Homogeneous enantioselective catalysis in a continuous-flow microreactor: Highly enantioselective borohydride reduction of Ketones catalyzed by optically active cobalt complexes

Article abstract of DOI:10.1021/op300061k

Highly enantioselective homogeneous catalysis under continuous-flow conditions was established for the cobalt-catalyzed borohydride reduction of tetralone derivatives. A microreactor allowed higher reaction temperature with the residence time of 12 min than the corresponding batch system to maintain enantioselectivity as well as reactivity. The present system was directly applied to gram-scale synthesis to afford the reduced product with 92% ee.

Full text of DOI:10.1021/op300061k

Communication
pubs.acs.org/OPRD
Homogeneous Enantioselective Catalysis in a Continuous-Flow
Microreactor: Highly Enantioselective Borohydride Reduction of
Ketones Catalyzed by Optically Active Cobalt Complexes
Takuo Hayashi,† Satoshi Kikuchi,† Yukako Asano,‡ Yoshishige Endo,§ and Tohru Yamada*,†
†Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
‡Hitachi Research Laboratory, Hitachi, Ltd., 832-2 Horiguchi, Hitachinaka, Ibaraki 312-0034, Japan
§Hitachi Plant Technologies, Ltd., 603 Kandatsu-machi, Tsuchiura, Ibaraki 300-0013, Japan
S
* Supporting Information
employed, and the “numbering-up”8 of the microreactors will
ABSTRACT: Highly enantioselective homogeneous cat-
alysis under continuous-flow conditions was established for
the cobalt-catalyzed borohydride reduction of tetralone
derivatives. A microreactor allowed higher reaction
temperature with the residence time of 12 min than the
corresponding batch system to maintain enantioselectivity
as well as reactivity. The present system was directly
applied to gram-scale synthesis to afford the reduced
product with 92% ee.
be effective. Although the continuous-flow system with a
microreactor9 is one of the most promising methods to shorten
the time or effort to scale up the reaction from R&D to the
plant stage, few homogeneous asymmetric reactions have been
reported to use the continuous-flow system.10 In addition, their
enantioselectivities and catalytic efficiencies were reported to be
lower than those of the original batch system. Herein, we
describe a continuous-flow microreactor system for the highly
enantioselective borohydride reduction catalyzed by optically
active cobalt complexes and its application for scale-up
synthesis.
INTRODUCTION
■
RESULTS AND DISCUSSION
■
The enantioselective reaction catalyzed by an optically active
metal complex has been employed as one of the most
competent methods1 to provide optically pure compounds
for the manufacturing of pharmaceuticals as well as functional
materials. A wide variety of enantioselective reactions using
metal complex catalysts has been proposed over past decades
and also developed using a batch system, while a continuous-
flow system has rarely been examined for these catalytic
reactions. Since the reaction rate of the metal complex-
catalyzed reactions can be regulated by their ligands as well as
the reaction conditions, they have a conclusive advantage in
volume efficiency compared to biocatalytic or enzymatic
reactions. Because the enantioselectivities are often sensitive
to the reaction temperature, in order to scale up the reaction,
especially for the exothermic reactions with a high reaction rate,
the precise control of the reaction temperature would be
required to maintain their high enantioselectivities. Our group
proposed the enantioselective borohydride reduction of
ketones catalyzed by optically active cobalt complexes2 and
applied3 it to various substrates and reaction conditions
(though the largest reaction scale was 350 g4) or reported on
a 10-g scale for the enantioselective reduction of 1,3-dicarbonyl
compounds.5
In the original procedure11 for the enantioselective borohydride
reduction catalyzed by optically active cobalt complexes,
sodium borohydride was treated with the appropriate amount
of ethanol and tetrahydrofurfuryl alcohol to afford the
corresponding activated borohydride solution, since sodium
borohydride itself is not soluble in ordinary organic solvents. In
order to improve the solubility, chloroform2 was employed as
the solvent. It was recently proposed12on the basis of analytical
and theoretical studies that chloroform not only acts as the
