Reusable cobalt(III) complex catalysts for enantioselective borohydride reduction of ketones

Article abstract of DOI:10.1246/bcsj.20130085

A reusable catalytic system was developed for the catalytic enantioselective borohydride reduction of ketones. The optically active 1-chlorovinylketoiminatocobalt(III) complexes were recovered after the reaction by silica gel column chromatography, and th

Full text of DOI:10.1246/bcsj.20130085

© 2013 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 86, No. 8, 983-986 (2013)
983
Reusable Cobalt(III) Complex Catalysts for Enantioselective
Borohydride Reduction of Ketones
³
Tatsuyuki Tsubo, Hsiu-Hui Chen, Minako Yokomori, Satoshi Kikuchi, and Tohru Yamada*
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522
Received March 29, 2013; E-mail: yamada@chem.keio.ac.jp
A reusable catalytic system was developed for the catalytic enantioselective borohydride reduction of ketones. The
optically active 1-chlorovinylketoiminatocobalt(III) complexes were recovered after the reaction by silica gel column
chromatography, and then efficiently catalyzed the enantioselective reduction several times without any loss of reactivity
as well as enantioselectivity.
Although the demand for various structures of optically
active compounds as chiral synthons has been increasing, the
varieties supplied from natural products are limited. Catalytic
and enantioselective syntheses are one of the most attractive
and reasonable solutions for these requirements in order to
provide a wide variety of optically active compounds, among
which the optically active secondary alcohols obtained by
the enantioselective reduction of ketones1 are one of the
most reliable building blocks for the syntheses of bioactive
compounds or highly functionalized materials. This research
group has reported the enantioselective borohydride (= tetra-
hydridoborato) reduction of various ketones using ketoiminato-
cobalt complex catalysts to afford the corresponding secondary
alcohols with high-to-excellent yields and high enantioselec-
tivities.2 In this reduction system, analytical and theoretical
studies revealed that a catalytic amount of haloalkanes, such as
chloroform or trichloroethane, effectively generated the reac-
tive cobalt(III) complex intermediate to achieve high enantio-
selectivity.3 For the reduction of aromatic ketones, the di-
chloromethyl group derived from chloroform was crucial to
provide the axial ligand for the reactive cobalt(III) intermediate
to accomplish high enantioselectivity as well as high yield. For
the enantioselective reduction of aliphatic ketones, screening of
various haloalkanes as the axial ligand precursors revealed that
1,1,1-tirchloroethane was a suitable additive for high enantio-
selectivities.4 The enantioselectivity was remarkably improved
in the presence of 1,1,1-trichloroethane and several aliphatic
ketones were successfully converted into corresponding alco-
hols with good-to-high enantioselectivities (Scheme 1). The
analytical and experimental examinations revealed that the
cobalt(III) complex coordinated by 1-chlorovinyl group was
generated and the 1-chlorovinylcobalt(III) complex 2 catalyzed
the enantioselective borohydride reduction.5 Meanwhile, it was
also suggested that the cobalt(III) complex 2 was stable enough
to be recovered as red-colored fractions by silica gel column
chromatography and analyzed by NMR as well as X-ray ana-
lyses of a single crystal. Moreover, the recovered complex 2
Reactive Intermediate
cat.
H
NaBH4
N
O
N
O
N
O
N
O
Co
CH3CCl3
Co
O
O
O
O
H
Cl
Cobalt(II) Complex 1
H
O
R
OH
Enantioselective Reduction
of Aliphatic Ketones
R
Scheme 1. Enantioselective reduction of aliphatic ketones
catalyzed by 1-chlorovinylketoiminatocobalt(III) complex.
was also found to catalyze the enantioselective borohydride
reduction in the presence of 1,1,1-trichloroethane (86% ee)
although the enantioselectivity decreased to 66% ee without
additional 1,1,1-trichloroethane due to the loss in the activity
by the gradual decomposition of the cobalt(III) complex 2
to the cobalt(II) complex 1 (Scheme 2). Encouraged by these
results, we tried to develop the reusable and recyclable catalyst
system to more efficiently improve the present cobalt cataly-
sis for providing optically active secondary alcohols. In this
short article, we describe a reusable catalyst system using the
ketoiminatocobalt(III) complex for the enantioselective boro-
hydride reduction of ketones.
