to be excellent aryl acceptors
for this thiophenyl transfer reaction, and provided the correspond-
ing products in good to high yields, and with excellent ee values
6
Cl
4a
2
Yieldb (%)
eec (%)
Entry
Ligand (mol %)
Temp/time (°C/h)
1
2
3
4
5
6
7
8
A (10)
B1 (10)
C (10)
B1 (20)
B1 (30)
B1 (5)
B1 (20)
B1 (20)
B1 (20)
B1 (20)
20/12
20/12
20/12
20/10
20/10
20/12
ꢀ10/12
ꢀ40/24
20/8
49
61
58
71
68
58
66
51
74
72
60
66
40
84
84
45
84
85
91
90
d
9
1
e
0
20/8
(
up to 96% ee).
a
Reactions of benzaldehyde gave an excellent ee value of 93%
Reactions were performed with 1.2 equiv of 2-thiophenylboronic acid and
.6 equiv of ZnEt in toluene.
Isolated yields.
3
2
with a good yield of 82% (Table 3, entry 1). Regardless of the elec-
tronic and steric properties of the substituents, the aromatic alde-
hydes 3b–l underwent the reactions to yield the optically active
adducts 4b–l in good yields and 81–96% ee. The position of the
substituent group on the aromatic aldehydes only slightly influ-
enced the enantioselectivity of the reaction: 2-methoxy-, 3-meth-
oxy-, and 4-methoxyphenyl-substituted aldehydes reacted
smoothly with thiophenylboronic acid to afford the desired sec-
ondary methanols with similar enantioselectivities (Table 3, en-
tries 8–10).
b
c
The enantiomeric excess was determined by HPLC analysis on a Chiralpak
column.
d
Using 10 mol % IMPEG as an additive.
Using 10 mol % DIMPEG as an additive.
e
Ph
Ph
Ph
Ph
Ph
OH
Furthermore, other aldehydes were also screened in this reac-
O
NHTs
OH
1
2
tion. The reaction of bulky aldehyde such as 2-naphthaldehyde
Table 3, entry 13) provided product 4m in 88% ee with a yield
HN
N
(
Ph
of 68%. The heteroaromatic aldehyde, 2-furaldehyde, was also
A
B1
C
Figure 1. Chiral ligands tested.
Table 3
Enantioselective thiophenyl transfer to aldehydes using B5 as the chiral ligandsa
OH
B
OH
1
) IMPEG (10mol%),
toluene, 70 C , 6 h
∗
Table 2
o
S
S
Asymmetric aryl transfer to 2-chlorobenzaldehyde using 2-thiophenylboronic acid
with different Schiff-base amino alcohol ligands
OH
+
ZnEt2
R
a
2) B5(20mol%)
3
) RCHO (3a-3n),
R1 Ph
1
1
1
1
2
o
B2: R = i-propyl R = Ph
20
C , 8 h
Ph
OH
2
2
2
2
2
4a-4n
B3: R = Ph
R
R
R
R
= Ph
B4: R = Bn
= Ph
Ph
N
B5: R = i-buty
= 9-anthryl
= 1-naphthyl
Ph
OH
R2
1
B6
:
R = i-buty
N
B5
1) toluene, 70 oC, 6 h
OH
*
OH
2
) ligand
S
S
B
OH
+ ZnEt2
3
) 2-ClC6H4CHO 3a
Yieldb (%)
eec (%)
Entry
R in RCHO
Phenyl
Product
Cl
4a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
82
74
72
83
79
67
83
79
77
81
61
85
68
77
93
92
81
85
92
94
2
2-Chlorophenyl
3-Chlorophenyl
4-Chlorophenyl
4-Fluorophenyl
2-Methylphenyl
4-Methylphenyl
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
2-Bromophenyl
4-Bromophenyl
2-Naphthyl
Entry
Ligand (mol %)
Temp/time (°C/h)
Yieldb (%)
eec (%)
1
2
3
4
5
B2 (20)
B3 (20)
B4 (20)
B5 (20)
B6 (20)
20/8
20/8
20/8
20/8
20/8
75
70
nd
74
70
89
68
40
92
91
d
d
84 (R)
95
93
96
95
92
88
82
a
Reactions were performed with 1.2 equiv of 2-thiophenylboronic acid and
in toluene, using 10 mol % IMPEG as an additive.