solvent but also activates the cobalt complex catalyst to
generate the reactive intermediates. The original color of the
cobalt complex is yellow-to-orange, whereas the activated
cobalt complex treated with the modified borohydride is
reddish violet. While this color is maintained, the enantiose-
lective reduction would proceed to afford the corresponding
reduced product in high yield with high enantioselectivity. In a
batch system, the modified borohydride solution was prepared
in the first vessel. To the second vessel containing the substrate
and a catalytic amount of the cobalt complex, the modified
borohydride solution was slowly injected (Scheme 1). Also, in
the continuous-flow system using a Micro Process Server from
Hitachi Plant Technology, Ltd., solution A containing the
substrate and a catalytic amount of the cobalt complex and
solution B with the modified borohydride were prepared. The
microreactor attached to the Micro Process Server is made of
SUS316 stainless steel and has a microchannel with a length of
434 mm and a diameter of 0.5 mm. As the shortest reaction
The potential advantage of using a microreactor, rather than
a conventional batch reactor, is using high-speed mixing to keep
the reaction conditions homogeneous.6 A direct result of the
reactor’s extremely high surface-to-volume ratio7 allows quick
removal of the reaction heat to precisely control the
temperature of the reactor in order to maintain the high
enantioselectivities. In order to scale up the reaction using a
microreactor, a simple extension of the operating time can be
Received: March 9, 2012
Published: May 21, 2012
© 2012 American Chemical Society
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length were evaluated (entries 2 and 3). When solutions A and
B were both fed into the reactor at 0.5 mL/min, the chemical
yield was improved to 51%. By using a SUS316 tube of 5000
mm length and 1.0 mm diameter instead of the tube 2000 mm
long, the yield was improved to 65%, although the
enantioselectivity was still much lower than that of the batch
system in Scheme 1. On the basis of these examinations, a
reasonable yield or selectivity was not observed, probably due
to the background reduction with the excess hydride in the
quench vessel. The fact that the excess hydride could not be
completely quenched in an ammonium chloride solution to
reduce the ketone without any control of the cobalt complex
led to the examination of several quencher systems. Eventually,
1.0 v/v % AcOH in THF was found to be a suitable quencher
system for the present continuous-flow reaction in order to
realize a constant yield and enantioselectivity up to 90% ee
(entry 4). When the SUS tube with a 10,000-mm length and
1.0-mm diameter was employed, the chemical yield was
improved to 63% (entry 5). In order to improve the chemical
yield of the product, the enhancement of the borohydride
reactivity was next examined. In a similar 1,4-reduction system
catalyzed by cobalt complexes using the modified borohydride,
the addition of methanol15 was reported to effectively enhance
the reactivity of the modified borohydride to improve the
chemical yield. It is assumed that the electron-donating
methanol would release the hydride from the borohydride;
consequently, the reactive cobalt hydride would be generated
and improve the chemical yield of the product. The addition of
methanol to solution A was then examined to efficiently
accelerate the continuous-flow reaction and to improve the
chemical yield as well as the enantioselectivity (entry 6). The
optimization of the reaction temperature or the rinsing
procedures also effectively improved the chemical yield as
Scheme 1. Batch system for cobalt-catalyzed enantioselective
borohydride reduction
time in the batch system was reported13 to be 15 min, the
original microreactor connected to a SUS316 tube (2000 mm
length and 0.5 mm diameter) was employed as the continuous-
flow reactor. From the end of the SUS tube, the reaction
mixture was directly poured into a saturated ammonium
chloride solution. The reaction temperature was set at 0 °C,
and solutions A and B were both fed at the flow rate14 of 1.0
mL/min. Under these conditions, the residence time in the
reactor was estimated to be 0.2 min. It would not be long
enough to complete the catalytic enantioselective reduction.
