Enantioselective borane reduction of aromatic ketones using chiral BINOL derivatives as ligands in an aluminum catalyst

Article abstract of DOI:10.1016/S0957-4166(02)00008-3

Chiral aluminum complex-catalyzed asymmetric borane reduction of aromatic ketones has been successfully carried out in the presence of (R)-BINOL derivatives as ligands. Secondary alcohols were obtained in high yields with good enantioselectivities (up to 90% e.e.).

Full text of DOI:10.1016/S0957-4166(02)00008-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3217–3221
Enantioselective borane reduction of aromatic ketones using
chiral BINOL derivatives as ligands in an aluminum catalyst
Yang-Miin Lin, I-Pin Fu and Biing-Jiun Uang*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 300, ROC
Received 25 September 2001; accepted 4 January 2002
Abstract—Chiral aluminum complex-catalyzed asymmetric borane reduction of aromatic ketones has been successfully carried out
in the presence of (R)-BINOL derivatives as ligands. Secondary alcohols were obtained in high yields with good enantioselectiv-
ities (up to 90% e.e.). © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
modified the BINOL system, envisaging enhanced
enantioselectivity by using them as ligands in the prepa-
ration of a chiral aluminum catalyst. Herein we report
our results obtained in the borane reduction of aro-
matic ketones using (R)-BINOL derivatives 2–5 as chi-
The asymmetric synthesis of enantiomerically enriched
secondary alcohols has gained immense importance in
view of their utility as versatile synthetic intermediates
for various functionalities as well as for many natural
11
ral ligands.
1
products. The enantioselective reduction of prochiral
ketones using chiral boron catalysts is one of the most
successful approaches to chiral secondary alcohol and
2. Results and discussion
2
3
the pioneering works of Itsuno and Corey in this area,
utilizing homochiral amino alcohols as ligands for a4
boron catalyst have received considerable attention.
Other chiral boron catalysts prepared from chiral sul-
2.1. Variation of the chiral ligand
We have chosen chiral BINOL derivatives 1–5 as lig-
ands in the asymmetric reduction of aromatic ketones.
As a representative example, reduction of acetophenone
was carried out with borane–dimethylsulfide complex in
the presence of chiral BINOL derivatives 1–5 and the
results are presented in Table 1. The highest enantiose-
5
6
7
foximines, phosphinamides, mercapto alcohols, and
8
b-diamines were also found to be effective for this
reaction.
Shibasaki et al. have employed an efficient binaphthol
based chiral catalyst ALB in the asymmetric Michael
reactions and Horner–Wadsworth–Emmons reactions
lectivity (71% e.e.) was observed when (R)-H –BINOL
8
5 was used as ligand (entry 11). Interestingly, when
3,3%-disubstituted BINOLs 2 and 4 were used, the abso-
lute configuration of the resultant carbinols was found
to be opposite to that observed with (R)-BINOL 1
(entries 3, 5 and 9). As our catalyst and Shibasaki’s
ALB have comparable basic components, we presumed
9
achieving excellent enantioselectivity. Recently, we
made use of a similar catalyst prepared in situ from
aluminum tri-iso-propoxide and (R)-BINOL in the
10
asymmetric borane reduction of aromatic ketones. To
explore the scope of our methodology, we have now
Br Br
Me
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Br Br
Me
1
2
3
4
5
*
0
Corresponding author. Tel.: +886-3-5721224; fax: +886-3-5711082; e-mail: bjuang@mx.nthu.edu.tw
957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00008-3