Isolated yields.
3
.6 equiv of ZnEt
2
b
c
The enantiomeric excess was determined by HPLC analysis on a Chiralpak
column.
2-Furyl
d
nd, Not determined.
a
All the reactions proceeded as described in Section 4.2.
Isolated yields.
The enantionmeric excess was determined by HPLC analysis on a Chiralpak
b
c
prepared from natural amino acids in three simple steps9f with
high yields. It was found that the structure of the ligand could be
highly influential on the enantioselectivity of the product. Simply
column.
d
The absolute configuration of 4g was assigned based on the comparison to the
literature data.5
f

6
18
X. Liu et al. / Tetrahedron: Asymmetry 20 (2009) 616–620
shown to be an efficient reagent, affording the addition product in
4.2.1. (S,E)-2-(Anthracen-9-ylmethyleneamino)-4-methyl-1,1-
8
2% ee (Table 3, entry 14).
diphenylpentan-1-ol B5
2
0
); 1H NMR (300 MHz,
3
Mp 175 °C; ½
a
ꢁ
¼ ꢀ136 (c 0.9, CHCl
D
CDCl ): d = 0.91–0.93 (d, J = 6.6 Hz, 3H), 1.09–1.11 (d, J = 6.6 Hz,
3
3
. Conclusion
3
4
3
2
H), 1.36–1.45 (m, 1H), 1.69–1.77 (m, 1H), 1.98–2.07 (m, 1H),
.03 (s, 1H), 4.76–4.80 (m, 1H), 7.14–7.25 (m, 3H), 7.28–7.34 (m,
H), 7.37–7.44 (m, 4H), 7.67–7.73 (m, 4H), 7.78–7.81 (m,
2
In summary, we have extended the applicability of ZnEt /
Schiff-base catalytic system for the arylation of aldehydes. A series
of readily available and inexpensive Schiff-base amino alcohols
have been identified as efficient chiral ligands in the thiophenyl
transfer to aldehydes. When a new Schiff-base B5 was used as li-
gand, the results indicated that thiophenylboronic acid could be
a suitable substrate to synthesize optically active thiophenyl meth-
anol derivatives.
H),7.93–7.95 (d, J = 8.4 Hz, 1H), 8.41 (s, 1H), 9.38 (s, 1H); 13
C
3
NMR (300 MHz, CDCl ): d = 21.2; 24.1; 24.4; 38.4; 76.5; 76.6;
7
1
1
1
9.8; 123.6; 124.5; 125.2; 125.5; 125.7; 126.1; 126.5; 126.6;
26.6; 128.4; 128.6; 128.7; 129.2; 129.3; 129.6; 131.1; 144.2;
47.7; 161.8; ESI-MS: m/z (%) 458.6 [M+]; IR (KBr); 3507, 2955,
ꢀ1
644, 1448, 1175, 1047, 909, 734, 702 cm . HRMS-EI (m/z): calcd
31NO: 457.2406; found: 457.2476, 0.4 ppm.
for C33
H
4
4
. Experimental
4
.3. General procedure for the enantioselective addition of
thiophenylboronic acid to aldehydes
.1. General
The general procedure: under an argon atmosphere, a well-
dried 5-ml vial was charged with thiophenylboronic acid 2
All reactions were carried out under an argon atmosphere
condition, and solvents were dried according to established pro-
cedures. Reactions were monitored by thin layer chromatogra-
phy (TLC), column chromatography purifications were carried
out using silica gel. All aldehydes, thiophene, and aminoacids
were purchased from Acros or Fluka. Diethylzinc was prepared
from EtI with Zn and then was diluted with toluene to 1.0 M.