After the usual workup process, the reduced product was
obtained in 38% yield with 57% ee (entry 1, Table 1). For
extending the residence time, the flow rate and the SUS tube
a
Table 1. Optimization of catalytic enantioselective borohydride reduction under continuous-flow conditions
e
e
entry
residence time/min
flow rate (A/B)/mL min−1
temperature (MR/tube) /°C
additive
yield /%
ee /%
b
,
f
,
g
m
1
2
3
4
5
6
7
0.2
0.4
4
1.0/1.0
0.5/0.5
0/0
0/0
none
none
none
none
none
37.8
57.4
50.4
83.1
89.7
88.8
89.4
90.2
b,
f,
g
m
50.7
c
c
,
,
f
,
h
m
0.5/0.5
0/0
64.7
i
4
0.4/0.6
0/0
58.5
63.1
88.2
90.6
d
d
d
,
,
,
j
8
0.4/0.6
0/10
0/10
−20/10
k
k
l
12
12
0.266/0.4
0.166/0.5
MeOH
l
MeOH
a
Reaction conditions: ketone (0.1 M), cobalt catalyst (5 mM), modified borohydride (0.12 M), solvent: CHCl3, quenched with 1.0 v/v % AcOH in
b
c
MeOH, microreactor: 0.5-mm diameter, 434-mm length. SUS tube: 0.5-mm diameter, 2.0-m length. SUS tube: 1.0-mm diameter, 5.0-m length.
d
e
f
g
SUS tube: 1.0-mm diameter, 10.0-m length. Determined by HPLC analysis. Quenched with sat. aq NH4Cl. The cobalt catalyst 1a was employed
h
i
j
k
instead of 1b. Cobalt catalyst (1 mM). Quenched with 1.0 v/v% AcOH in THF/H2O = 1:1. Modified borohydride: 0.21 M. Rinsing procedure
was improved. 0.45 M of methanol was employed as an additive. Isolated yield.
l
m
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well as the enantioselectivity. For the batch system of the
present reaction, a long reaction time was required at −20 °C
to achieve high enantioselectivity. The 0 °C reaction temper-
ature was then used to balance the reactivity and selectivity,
whereas the examination using the continuous-flow system
revealed that cooling at −20 °C during the initial step for
mixing of both solutions effectively realized high enantiose-
lectivity and that the following step for the reaction could be
performed at 10 °C in order to shorten the reaction time due to
the efficient removal of the mixing and/or reaction heat by the
microreactor. While the flow ratio of solution B vs A was
increased to 3.0 in order to obtain high yield, a considerably fast
reaction rate in a microreactor and the consequent reaction
heat could be controlled by its high heat transfer efficiency,
allowing both high yield and enantioselectivity. Eventually, the
reduced product was obtained in 91% yield with 90% ee in a
12-min residence time (entry 7). It was concluded that the
continuous-flow microreactor system could be employed for
the enantioselective reaction catalyzed by the optically active
metal complexes, since the current chemical yield, enantiose-
lectivity, and reaction time results are the same as those of the
batch system.
product was obtained in 12 min in 80% yield with 87% ee. In
the continuous-flow system in 12 min residence time, the
reaction smoothly proceeded to afford the desired product in
92% yield with 90% ee (entry 1). For 6-methoxy-1-tetralone,
the flow ratio of solution B vs A was optimized to be 3.0 to
afford the reduced product in 91% yield with 90% ee (entry 2).
For 7-methoxy-1-tetralone or 1-tetralone, the optimized flow
ratio was 2.5, and the reduced products were obtained in 88%
or 84% yield with 91% or 90% ee, respectively (entries 3 and
4). In these examinations, it was confirmed that an
enantioselective reaction catalyzed by optically active metal
complexes could be applied to the continuous-flow micro-
reactor system. Fast reaction was realized, and the chemical
yield and the enantioselectivity were rather improved compared
with those from the corresponding batch system. For an acyclic
ketone or a steric demanding ketone, the enantioselectivities in
the batch system16 were reproduced in the continuous-flow
system (entries 5 and 6). Reaction heat generated in the batch
system might lead to overreaction due to manual handling of
syringes and less efficient heat transfer than that in the flow
system. Therefore, in entries 4 and 5, yields in the continuous-
flow system were lower than those in the batch system.