Under the previously reported conditions, 1-adamantyl
methyl ketone (3) was reduced to the corresponding alcohol
4 in high yield and enantioselectivity (94% yield, 85% ee)
using 10 mol % cobalt(II) complex 1 (Table 1, Run 1). During
the purification process by silica gel column chromatography,
the red-colored fractions were collected with a high-polarity
eluent (ethyl acetate (AcOEt)/diethyl ether (Et2O) = 4/1) after
isolation of the produced alcohols (eluent: AcOEt/hexane =
1/15). In the second run, the recovered red-colored cobalt(III)
complex 2 was employed as a catalyst with additional 1,1,1-
trichloroethane to give the reduced product in a comparable
yield and enantioselectivity. Although the reduction proceeded
for five runs, the enantiomeric excesses decreased to 77% ee
(Runs 2-5). An improvement in the recovery methods was then
required to maintain the high selectivity.
³ Present address: Department of Chemistry, National Kaohsiung
Normal University, Shenjhong Rd., Kaohsiung, Taiwan 82446
Published on the web August 15, 2013; doi:10.1246/bcsj.20130085

984
Bull. Chem. Soc. Jpn. Vol. 86, No. 8 (2013)
Reusable Cobalt(III) Complex Catalysts
5 mol%
N
O
N
Recovered
Co
O
O
Cl
O
O
OH
Cobalt(III) Complex 2
NaBH4, MeOH, THF
-20 °C, 24 h
3
4
No Additive
66% ee (88% yield)
CH3CCl3 20 mol% 86% ee (95% yield)
Scheme 2. Effect of addition of 1,1,1-trichloroethane on the enantioselectivities of the reaction with the recovered cobalt(III) complex.
Table 1. Reuse of the Cobalt Complex in the Reduction of
Eluent
(AcOEt / Et2O)
1-Adamantyl Methyl Ketonea)
1st Run
Co(II) Complex 1 (10 mol%)
2nd-5th Runs
Red Fractions (mixture)
4 / 1
O
OH
Recovered Complex 2
1 / 12
4 / 1
Yellow Fractions
Red Fractions
CH3CCl3 (40 mol%)
NaBH4, MeOH
THF
3
4
Run
Yield/%
ee/%
Figure 1. The column chromatography conditions for
recovery of the cobalt(III) complexes.
1
2
3
4
5
94
91
90
94
91
85
83
83
80
77
Table 2. Reuse of the Cobalt Complex in the Reduction of
1-Adamantyl Methyl Ketone Using the Improved Recov-
ery Processa)
1st Run
a) Reaction conditions: [1st run] ketone 3 (0.25 mmol), (S,S)-2
(10 mol %), NaBH4 (0.50 mmol, 2.0 equiv), MeOH (3.0 mmol,
12 equiv), CH3CCl3 (40 mol %) at ¹20 °C, 24 h. [2nd-5th runs]
The complexes recovered in last cycle were used. Yields are
of product isolated. Chromatography conditions: the product
alcohols were isolated by silica gel chromatography with an
eluent (AcOEt/hexane = 1/15). The complexes were recov-
ered with an eluent (AcOEt/Et2O = 4/1). Enantiomeric excess
was determined by HPLC analysis of 1-naphthoate derivative
(Chiralpak IB).
Co(II) Complex 1 (10 mol%)
2nd-5th Runs
Recovered Complex 2
(used only red fractions)
O
OH
CH3CCl3 (40 mol%)
NaBH4, MeOH
THF
3
4
Run
Yield/%
ee/%
1
2
3
4
5
94
89
87
96
88
86
84
85
85
85
In these procedures, it was confirmed that the red-colored
fractions consisted of two contents after simple change to a
polar eluent in the silica gel column chromatography purifica-
tion. After detailed examination, it was found that the yellow-
colored fractions6 came out before the red-colored ones with
a lower-polarity eluent. Based on this observation, the red-
colored fractions were only collected with the high-polarity
eluent (AcOEt/Et2O = 4/1) after elimination of the yellow-
colored fractions with a lower-polarity eluent (AcOEt/Et2O =
1/12) (Figure 1). By using these obtained pure red-colored
fractions, the enantioselectivities remained at a high level in
every run, 84-86% ee (Table 2).