Melting points are uncorrected and were recorded on an X-4
(
2
32 mg, 0.24 mmol) and 10% IMPEG (FW = 1100 g/mol, 0.02 mmol,
2 mg), and then Et Zn (0.72 ml, 0.72 mmol, 1.0 M solution in tol-
uene) was added using a syringe. The mixture was stirred for 6 h at
0 °C and subsequently cooled to room temperature. Then the mix-
ture was added into another vial containing ligand B5 (18 mg,
.04 mmol) using a syringe and was stirred for 30 min at room
2
7
0
melting point apparatus. 1H NMR and C NMR spectra were re-
13
temperature. Then, the mixture was cooled to 0 °C and stirred for
another 10 min followed by the addition of aldehyde (0.2 mmol).
After stirring for 8 h at room temperature, the reaction was
quenched with saturated ammonium chloride and extracted with
corded in CDCl using Bruker 300 MHz. IR spectra were obtained
3
on a FTIR spectrometer. Optical rotations were recorded on a
Perkin–Elmer 341 polarimeter. HR-MS was measured with an
APEX II 47e mass spectrometer and EI was recorded on a TRACE
DSQ Gas Chromatography–Mass spectrometer. The ee value
determination was carried out using chiral HPLC with Daicel
Chiralpak OD-H, AS-H, or AD-H column on Waters with a 996
UV-detector.
2 4
ether and dried over Na SO . The solvent was evaporated under re-
duced pressure to give the crude product. After column chroma-
tography on silica gel eluted with 5–10% ethyl acetate in
petroleum ether, the optically active product was isolated. The
enantiomeric purity of the product was determined by using HPLC.
The absolute configuration of adducts was assigned by comparison
5
f
to the literature data.
4
.2. Procedure for the preparation of ligand B59f,13
0
4
.3.1. (Phenyl)-(2 -thienyl)methanol 4a
As in Scheme 1, compound 7 was prepared according to known
procedures in two steps from L
-leucine.12 Then to a solution of 7
Yield (82%), 93% ee determined by HPLC analysis (Chiralpak
AS-H column, IPA:hexane = 2:98, 0.5 ml/min, 254 nm UV detec-
tion). Retention time: tminor = 35.5 min and tmajor = 39.9 min; white
(
(
1.07 g, 4 mmol) in 40 ml 95% EtOH was added 9-anthraldehyde
0.82 g, 4 mmol). The resulting solution was stirred for 24 h at
room temperature, then the reaction mixture was vacuum filtered
to provide crude product which was purified by recrystallization
from ethyl acetate–hexane and gave the pure product B5 as a yel-
low solid (1.57 g) with the yield of 86%.
2
D
0
1
solid, mp 37–38 °C, ½
aꢁ
¼ ꢀ3:6 (c 1.89, CHCl
3
); H NMR (300 MHz,
CDCl ): 2.60–2.61 (d, J = 3.6 Hz, 1H); 5.98–5.99 (d, J = 3 Hz, 1H);
3
1
2
6
7
7
1
1
.84–6.85 (m, 1H); 6.90–6.93 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H);
.22–7.24 (dd, J = 1.5 Hz, J = 3.6 Hz, 1H); 7.30–7.34 (m, 3H);
.40–7.42 (m, 2H);
25.4; 126.3; 126.7; 128.0; 128.6; 143.1; 148.2; IR (KBr): 3271,
1
2
1
3
3
C NMR (300 MHz, CDCl ): 72.4; 124.9;
ꢀ1
450, 1159, 1017, 824, 702 cm ; MS: m/z (%) 190 [M+], 110
(
35), 104 (100), 84 (52), 83 (53), 76 (33).