A long operating time for the large-scale synthesis was also
examined (Scheme 2). In order to prevent blockage by the
The optimized conditions for the continuous-flow micro-
reactor were successfully applied to enantioselective borohy-
dride reduction of several substrates (Table 2). In a batch
reaction of 5-methoxy-1-tetralone, the corresponding reduced
Scheme 2. Long operating time for large-scale synthesis
Table 2. Catalytic enantioselective borohydride reduction of
a
various ketones under continuous-flow conditions vs batch
reactions
precipitated reagents, each flow rate was 2 times faster than the
preliminary examination; e.g., 0.333 mL/min for solution A and
1.0 mL/min for solution B. A 19-m length SUS316 tube was
employed as an after-reactor in order to keep the residence
time at 12 min. On the basis of the small-scale examination, for
the initial step of mixing, both solutions were cooled to −30
°C, and the following reaction step was operated at 10 °C. After
some optimization, a long operating time for a gram-scale
synthesis was developed; 3.1 g of a ketone was effectively
reduced by the modified borohydride in the presence of 5 mol
% of the optically active cobalt complex catalyst to afford the
corresponding alcohol (3.0 g) in 96% yield with 92% ee. The
total operating time of the microreactor system was 9.75 h. For
the large-scale synthesis, it was demonstrated that a longer
operating time could be used for the enantioselective catalysis.
For scale-up, the “numbering-up” with a multireactor in parallel
could be employed in principle.
a
Reaction conditions: ketone (0.1 M), cobalt catalyst (5 mM),
modified borohydride (0.12 M), MeOH (0.45 or 0.90 M), solvent:
CHCl3, quenched with 1.0 v/v % AcOH in MeOH, microreactor: 0.5-
mm diameter, 434-mm length. SUS316 tube: 1.0-mm diameter, 10-m
length. For batch reactions, the ratio of volume B/A corresponded to
In conclusion, it was determined that a continuous-flow
microreactor could be used for the enantioselective borohy-
dride reduction of ketones catalyzed by the optically active
cobalt complexes to afford the corresponding reduced product
with the same level in chemical yield and enantioselectivity as
the batch system even at a higher reaction temperature. Also, a
b
c
that of flow rate B/A. Determined by HPLC analysis. MeOH (0.90
d
e
f
M). Flow ratio B/A = 1.5. MeOH (0.45 M). Flow ratio B/A = 3.0.
g
h
Flow ratio B/A = 2.5. Catalyst 1a was employed instead of 1b.
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long operating time for the large-scale synthesis was
successfully demonstrated to afford a product on a gram scale
with high enantioselectivity.
introduced at the flow rate of 0.166 mL/min and 0.5 mL/min,
respectively. Step 4: In order to rinse solution A in Teflon tube,
syringe A and the pathway, 1.0 mL of dehydrated CHCl3 from
syringe A and 3.0 mL of solution B from syringe B were fed at
the flow rate of 0.166 mL/min and 0.5 mL/min, respectively.
Subsequently, 1.0 and 2.0 mL (0.222 mL/min and 0.444 mL/
min) and then 1.0 and 1.0 mL (0.333 mL/min each) were
employed to rinse solution A. Step 5: 5.0 mL (0.333 mL/min)
of dehydrated CHCl3 were fed from both syringes to give the
mixture of product. Water was added to the solution, and the
resulting mixture was extracted with CHCl3 three times. The
combined organic layers were washed with sat. aq NaHCO3
and brine, dried over Na2SO4, filtered, and concentrated. The
HPLC analysis of the crude product showed that the
corresponding alcohol 3b was obtained in 91% yield with
90% ee.
Batch System Using a Round-Bottom Flask. Solutions
A and B used in the batch system were the same as those used
in the flow system. To solution A (1.0 mL) was added 3.0 mL
of solution B with stirring at −20 °C. Soon after that, the
temperature was raised to 10 °C, and the mixture stirred for 12
min. The solution of 1 v/v % AcOH in MeOH was added.
Then water was added, and the resulting mixture was extracted
with CHCl3 three times. The combined organic layers were
washed with sat. aq NaHCO3 and brine, dried over Na2SO4,
filtered, and concentrated. The HPLC analysis of the crude
product showed that the corresponding alcohol 3b was
obtained in 95% yield with 92% ee.