3
218
Y.-M. Lin et al. / Tetrahedron: Asymmetry 12 (2001) 3217–3221
Table 1. Enantioselective reduction of acetophenone with chiral BINOL derivatives as ligands
O
OH
CH3
Ligand (21 mol%)
CH2Cl2, rt
+
BH3.SMe2 (1.1 eq.)
Ph
CH3
Ph
6a
7a
i
% e.e.a
Config.b
Entry
Ligand
Al(O Pr) (mol%)
Time (h)
Yield (%)
3
1
2
3
4
5
6
7
8
9
–
–
1
1
2
2
3
3
4
4
5
5
10
–
10
–
10
–
10
–
10
–
10
–
24
24
0.3
24
0.5
24
1
24
2
99
91
97
78
94
90
98
96
97
93
95
91
0
0
60
0
46
0
0
0
10
0
71
0
–
–
S
–
R
–
–
–
R
–
S
–
10
11
12
24
0.5
24
a
Determined by HPLC analysis.
Absolute configurations were determined by comparison of specific rotations with literature values.
b
that they have close structural similarity. However, our
attempts to elucidate the structure of our catalyst could
not succeed owing to its moisture sensitivity.
these solvents indicating that the solvent has no signifi-
cant effect on enantioselectivity. As shown in Table 2,
the optimum temperature appears to be around 40°C
(
entries 1 and 8).
In view of these observations, H –BINOL 5 was chosen
8
as a ligand for the further investigation of various
parameters such as temperature, solvent, catalyst ratio,
and nature of substrate which could influence the enan-
2.3. Effect of catalyst ratio
Variation of enantioselectivity with the catalyst ratio is
12
tioselectivity in the asymmetric reduction of ketones.
.2. Effect of solvent and reaction temperature
Since the coordinative solvents appear to be deleterious
shown in Table 3. The best molar ratio of
i
Al(O Pr) :ligand seems to be 1:2, and lower e.e. was
3
i
2
observed when the quantity of Al(O Pr) or ligand was
decreased (entries 1–4 and 9–10). However, there was
3
no apparent change in e.e. when the quantity of
10
i
to the enantioselectivity, the reactions were conducted
in chlorinated solvents such as dichloromethane and
Al(O Pr) was increased (entries 5–7). An experiment to
3
increase the S/C ratio was also conducted, but less
1,2-dichloroethane. Similar e.e. was observed in all
satisfactory results were obtained (entry 8).
Table 2. Effect of temperature and solvent on the enantioselectivity in the reduction of acetophenone
O
OH
i
Al(O Pr)3 (10 mol%)
+
BH3.SMe2 (1.1 eq.)
Ph
CH3
Ph
CH3
5
(21 mol%)
6a
(S)-7a
Entry
Temp (°C)
Solvent
CH Cl
Time (min)
Yield (%)
% e.e.a
1
2
3
4
5
6
7
8
9
40
30
20
0
70
60
50
40
40
40
40
10
10
30
2880
10
10
10
10
10
10
99
90
95
87
95
94
99
96
90
84
80
81
77
73
40
64
72
78
80
79
78
75
2
2
2
2
2
CH Cl
2
CH Cl
2
CH Cl
2
CH ClCH Cl
2 2
CH ClCH Cl
2
2
CH ClCH Cl
2
2
CH ClCH Cl
2
2
CHCl3
Chlorobenzene
1,2-Dichlorobenzene
1
1
0
1
10
a
Determined by HPLC analysis.