a) Reaction conditions: [1st run] ketone 3 (0.25 mmol), (S,S)-2
(10 mol %), NaBH4 (0.50 mmol, 2.0 equiv), MeOH (3.0 mmol,
12 equiv), CH3CCl3 (30 mol %) at ¹20 °C, 24 h. [2nd-5th runs]
The complexes recovered in last cycle were used. Yields are
of product isolated. Chromatography conditions: the product
alcohols were isolated by silica gel chromatography with an
eluent (AcOEt/hexane = 1/15). The complexes were recov-
ered with an eluent (AcOEt/Et2O = 1/12 to 4/1). Enantio-
meric excess was determined by HPLC analysis of 1-naph-
thoate derivative (Chiralpak IB).
For the reduction of aliphatic ketones, the recovery and reuse
of the cobalt(III) complex were realized using 1,1,1-trichloro-
ethane as a precursor of an axial ligand as well as the enantio-
selectivity being improved. Application of the reusable cata-
lytic system to aromatic ketones was also expected. According
to the original conditions using the complex 8 in the presence
of 1,1,1-trichloroethane, butyl phenyl ketone (6) was reduced
to 1-phenyl-1-pentanol (7) in a high yield and enantioselectiv-
ity (Table 3, Entry 1). However for this reaction, the expected
cobalt(III) complex with 1-chlorovinyl group could not be
recovered. The color of the reaction mixture changed from

T. Tsubo et al.
Bull. Chem. Soc. Jpn. Vol. 86, No. 8 (2013)
985
Table 3. Reduction of Aromatic Ketone with Various Cobalt
Complexesa)
Table 4. Reuse of the Cobalt Complex in the Reduction of
Butyl Phenyl Ketone with Different Recovery Methodsa)
1st Run
5 mol%
Co(II) Complex 11 (10 mol%)
2nd-5th Runs
O
OH
Recovered Complex
R
O
N
O
N
O
R
O
NaBH4, MeOH, CH3CCl3
Co
THF, -20 °C
O
OH
6
7
Method A
Method B
NaBH4, MeOH, CH3CCl3
Run
THF, -20 °C
6
7
Yield/%
ee/%
Yield/%
ee/%
1
2
3
4
95
89
86
88
88
88
89
87
80
88
Entry
1b)
Complex
Yield/% ee/%
87
76b)
71c)
98b)
95b)
91b)
8
88
96
Me
O
Me
O
N
O
N
O
a) Reaction conditions: [1st run] ketone 6 (0.25 mmol), (S,S)-
11 (10 mol %), NaBH4 (0.375 mmol, 1.5 equiv), MeOH (2.25
mmol, 9 equiv), CH3CCl3 (40 mol %) at ¹20 °C, 5 h. [2nd-5th
runs] The complexes recovered in last cycle were used. Yields
are of product isolated. Enantiomeric excess was determined
by HPLC analysis (Chiralcel OD-H). Chromatography con-
ditions: [Method A] the product alcohols were isolated by
silica gel chromatography with an eluent (AcOEt/hexane =
1/20). The complexes were recovered with an eluent (AcOEt/
Et2O = 4/1). [Method B] the product alcohols were isolated
by silica gel chromatography with an eluent (THF/hexane =
1/25). The complexes were recovered with an eluent (THF/
Et2O = 1/10). b) The reaction time was 6 h. c) The reaction
time was 8 h.
Co
2
3
1
9
97
90
66
67
N
O
N
O
Co
O
O
N
O
N
O
Co
Co
Co
O
O
O
O
O
O
4c)
10
11
85
93
83
88
tivities could not be improved. These ligands were attached
by ortho-substituted aromatic ketones in order to stabilize the
intermediates with their steric demand. It was found that the
cobalt(II) complex 11 with the ligand containing 3,5-dimethyl-
phenyl group effectively catalyzed the reduction of aromatic
ketone 6 to afford the corresponding alcohol with high enantio-
selectivity (Entry 5).