COOH
COOMe
NH HCl
SOCl2
MeOH
0
4
.3.2. (2-Chlorophenyl)-(2 -thienyl)methanol 4b
NH2
2
Yield (74%), 92% ee determined by HPLC analysis (Chiralpak AD-
5
6
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 12.8 min and tmajor = 14.0 min; gray oil,
2
D
0
1
½
a
1
ꢁ
¼ ꢀ31 (c 1.0, CHCl
3
); H NMR (300 MHz, CDCl
3
): 2.75 (br s,
PhMgBr THF
H); 6.38 (s, 1H); 6.88–6.94 (m, 2H); 7.20–7.25 (m, 2H); 7.28–
7.34 (m, 2H); 7.66–7.69 (s, 1H); C NMR (300 MHz, CDCl
Ph
1
3
Ph
OH
3
): 68.9;
1
1
25.3; 125.5; 126.7; 127.2; 127.5; 129.1; 129.6; 132.2; 140.5;
46.3; IR (KBr): 3355, 1440, 1016, 751, 703 cm ; MS: m/z (%)
Ph Ph
OH
N
EtOH
ꢀ1
9
-Anthraldehyde
224 [M+], 224 (38), 139 (71), 113 (30), 111 (37), 85 (100).
NH2
0
4
.3.3. (3-Chlorophenyl)-(2 -thienyl)methanol 4c
Yield (72%), 81% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
B5
7
Scheme 1. The synthesis of chiral Schiff-base amino alcohol ligand B5.
Retention time: tminor = 15.4 min and tmajor = 16.4 min; gray oil,

X. Liu et al. / Tetrahedron: Asymmetry 20 (2009) 616–620
619
2
D
0
); 1H NMR (300 MHz, CDCl
H); 5.95 (s, 1H); 6.85–6.86 (d, J = 3.3 Hz, 1H); 6.91–6.94 (dd,
1
2
½
a
ꢁ
¼ ꢀ13 (c 1.0, CHCl
3
3
): 2.79 (br s,
2H); 6.96–6.98 (dd, J = 0.9 Hz, J = 6.6 Hz, 1H); 7.19–7.32 (m,
1
3
1
3H); C NMR (300 MHz, CDCl
124.7; 126.6; 127.6; 129.1; 131.2; 148.0; 156.6; IR (KBr): 3417,
2936, 1597, 1490, 1462, 1244, 1027, 756, 703 cm ; MS: m/z (%)
220 [M+], 220 (42), 135 (100).
3
): 55.5; 69.4; 111.0; 120.9; 124.3;
1
2
13
J = 3.6 Hz, J = 1.5 Hz, 1H); 7.23–7.28 (m, 4H); 7.41 (s, 1H);
NMR (300 MHz, CDCl ): 71.6; 124.4; 125.2; 125.8; 126.4; 126.8;
28.1; 129.8; 134.4; 145.0; 147.3; IR (KBr): 3407, 2921, 1602,
488, 1459, 1434, 1258, 1037, 700 cm ; MS: m/z (%) 224 [M+],
11 (43), 85 (100), 84 (38).
C
ꢀ1
3
1
1
1
ꢀ1
0
4.3.9. (3-Methoxyphenyl)-(2 -thienyl)methanol 4i
Yield (77%), 93% ee determined by HPLC analysis (Chiralpak OD-
H column, IPA:hexane = 10:90, 1.0 ml/min, 254 nm UV detection).
Retention time: tmajor = 16.7 min and tminor = 18.4 min; yellow so-
0
4
.3.4. (4-Chlorophenyl)-(2 -thienyl)methanol 4d
Yield (83%), 85% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 2:98, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 30.2 min and tmajor = 35.6 min; yellow so-
lid, mp 55–56 °C, ½ ¼ ꢀ19 (c 1.0, CHCl
CDCl ): 2.73 (br s, 1H); 5.96 (s, 1H); 6.84–6.85 (d, J = 3.6 Hz, 1H);
.91–6.94 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H); 7.24–7.26 (dd,
J = 1.2 Hz, J = 3.9 Hz, 1H); 7.28–7.31 (dd, J = 2.7 Hz, J = 3.6 Hz,
H); 7.32–7.35 (dd, J = 2.7 Hz, J = 3.6 Hz, 2H);
2
0
1
lid, mp 55–56 °C, ½
CDCl ): 2.75 (br s, 1H); 3.76 (s, 3H); 5.96 (s, 1H); 6.80–6.86 (m,
2H); 6.89–6.92 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H); 6.97–6.99 (m,
aꢁ
3
¼ ꢀ10 (c 1.0, CHCl ); H NMR (300 MHz,
D
3
2
D
0
1
1
2
aꢁ
3
); H NMR (300 MHz,
1
3
3
3
2H); 7.22–7.24 (m, 2H); C NMR (300 MHz, CDCl ): 55.3; 72.3;
1
2
6
111.7; 113.5; 118.7; 124.9; 125.4; 126.7; 129.6; 144.8; 145.0;
159.7; IR (KBr): 3414, 1602, 1488, 1260, 1150, 1038, 755,
1
2
1
2
1
2
13
ꢀ1
2
C
NMR
703 cm ; MS: m/z (%) 220 [M+], 220 (43), 135 (100).