Y.-M. Lin et al. / Tetrahedron: Asymmetry 12 (2001) 3217–3221
3219
Table 3. Effect of catalyst ratio on the enantioselectivity
in the reduction of acetophenone
3. Conclusion
o
In conclusion, (R)-H –BINOL 5 is demonstrated to be
O
CH Cl , 40 C
OH
8
2
2
+
BH3.SMe2
an ideal chiral ligand for aluminum-catalyzed borane
reduction of aromatic ketones providing 1-phenyl-
propanol 7b in 99% yield with 90% e.e. There is signifi-
cant enhancement of enantioselectivities with ligand 5
when compared to that of our earlier reported ligand 1
making the present finding more useful. Efforts to
establish the structure of the catalyst are under active
exploration.
Ph
CH3
catalyst
Ph
CH3
(1.1 eq.)
6a
(S)-7a
i
% e.e.a
Entry
5 (mol%)
Al(O Pr)
Yield (%)
3
(
mol%)
1
2
3
4
5
6
7
8
9
21
21
21
21
21
21
21
10.5
10.5
5.5
2.5
5
7.5
10
20
30
100
5
10
10
99
57
66
75
81
77
75
76
26
68
38
96
94
99
91
95
90
92
90
89
4
. Experimental
4
.1. General
1
13
H and C NMR were recorded on a Varian Mercury-
4
00 or a Varian Unity-400 spectrometer. HPLC analy-
1
0
ses were performed on HITACHI L-6200
a
a
chromatography with L-4200 UV detector. Chiral
columns were purchased from Daicel Chemical Indus-
tries, Ltd. Optical rotations were measured on a Jasco
DIP-1000 polarimeter. Anhydrous solvents were freshly
distilled under argon. All reactions were performed
under an argon atmosphere.
Determined by HPLC analysis.
2
.4. Effect of substrate
To examine the efficacy of our procedure, a variety of
aromatic ketones were subjected to the conditions
under the reaction conditions optimized for acetophe-
none (40°C, CH Cl as solvent, catalyst prepared in situ
4
.2. Typical procedure of catalytic asymmetric borane
reduction
2
2
i
from 10 mol% Al(O Pr) and 21 mol% 5) (Table 4). In
3
i
To a mixture of Al(O Pr)3 (40 mg, 0.2 mmol) and
R)-H –BINOL (123 mg, 0.42 mmol) in dichloro-
the reduction of ketones 6a–6e, the e.e. of the corre-
sponding alcohols decreased with increasing size of
alkyl group, except in the case of propiophenone 6b
which has undergone reduction with the highest e.e.
(
8
methane (10 mL) previously stirred for 1 h was added
acetophenone 6a (0.24 mL, 2 mmol) under Ar at room
temperature. After 0.5 h stirring, the reaction mixture
was heated to 40°C and borane dimethylsulfide com-
plex (2.2 mL, 1 M in CH Cl ) was added. Once all the
(
90%) (entries 1–5). However, a dramatic decrease in
selectivity was observed with cyclic ketones, which
probably results from their relatively rigid conforma-
tions (entries 6–7). A halogen substituent appears to
have a little influence on the e.e. (entry 8–11), as does
the 2-naphthyl group and electron-withdrawing nitro
group (entry 13–14), but the presence of an electron-
donating group seems to decrease the enantioselectivity
2
2
acetophenone had been exhausted (monitored by TLC)
the reaction was quenched with 1N HCl (10 mL). The
aqueous phase was extracted with CH Cl (2×10 mL),
2
2
the combined organic extracts were washed with brine,
dried (Na SO ) and concentrated. The residue was dis-
2
4
tilled under reduced pressure (100°C/0.3 mmHg) to give
the 1-phenylethanol 7a (239 mg, 99% yield) in 90% e.e.
(
entry 12).
Table 4. Enantioselective reduction of aromatic ketones
Entry
Ketone
Time (min)
Yield (%)
% e.e.a (config.)b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
Acetophenone 6a
Propiophenone 6b
2-Methylpropiophenone 6c
2,2-Dimethylpropiophenone 6d
Heptanophenone 6e
10
10
120
720
10
20
30
10
10
10
10
10
20
99
99
94
93
96
90
89
92
93
90
92
89
94
87
81 (S)
90 (S)
50 (S)
32 (S)
78 (S)
62 (S)
31 (S)
72 (R)
85 (R)
76 (S)
70 (S)
52 (S)
78 (S)
83 (S)
a-Tetralone 6f
1-Indanone 6g
2-Chloroacetophenone 6h
2-Bromoacetophenone 6i
4%-Chloroacetophenone 6j
3%-Chloroacetophenone 6k
4%-Methoxyacetophenone 6l
4%-Nitroacetophenone 6m
2%-Acetonaphthone 6n
0
1
2
3
4
10
a
Determined by HPLC analysis.
Absolute configurations were determined by comparison of specific rotations with literature values.
b

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Y.-M. Lin et al. / Tetrahedron: Asymmetry 12 (2001) 3217–3221
4
.3. Determination of the enantiomeric excess for the
Acknowledgements
secondary alcohols by HPLC
2
4
13
We are grateful to the National Science Council,
Republic of China, for the financial support of this
work.
4
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.3.2. 1-Phenylpropanol 7b. [h]
−43.7 (c 0.65,
D
1
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