Procedure for Enantioselective Borohydride Reduc-
tion of 2b on a Large Scale in Continuous-Flow System
Using a Microreactor. Solutions A1 and A2: Solutions were
prepared in two vessels and both of them were simultaneously
used for two syringes during the operation. To solutions of
cobalt complex 1b (333.3 mg, 0.44 mmol and 330.2 mg, 0.438
mmol) and substrate 2b (1.5484 g, 8.8 mmol and 1.5412 g, 8.8
mmol) in CHCl3 (86.4 mL for each vessel) were added MeOH
(3.14 mL, 77.6 mmol for each vessel) at room temperature
under nitrogen atmosphere. Solutions B1 and B2: Solutions
were prepared in two vessels. After the first solution was used
up, the second one was used. Mixtures of NaBH4 (1.15 g, 30.4
mmol and 2.29 g, 60.5 mmol), tetrahydrofurfuryl alcohol (40
mL, 412.8 mmol and 80 mL, 825.6 mmol) and EtOH (1.75
mL, 30.0 mmol and 3.52 mL, 60.3 mmol) in CHCl3 (200 and
400 mL) were stirred at 0 °C for 3 and 3.5 h under nitrogen
atmosphere respectively. MPS-α200 with four syringes and
software to control syringe pumps was used. Syringes A1 and
A2 were 10 mL and B1 and B2 were 25 mL for solution A and
B, respectively. The inlets of a microreactor and two syringes
were connected by Teflon tubes and the 20-m length stainless
tube (SUS316) was equipped to the outlet of the microreactor.
The microreactor and 1-m length of the SUS tube were kept at
−30 °C, and the rest of SUS tube was kept at 10 °C. The end
of the SUS tube was dipped in 300 mL of 1 v/v % AcOH in
MeOH with stirring at 0 °C for every 115 mL of solution B.
Step 1: The inside of the pathway was washed with MeOH
(150 mL) and CHCl3 (150 mL). Subsequently, it was washed
with 5 mL of dehydrated CHCl3 from vessels under nitrogen
atmosphere (5 times from each syringe, 100 mL). Step 2: 1.0
mL of dehydrated CHCl3 from syringe A and 3.0 mL of
solution B from syringe B were fed into the pathway at the flow
rate of 1.0 mL/min and 3.0 mL/min, respectively. Step 3: The
program for continuous-flow reactions in the software was
used: 2.5 mL of solution A (0.333 mL/min) and 7.5 mL of
EXPERIMENTAL SECTION
■
MPS-α100 or MPS-α200 from Hitachi Plant Technology, Ltd.
was used for experiments under continuous-flow conditions. 1H
and 13C NMR spectra were recorded on a JEOL α-400 or AL-
400 spectrometer using CDCl3 as a solvent. Melting point was
measured with a Stanford Research Systems MPA100 or
Shimadzu differential scanning calorimeter DSC-60. Column
chromatography was conducted on silica gel (Kanto 60 N).
HPLC analyses were performed with a Shimadzu LC-10AVP
chromatograph using chiral column (Daicel Chiralpak IA or
Chiralpak IB); the peak areas were obtained with a Shimadzu
SPD-M10AVP diode array detector and Shimadzu Class-VP.
Optical rotation was recorded on JASCO P-2200 digital
polarimeters.
Dehydrated CHCl3 was purchased from Kanto Chemical
Co., Inc. and used without further purification.
Ee’s of alcohols were determined by HPLC analysis. Yields of
alcohols were determined by HPLC analysis by using standard
curves (see Supporting Information) except for gram-scale
synthesis.
Preparation of Cobalt Complex 1b.17 To a solution of
(S,S)-ligand17 for 1b (4.12 g, 5.9 mmol) and Et3N (1.73 mL,
12.4 mmol) in degassed MeOH (90.0 mL) was added CoCl2
(1.1307 g, 8.7 mmol) in degassed MeOH (23.0 mL) at 58 °C
for 30 min under nitrogen atmosphere. After cooled to room
temperature, to the solution was added degassed water (12.6
mL) to give precipitate. The resulting mixture was filtered,
washed with degassed water (11.7 mL) and degassed MeOH
(16.2 mL) and dried in vacuo for 4 h to afford orange-to-green
solid (86% yield). Mp 334.68 °C (DSC).