(
1
300 MHz, CDCl
3
): 71.6; 125.1; 125.7; 126.8; 127.7; 128.7; 133.7;
ꢀ1
0
41.5; 147.6; IR (KBr): 3356, 1490, 1089, 1011, 829, 704 cm
;
4.3.10. (4-Methoxyphenyl)-(2 -thienyl)methanol 4j
MS: m/z (%) 224 [M+], 139 (77), 111 (64), 85 (100), 84 (46).
Yield (81%), 96% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 23.5 min and tmajor = 26.9 min; yellow so-
0
4
.3.5. (4-Fluorophenyl)-(2 -thienyl)methanol 4e
2
0
1
Yield (79%), 92% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 13.7 min and tmajor = 15.0 min; white solid,
lid, mp 51–52 °C, ½
CDCl ): 2.73 (br s, 1H); 3.77 (s, 3H); 5.94 (s, 1H); 6.82–6.87 (m,
3H); 6.90–6.92 (dd, J = 3.6 Hz, J = 1.2 Hz, 1H); 7.21–7.23 (dd,
aꢁ
3
¼ ꢀ16 (c 1.0, CHCl ); H NMR (300 MHz,
D
3
1
2
2
D
0
1
1
2
13
mp 47–48 °C, ½
a
ꢁ
¼ ꢀ15 (c 1.0, CHCl
3
); H NMR (300 MHz, CDCl
3
):
J = 1.2 Hz, J = 3.9 Hz, 1H); 7.30–7.33 (d, J = 8.4 Hz, 2H); C NMR
(300 MHz, CDCl ): 55.3; 72.0; 113.9; 124.7; 125.2; 126.7; 127.7;
2
.47–2.48 (d, J = 2.7 Hz, 1H); 6.03–6.04 (d, J = 3 Hz, 1H); 6.87–6.88
3
1
2
(
2
m, 1H); 6.93–6.96 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H); 7.02–7.07 (m,
H); 7.25–7.28 (m, H); 7.39–7.42 (m, 2H); 13C NMR (300 MHz,
CDCl ): 71.7; 115.2, 115.5; 124.9; 125.6; 126.7; 128.0, 128.1;
38.9, 138.9; 147.9; 160.8, 164.0; IR (KBr): 3384, 2921, 1604,
508, 1226, 1156, 1037, 837, 703 cm ; MS: m/z (%) 207 [M+],
07 (38), 192 (56), 191 (100).
135.6; 148.6; 159.3; IR (KBr): 3356, 1575, 1430, 1195, 1016,
ꢀ1
703 cm ; MS: m/z (%) 220 [M+], 220 (30), 135 (100), 109 (33).