N
O
N
O
5
N
O
N
O
Eventually, the reuse of the catalyst for several times was
carried out with the newly designed complex 11 (Table 4). The
enantioselectivity was maintained over five runs, but the high
yield decreased. It seemed that the cobalt(III) complex derived
from the complex 11 was relatively less stable than the com-
plex 2 due to the bulky difference between 3,5-dimethylphenyl
group and 2,4,6-trimethylphenyl group. It was expected that the
coordinative saturation of the cobalt complex by the solvent,
such as tetrahydrofuran (THF), could stabilize the chlorovinyl-
cobalt complex during the recovery process. When the eluent
used in the silica gel column chromatography was changed
from Method A (AcOEt) to Method B (THF), the product
yields were improved.
In summary, it was demonstrated that the reusable and recy-
clable cobalt catalyst system for the enantioselective boro-
hydride reduction of ketones was effectively achieved. The
cobalt(III) complex with 1-chlorovinyl group recovered by a
silica gel column chromatography could be reused several
times along with 1,1,1-trichloroethane. The reusable system
of the cobalt complex was also employed after optimization
of the ligand and recovery process to efficiently provide
optically active secondary alcohols from aliphatic and aromatic
ketones.
a) Reaction conditions: ketone 6 (0.25 mmol), cobalt complex
(5 mol %), NaBH4 (0.50 mmol, 2.0 equiv), MeOH (3.0 mmol,
12 equiv), CH3CCl3 (20 mol %) at ¹20 °C, 24 h. Yields are
of product isolated. Chromatography conditions: the product
alcohols were isolated by silica gel chromatography with
an eluent (AcOEt/hexane = 1/20). Enantiomeric excess was
determined by HPLC analysis (Chiralcel OD-H). b) The red-
colored cobalt complexes could not be recovered. c) (R,R)-10
was used.
purple-red to yellow during the isolation process; the chloro-
vinyl-cobalt(III) complex derived from the cobalt(II) complex
8 seemed less stable than the complex 2. Thus, complex 1, the
precursor of the sufficiently stable catalyst 2, was used instead
for the reduction of aromatic ketones. The recovery of the cata-
lyst was successful, however, the enantiomeric excess signifi-
cantly decreased (Entry 2). These results suggested that the
ketoimine ligand with sterically demanding aromatic groups
on the side chains (R in Table 3) was required to stabilize
the corresponding cobalt(III) complex catalyst for recycling.
Several ketoimine ligands containing arylketones on their side
chains were then examined (Entries 2-4), but the enantioselec-

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Bull. Chem. Soc. Jpn. Vol. 86, No. 8 (2013)
Experimental
Reusable Cobalt(III) Complex Catalysts
added the prepared borohydride mixture as above at ¹20 °C
over 20 min. After stirring for 5-6 h at ¹20 °C, the reaction
was quenched with 1.5 mL of cooled aqueous THF. To the
solution was added water and AcOEt, extracted 3 times with
AcOEt, then washed with brine. The combined organic layers
were dried over Na2SO4 and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography pressurized by nitrogen with an eluent (THF/
hexane = 1/25) to afford the corresponding alcohol 7. HPLC
analysis was performed without further purification.3a After
elimination of the yellow-colored fractions, the red-colored
fractions were collected with an eluent (THF/Et2O = 1/10).
The collected red-colored fractions evaporated under reduced
pressure (Do not evaporate completely under high vacuum.
When the red-colored fractions were dried completely, the
enantiomeric excesses decreased).
General Information. All reactions were carried out in dry
solvents under a nitrogen atmosphere in dried glassware. The
ESI high-resolution mass spectra were obtained using a Waters
LCT Premier XE mass spectrometer. Column chromatography
was conducted on silica gel (Kanto 60 N). The HPLC ana-
lyses were performed by a Shimadzu LC-6A or LC-10A chro-
matograph using chiral columns (Daicel Chiralcel OD-H,
Chiralpak IB); the peak areas were obtained using a Shimadzu
SPD-M10AVP diode array detector/Shimadzu Class-VP or
Shimadzu SPD-6A UV detector/JASCO ChromNAV. DSC
analyses were performed with Shimadzu DSC-60 under nitro-
gen atmosphere. NaBH4 was purchased from Kanto Chemical
Co., Inc. Anhydrous THF was purchased from Kanto Chemical
Co., Inc., and used without further purification. MeOH was
distilled over CaH2 before use.