General Procedure for Enantioselective Borohydride
Reduction of Ketones (Tables 1 and 2). Solution A: To a
solution of cobalt complex 1b (24.8 mg, 0.033 mmol) and
substrate 2b (107.2 mg, 0.61 mmol) in dehydrated CHCl3 (6.0
mL) was added MeOH (0.109 mL, 2.7 mmol) at room
temperature under nitrogen atmosphere. Solution B: A mixture
of NaBH4 (118.0 mg, 3.1 mmol), tetrahydrofurfuryl alcohol
(4.0 mL, 41.3 mmol), and EtOH (0.176 mL, 3.0 mmol) in
dehydrated CHCl3 (20.0 mL) was stirred at 0 °C for 3 h under
nitrogen atmosphere.
Continuous-Flow System Using a Microreactor. For
reactions in Table 1 and 2, MPS-α100 with two syringes and
software to control the syringe pumps were used. Capacity of
syringe A was 5 mL and that of syringe B was 25 mL. Syringe A
and B were used for solution A and B, respectively. The inlets
of a microreactor and two syringes were connected by Teflon
tubes and 10-m length stainless tube (SUS316) was equipped
to the outlet of the microreactor. The microreactor was kept at
−20 °C and the SUS tube was at 10 °C. The end of the SUS
tube was dipped in 50 mL of 1 v/v% AcOH in MeOH with
stirring at −20 °C. Step 1: The inside of the pathway was
washed with MeOH (150 mL) and then with CHCl3 (150
mL). Subsequently, it was washed with 5 mL of dehydrated
CHCl3 from vessels under nitrogen atmosphere (5 times from
each syringe, 50 mL). Step 2: 2.0 mL of dehydrated CHCl3
from syringe A and 6.0 mL of solution B from syringe B were
fed into the pathway at the flow rate of 2.0 mL/min and 6.0
mL/min, respectively. Step 3: 5.0 mL of solution A from
syringe A and 15.0 mL of solution B from syringe B were
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solution B (1.0 mL/min) were introduced. Meanwhile, 2.5 mL
of solution A (0.375 mL/min) and 8.5 mL of solution B (1.229
mL/min) were charged into syringes, and 1.0 mL of solution B
(6.0 mL/min) was pushed away to another vessel in order to
exhaust generated hydrogen gas. Step 4: When the amounts of
solutions A1 and A2 became less than 2.5 mL, dehydrated
CHCl3 was added to prevent introduction of gas to the pathway
and to rinse and wash the pathway. The total amount of
solution A including dehydrated CHCl3 (195 mL) and solution
B (585 mL) were consumed for a total operating time of 9.75 h.
After the same workup as mentioned before, cobalt complex
was removed by silica gel column chromatography (hexane/
ethyl acetate = 10:1 to 4:1). Tetrahydrofurfuryl alcohol was
removed under reduced pressure (8.0 mmHg, 75 °C).
Purification by silica gel column chromatography (hexane/
ethyl acetate = 10:1, 8:1, 7:1 to 6:1) and the second time
(hexane/ethyl acetate = 10:1, 6:1 to 4:1) gave the
corresponding alcohol 3b in 2.9964 g (96% yield) with 92% ee.
1,2,3,4-Tetrahydro-5-methoxy-1-naphthalenol11,18
2H), 4.25 (s, 1H), 7.10 (m, 1H), 7.16−7.21 (m, 2H), 7.43 (m,
1H); 13C NMR (CDCl3) δ 22.5, 25.6, 25.9, 31.9, 33.8, 76.6,
126.1, 127.3, 128.7, 128.8, 135.8, 138.4; HPLC Daicel chiralpak
IA (1.0% EtOH in hexane; flow = 1.0 mL/min), 5.2 min
(ketone), 13.3 min (minor), 15.9 min (major).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Analytical data including H, 13C NMR, and HPLC data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*yamada@chem.keio.ac.jp.
Notes
The authors declare no competing financial interest.