3
0
1
1
2
4.3.11. (2-Bromophenyl)-(2 -thienyl)methanol 4k
ꢀ1
Yield (61%), 95% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 14.8 min and tmajor = 16.7 min; brown oil,
0
20
D
1
4
.3.6. (2-Methylphenyl)-(2 -thienyl)methanol 4f
½
aꢁ
¼ ꢀ49 (c 1.0, CHCl
3 3
); H NMR (300 MHz, CDCl ): 2.74 (br s,
Yield (67%), 94% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 12.6 min and tmajor = 14.5 min; colorless
1H); 6.36 (s, 1H); 6.90–6.93 (m, 2H); 7.13–7.18 (m, 1H); 7.23–
7.26 (dd, J = 1.5 Hz, J = 3.3 Hz, 1H); 7.32–7.38 (m, 1H); 7.50–
7.53 (dd, J = 0.9 Hz, J = 7.2 Hz, 1H); 7.66 (d, J = 1.5 Hz, 1H);
1
2
1
2
13
C
2
D
0
1
oil, ½
a
ꢁ
¼ ꢀ24 (c 1.3, CHCl
3
); H NMR (300 MHz, CDCl
3
): 2.27 (s,
NMR (300 MHz, CDCl ): 71.1; 122.4; 125.5; 125.6; 126.7; 127.9;
3
3
1
1
1
1
1
H); 2.33 (br s, 1H); 6.20–6.21 (d, J = 3.3 Hz, 1H); 6.81–6.83 (m,
H); 6.91–6.94 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H); 7.13–7.16 (m,
127.9; 129.4; 132.8; 142.1; 146.3; IR (KBr): 3356, 1467, 1437,
1
2
ꢀ1
1012, 749, 703 cm ; MS: m/z (%) 270 [M+], 189 (77), 185 (45),
1
2
H); 7.20–7.28 (m, 3H); 7.60–7.63 (dd, J = 1.8 Hz, J = 5.4 Hz,
183 (45), 85 (100), 84 (69).
H); 1 C NMR (300 MHz, CDCl
3
): 19.1; 69.2; 125.3; 125.6; 126.3;
3
0
26.6; 127.9; 130.5; 135.0; 141.1; 147.3; IR (KBr): 3367, 1460,
228, 1035, 746, 702 cm ; MS: m/z (%) 204 [M+], 119 (100), 91
4.3.12. (4-Bromophenyl)-(2 -thienyl)methanol 4l
ꢀ1
Yield (85%), 92% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 15.6 min and tmajor = 18.6 min; yellow so-
(
21).
0
20
D
1
4
.3.7. (R)-(4-Methylphenyl)-(2 -thienyl)methanol 4g
Yield (83%), 84% ee determined by HPLC analysis (Chiralpak AD-
lid, mp 63–64 °C, ½
CDCl
6.93 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H); 7.23–7.28 (m, 3H); 7.43–
a
ꢁ
¼ ꢀ17 (c 1.0, CHCl
3
); H NMR (300 MHz,
3
): 2.78 (br s, 1H); 5.93 (s, 1H); 6.83–6.84 (m, 1H); 6.90–
1
2
H column, IPA: hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
1
3
Retention time: tminor = 15.2 min and tmajor = 17.6 min; white solid,
7.47 (m, 2H); C NMR (300 MHz, CDCl
3
): 71.7; 121.8; 125.1;
2
D
0
1
mp 38–39 °C, ½
a
ꢁ
¼ ꢀ16 (c 1.0, CHCl
3 3
); H NMR (300 MHz, CDCl ):
125.8; 126.8; 128.0; 131.6; 142.0; 147.5; IR (KBr): 3357, 1485,
ꢀ1
2
.34 (s, 3H); 2.39–2.43 (d, J = 9.6 Hz, 1H); 6.00 (s, 1H); 6.85–6.87
m, 1H); 6.91–6.94 (dd, J = 3.6 Hz, J = 1.5 Hz, 1H); 7.15–7.18 (d,
1401, 1071, 1008, 825, 704 cm ; MS: m/z (%) 270 [M+], 185
1
2
(
(44), 183 (47), 111 (50), 85 (100), 84 (41).