Supporting Information
Procedure for Reusable Catalytic System in Reduction of
1-Adamantyl Methyl Ketone (3). Under a nitrogen atmos-
phere, NaBH4 (18.9 mg, 0.50 mmol) and MeOH (121 ¯L, 3.0
mmol) in 3.9 mL of THF was stirred at 20 °C for 2 h. To a
solution of cobalt complex 1 (19.5 mg, 25 ¯mol, 10 mol %) or
recovered complex 2, 1-adamantyl methyl ketone (3) (44.6
mg, 0.25 mmol) and 1,1,1-trichloroethane (7.5 ¯L, 75 ¯mol,
30 mol %) in THF (2.5 mL) was added the prepared boro-
hydride mixture at ¹20 °C over 20 min. After stirring for 24 h
at ¹20 °C, the reaction was quenched with 1.5 mL of cooled
aqueous THF. To the solution was added water and AcOEt,
extracted 3 times with AcOEt, then washed with brine. The
combined organic layers were dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The residue
was purified by silica gel column chromatography pressurized
by nitrogen with an eluent (AcOEt/hexane = 1/15) to afford
the corresponding alcohol 4. After elimination of the yellow-
colored fractions with an eluent (AcOEt/Et2O = 1/12), the
red-colored fractions were collected with an eluent (AcOEt/
Et2O = 4/1). The collected red-colored fractions evaporated
under reduced pressure (Do not evaporate completely under
high vacuum. When the red-colored fractions were dried
completely to obtain the recycled catalyst, the enantiomeric
excesses decreased). The secondary alcohol 4 was followed by
esterification with 1-naphthoyl chloride for HPLC analysis.5
Procedure for Reusable Catalytic System in Reduction of
Butyl Phenyl Ketone (6). To a solution of the cobalt complex
11 (18.8 mg, 25 ¯mol, 10 mol %) or recovered complex, butyl
phenyl ketone (6) (40.6 mg, 0.25 mmol) and 1,1,1-trichloro-
ethane (10.0 ¯L, 100 ¯mol, 20 mol %) in THF (2.5 mL) was
Analytical data of cobalt complexes 9-11 and recovered
cobalt(III) complex derived from cobalt(II) complex 11. This
material is available free of charge on the web at: http://www.
csj.jp/journals/bcsj/.
References
1
a) H. Nishiyama, K. Itoh, in Catalytic Asymmetric Synthe-
sis, 2nd ed., ed. by I. Ojima, Wiley VCH, New York, 2000,
Chap. 2. doi:10.1002/0471721506.ch2. b) H. Nishiyama, in
Comprehensive Asymmetric Catalysis, ed. by E. N. Jacobsen, A.
Pfaltz, H. Yamamoto, Springer-Verlag, New York, 1999, Vol. 1,
Chap. 6.
2
a) T. Nagata, K. Yorozu, T. Yamada, T. Mukaiyama, Angew.
Chem., Int. Ed. Engl. 1995, 34, 2145. b) T. Yamada, T. Nagata,
K. D. Sugi, K. Yorozu, T. Ikeno, Y. Ohtsuka, D. Miyazaki, T.
Mukaiyama, Chem.®Eur. J. 2003, 9, 4485.
3
a) I. Iwakura, M. Hatanaka, A. Kokura, H. Teraoka, T.
Ikeno, T. Nagata, T. Yamada, Chem.®Asian J. 2006, 1, 656. b) A.
Kokura, S. Tanaka, H. Teraoka, A. Shibahara, T. Ikeno, T. Nagata,
T. Yamada, Chem. Lett. 2007, 36, 26.
4
T. Tsubo, H.-H. Chen, M. Yokomori, K. Fukui, S. Kikuchi,
T. Yamada, Chem. Lett. 2012, 41, 780.
T. Tsubo, M. Yokomori, H.-H. Chen, K. Komori-Orisaku,
S. Kikuchi, Y. Koide, T. Yamada, Chem. Lett. 2012, 41, 783.
The yellow-colored fractions were assumed to be the
5
6
cobalt(II) complex 1 based on ESI-MS analysis. However, the
reactivity and selectivity of the reaction with the recovered yellow
catalyst were different from original cobalt(II) complex 1. The
recovered cobalt(II) complex would be damaged by air (especially
oxygen) during the recovery process. See Supporting Information.