1
(3a): white solid; mp 76.3−77.3 °C; H NMR (CDCl3) δ
REFERENCES
■
1.72−2.00 (m, 4H), 2.56 (m, 1H), 2.74 (m, 1H), 3.83 (s, 3H),
4.78 (m, 1H), 6.76 (d, 1H, J = 8.0 Hz), 7.06 (d, 1H, J = 8.0
Hz), 7.20 (dd, 1H, J = 8.0 Hz); 13C NMR (CDCl3) δ 18.0,
22.9, 31.7, 55.3, 68.1, 108.6, 120.5, 126.0, 126.5, 140.0, 157.0;
HPLC Daicel chiralpak IA (2.5% EtOH in hexane; flow = 1.0
mL/min), 8.0 min (ketone), 12.8 min (minor), 14.5 min
(major).
(1) Mikami, K.; Lautens, M., Eds. New Frontiers in Asymmetric
Catalysis; John Wiley & Sons, Inc.: New York, 2007; Ojima, I., Ed.
Catalytic Asymmetric Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New
York, 2010.
(2) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2145−2147.
(3) Yamada, T.; Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno, T.;
Ohtsuka, Y.; Miyazaki, D.; Mukaiyama, T. Chem.Eur. J. 2003, 9,
4485−4509.
1,2,3,4-Tetrahydro-6-methoxy-1-naphthalenol11,19
1
(3b): yellow oil; H NMR (CDCl3) δ 1.75 (m, 2H), 1.92 (m,
(4) Nagata, T. Unpublished results.
3H), 2.64−2.83 (m, 2H), 3.78 (s, 3H), 4.73 (t, 1H, J = 4.4 Hz),
6.62 (d, 1H, J = 2.8 Hz), 6.76 (dd, 1H, J = 3.0, 8.0 Hz), 7.32 (d,
1H, J = 8.8 Hz); 13C NMR (CDCl3) δ 18.5, 29.6, 32.3, 55.2,
67.6, 112.4, 113.3, 130.1, 131.2, 138.6, 158.8; HPLC Daicel
chiralpak IA (2.0% EtOH in hexane; flow = 1.0 mL/min), 16.9
(5) Ohtsuka, Y.; Kubota, T.; Ikeno, T.; Nagata, T.; Yamada, T. Synlett
2000, 535−537.
(6) Benson, R. S.; Ponton, J. W. Trans. Inst. Chem. Eng. 1993, A71,
160−168.
(7) Schubert, K.; Bier, W.; Keller, W.; Linder, G.; Seidel, D. Chem.
Eng. Process 1993, 32, 33−43.
min (ketone), 19.7 min (major), 26.1 min (minor).; [α]D
23
+22.8 (c 1.08, CHCl3) (ref 5.: [α]D +23.4 (c 1.01, CHCl3),
(8) Asano, Y.; Togashi, S.; Tsudome, H.; Murakami, E. Pharm. Eng.
2010, 30 (Jan/Feb), 1−8.
20
98% ee (S)).
1,2,3,4-Tetrahydro-7-methoxy-1-naphthalenol11,20
(9) (a) Yoshida, J.-i.; Saito, K.; Nokami, T.; Nagaki, A. Synlett 2011,
1
1189−1194. (b) Jahnisch, K.; Hessel, V.; Lowe, H.; Baerns, M. Angew.
̈
̈
(3c): yellow oil; H NMR (CDCl3) δ 1.70−2.02 (m, 4H),
Chem., Int. Ed. 2004, 43, 406−446. (c) Mason, B. P.; Price, K. E.;
Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007,
107, 2300−2318. (d) Baumann, M.; Baxendale, I. R.; Ley, S. V. Mol.
Diversity 2011, 15, 613−630. (e) Ahmed-Omer, B.; Brandt, J. C.;
Wirth, T. Org. Biomol. Chem. 2007, 5, 733−740.
2.61−2.80 (m, 2H), 3.80 (s, 3H), 4.75 (t, 1H, J = 4.8 Hz), 6.78
(dd, 1H, J = 3.0, 8.0 Hz), 6.97−7.04 (m, 2H); 13C NMR
(CDCl3) δ 19.1, 28.3, 32.3, 55.2, 68.4, 112.6, 114.2, 129.0,
129.8, 139.8, 157.9; HPLC Daicel chiralpak IA (2.5% EtOH in
hexane; flow = 1.0 mL/min), 8.5 min (ketone), 17.2 min
(minor), 18.5 min (major).