J = 5.1 Hz, 2H); 7.23–7.25 (m, 1H); 7.30–7.33 (d, J = 8.1 Hz, 2H);
1
3
0
C NMR (300 MHz, CDCl
3
): 21.2; 72.3; 124.8; 125.3; 126.3;
4.3.13. (2-Naphthyl)-(2 -thienyl)methanol 4m
1
1
26.6; 129.2; 137.8; 140.3; 148.4; IR (KBr): 3414, 1611, 1512,
248, 1176, 1032, 834, 705, 577 cm ; MS: m/z (%) 204 [M+], 203
Yield (68%), 88% ee determined by HPLC analysis (Chiralpak AS-
H column, IPA:hexane = 2:98, 1.0 ml/min, 254 nm UV detection).
Retention time: tminor = 25.3 min and tmajor = 30.0 min; brown oil,
ꢀ1
(
52), 188 (61), 187 (100).
2
0
1
mp 70–71 °C, ½
a
ꢁ
¼ ꢀ57 (c 1.0, CHCl
3 3
); H NMR (300 MHz, CDCl ):
D
0
4
.3.8. (2-Methoxyphenyl)-(2 -thienyl)methanol 4h
Yield (79%), 95% ee determined by HPLC analysis (Chiralpak AD-
2.90 (br s, 1H); 6.05 (s, 1H); 6.81–6.82 (d, J = 3.3 Hz, 1H); 6.85–6.88
1
2
(dd, J = 3.6 Hz, J = 1.2 Hz, 1H); 7.15–7.20 (m, 1H); 7.40–7.45 (m,
1
3
H column, IPA:hexane = 5:95, 1.0 ml/min, 254 nm UV detection).
3
3H); 7.72–7.78 (m, 3H); 7.82 (s, 1H); C NMR (300 MHz, CDCl ):
Retention time: tmajor = 19.9 min and tminor = 21.4 min; brown oil,
72.5; 124.6; 125.0; 125.2; 125.6; 126.2; 126.3; 126.8; 127.8;
128.2; 128.4; 133.1; 133.3; 140.6; 148.0; IR (KBr): 3376, 3056,
1601, 1508, 1364, 1230, 1118, 1020, 823, 757, 703, 478 cm ;
20
1
½
a
ꢁ
¼ ꢀ20 (c 0.95, CHCl
3
); H NMR (300 MHz, CDCl
3
): 3.44 (br s,
D
ꢀ
1
1
H); 3.80 (s, 3H); 6.18 (s, 1H); 6.82–6.83 (m, 1H); 6.88–6.94 (m,

6
20
X. Liu et al. / Tetrahedron: Asymmetry 20 (2009) 616–620
MS: m/z (%) 240 [M+], 240 (78), 155 (100), 129 (51), 128 (50), 127
40), 110 (57).
H.-C.; Wang, M.-G.; Yin, M.-M.; Wang, M. Tetrahedron: Asymmetry 2007, 18,
734–741; (h) Jin, M.-J.; Sarkar, S. M.; Lee, D.-H.; Qiu, H.-L. Org. Lett. 2008, 10,
(
1235–1237; (i) Wang, M.-C.; Zhang, Q.-J.; Zhao, W.-X.; Wang, X.-D.; Ding, X.;
Jing, T.-T.; Song, M.-P. J. Org. Chem. 2008, 73, 168–176; (j) Kuriyama, M.;
Shimazawa, R.; Shirai, R. J. Org. Chem. 2008, 73, 1597–1600; (k) Jimeno, C.;
Sayalero, S.; Fjermestad, T.; Colet, G.; Maseras, F.; Peric, M. A. Angew. Chem., Int.
Ed. 2008, 47, 1098–1101.
Cho, W.-S.; Kim, H.-J.; Littler, B. J.; Miller, M. A.; Lee, C.-H.; Lindsey, J. S. J. Org.
Chem. 1999, 64, 7890–7901.
0
4
.3.14. (2-Furanyl)-(2 -thienyl)methanol 4n
Yield (77%), 82% ee determined by HPLC analysis (Chiralpak AD-
H column, IPA:hexane = 2:98, 1.0 ml/min, 254 nm UV detection).
7
.