(10) (a) Jonsson, C.; Lundgren, S.; Haswell, S. J.; Moberg, C.
̈
Tetrahedron 2004, 60, 10515−10520. (b) Odedra, A.; Seeberger, P. H.
Angew. Chem., Int. Ed. 2009, 48, 2699−2702. (c) Hamberg, A.;
Lundgren, S.; Wingstrand, E.; Moberg, C.; Hult, K. Chem.Eur. J.
2007, 13, 4334−4341.
1,2,3,4-Tetrahydro-1-naphthalenol11,19 (3d): orange oil;
1H NMR (CDCl3) δ 1.66 (br s, 1H), 1.78 (m, 1H), 1.86−2.05
(m, 3H), 2.68−2.78 (m, 1H), 2.79−2.90 (m, 1H), 4.79 (t, 1H, J
= 4.8 Hz), 7.11 (m, 1H), 7.18−7.25 (m, 2H), 7.44 (m, 1H);
13C NMR (CDCl3) δ 18.7, 29.2, 32.2, 68.1, 126.1, 127.5, 128.6,
128.9, 137.0, 138.7; HPLC Daicel chiralpak IB (0.8% EtOH in
hexane; flow = 1.0 mL/min), 7.2 min (ketone), 15.9 min
(major), 17.7 min (minor).
(11) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1996, 737−738.
(12) Iwakura, I.; Hatanaka, M.; Kokura, A.; Teraoka, H.; Ikeno, T.;
Nagata, T.; Yamada, T. Chem.Asian J. 2006, 1, 656−663.
(13) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1996, 1081−1082.
(14) In a flow rate lower than 1.0 mL/min, efficient mixing cannot be
expected.
(15) Yamada, T.; Ohtsuka, Y.; Ikeno, T. Chem. Lett. 1998, 1129−
1130.
1-Phenyl-1-butanol11,21 (3e): colorless oil; 1H NMR
(CDCl3) δ 0.93 (t, 3H, J = 7.4 Hz), 1.23−1.50 (m, 2H),
1.62−1.87 (m, 3H), 4.69 (m, 1H), 7.22−7.38 (m, 5H); 13C
NMR (CDCl3) δ 14.0, 19.0, 41.2, 74.4, 125.9, 127.5, 128.4,
144.9; HPLC Daicel chiralpak IB (0.8% EtOH in hexane; flow
= 1.0 mL/min), 4.9 min (ketone), 11.3 min (minor), 12.8 min
(major).
(16) Nagata, T.; Sugi, K. D.; Yamada, T.; Mukaiyama, T. Synlett
1996, 1076−1078.
(17) Nagata, T.; Imagawa, K.; Yamada, T.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2001, 74, 2139−2150.
1,2,3,4-Tetrahydro-2,2-dimethyl-1-naphthalenol16,22
(18) Penick, M. A.; Mahindaratne, M. P. D.; Gutierrez, R. D.; Smith,
T. D.; Tiekink, E. R. T.; Negrete, G. R. J. Org. Chem. 2008, 73, 6378−
6381.
1
(3f). Colorless oil; H NMR (CDCl3) δ 0.97 (s, 3H), 0.99 (s,
3H), 1.53 (m, 1H), 1.68 (br s, 1H), 1.81 (m, 1H), 2.79 (m,
1239
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Organic Process Research & Development
Communication
(19) Matsumura, K.; Arai, N.; Hori, K.; Saito, T.; Sayo, N.; Ohkuma,
T. J. Am. Chem. Soc. 2011, 133, 10696−10699.
(20) Inagaki, T.; Ito, A.; Ito, J.; Nishiyama, H. Angew. Chem., Int. Ed.
2010, 49, 9384−9387.
(21) Ooka, H.; Arai, N.; Azuma, K.; Kurono, N.; Ohkuma, T. J. Org.
Chem. 2008, 73, 9084−9093.
(22) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.;
Muniz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288−8289.
̃
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