Retention time: tmajor = 34.5 min and tminor = 36.2 min; brown so-
2
D
0
1
8. (a) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995, 60, 10–11; (b)
Richards, C. J.; Mulvaney, A. W. Tetrahedron: Asymmetry 1996, 7, 1419–1430; (c)
Bolm, C.; Muñiz-Fernández, K.; Seger, A.; Raabe, G.; Günther, K. J. Org. Chem.
1998, 63, 7860–7867.
lid, mp 31–32 °C, ½
CDCl ): 2.72 (br s, 1H); 6.04 (s, 1H); 6.27–6.35 (m, 2H); 6.96–
.01 (m, 2H); 7.24–7.29 (m, 2H); 7.40 (d, J = 1.2 Hz, 1H); C NMR
300 MHz, CDCl ): 66.3; 107.4; 110.3; 125.3; 125.6; 126.7; 142.6;
44.5; 154.9; IR (KBr): 3427, 3110, 1742, 1231, 1144, 1011, 704,
a
ꢁ
¼ ꢀ11 (c 1.7, CHCl
3
); H NMR (300 MHz,
3
13
7
(
1
5
9
.
Selected reports (a) Xu, Z.-Q.; Wang, R.; Xu, J.-K.; Da, C.-S.; Yan, W.-J.; Chen, C.
Angew. Chem., Int. Ed. 2003, 42, 5747–5749; (b) Xu, Z.-Q.; Chen, C.; Xu, J.-K.;
Miao, M.; Yan, W.-J.; Wang, R. Org. Lett. 2004, 6, 1193–1195; (c) Zhou, Y.-F.;
Wang, R.; Xu, Z.-Q.; Yan, W.-J.; Liu, L.; Kang, Y.-F.; Han, Z.-J. Org. Lett. 2004, 6,
3
ꢀ1
+
98 cm ; MS: m/z (%) 180 [M ], 162 (100).
4147–4149; (d) Ni, M.; Wang, R.; Han, Z.-J.; Mao, B.; Da, C.-S.; Liu, L.; Chen, C.
Adv. Synth. Catal. 2005, 347, 1659–1665; (e) Kang, Y.-F.; Liu, L.; Wang, R.; Zhou,
Y.-F.; Yan, W.-J. Adv. Synth. Catal. 2005, 347, 243–247; (f) Xu, Z.-Q.; Lin, L.; Xu,
J.-K.; Yan, W.-J.; Wang, R. Adv. Synth. Catal. 2006, 348, 506–514; (g) Chen, C.;
Hong, L.; Xu, Z.-Q.; Liu, L.; Wang, R. Org. Lett. 2006, 8, 2277–2280; (h) Lin, L.;
Jiang, X.-X.; Liu, W.-X.; Qiu, L.; Xu, Z.-Q.; Xu, J.-K.; Chan, A. S. C.; Wang, R. Org.
Lett. 2007, 9, 2329–2332.
Acknowledgments
We are grateful for the grants from the National Natural Science
Foundation of China (Nos. 20525206, 20621091, and 20772052)
and the Chang Jiang Program of the Ministry of Education of China
for financial support.
1
0. Kabalka, G. W.; Sastry, U.; Sastry, K. A. R.; Knapp, F. F. K., Jr.; Srivastava, P. C. J.
Organomet. Chem. 1983, 259, 269.
1
1. Selected references for the salen-schiff base as chiral catalysts: (a) Nagata,
T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1995,
34, 2145–2147; (b) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. 1997, 36, 1704; (c)
Belokon, Y. R.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V.
N.; Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V. I.;
Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121,
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1
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1
1
2. (a) Under the same conditions, we also uesd B5 in the addition of 2-
thiophenylboronic acid to two aliphatic aldehydes: isobutyl-aldehyde and
cyclohexanecarboxaldehyde. The enantioselectivities were determined by
chiral HPLC on a Chiracel OD column and were found to be 40 and 61% ee,
respectively.; (b) To evaluate the asymmetry-inducing ability of B5, the
reaction of 2-chlorobenzaldehyde with phenyl-boronic acid was performed
under the same conditions, and we obtained an ee value of 94% with a good
yield of 91%.
6
.
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