Enantioselective reduction of prochiral ketones with NaBH 4/Me2SO4/(S)-Me-CBS

Article abstract of DOI:10.1080/00397911.2013.862834

The enantioselective reduction of prochiral ketones with NaBH ₄/Me₂SO₄/(S)-Me-CBS is described. Borane is generated in situ via the reaction of NaBH₄ with Me ₂SO₄ in tetrahydrofuran, which

Full text of DOI:10.1080/00397911.2013.862834

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Enantioselective Reduction of Prochiral
Ketones with NaBH4/Me2SO4/(S)-Me-CBS
Yuhan Zhou a , Guchao Gao a , Yuming Song a & Jingping Qu a
a State Key Laboratory of Fine Chemicals , School of Pharmaceutical
Science and Technology, Dalian University of Technology , Dalian ,
China
Accepted author version posted online: 10 Feb 2014.Published
online: 29 Apr 2014.
To cite this article: Yuhan Zhou , Guchao Gao , Yuming Song & Jingping Qu (2014) Enantioselective
Reduction of Prochiral Ketones with NaBH4/Me2SO4/(S)-Me-CBS, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:10, 1515-1520,
DOI: 10.1080/00397911.2013.862834
To link to this article: http://dx.doi.org/10.1080/00397911.2013.862834
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Synthetic Communications1, 44: 1515–1520, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.862834
ENANTIOSELECTIVE REDUCTION OF PROCHIRAL
KETONES WITH NaBH4/Me2SO4/(S)-Me-CBS
Yuhan Zhou, Guchao Gao, Yuming Song, and Jingping Qu
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science
and Technology, Dalian University of Technology, Dalian, China
GRAPHICAL ABSTRACT
Abstract The enantioselective reduction of prochiral ketones with NaBH4/Me2SO4/(S)-Me-
CBS is described. Borane is generated in situ via the reaction of NaBH4 with Me2SO4 in
tetrahydrofuran, which is as efficient as the commercial one. Such in situ–generated borane
reagent was applied to reduce prochiral ketones in the presence of chiral oxazaborolidine
catalyst directly. The corresponding chiral secondary alcohols were obtained with excellent
enantiomeric excesses (93–99% ee) and good to excellent yield (80–99%).
Keywords Asymmetric reduction; chiral alcohols; chiral oxazaborolidine; dimethyl
sulfate; sodium borohydride
INTRODUCTION
Borane is among the most important reducing agents in both laboratory and
industry.[1] It has been widely used in the hydroboration of unsaturated C–C
bonds,[2] and reduction of carbonyl compounds,[3] oximes,[4] imines,[5] and amide.[6]
One of the most important applications of borane is reducing prochiral ketones to
the corresponding enantioenriched second aryl alcohols in the presence of chiral
catalyst.[7] Enantiomerically pure secondary alcohols are important building blocks
for the synthesis of various other organic compounds such as halides, esters, ethers,
ketones, amines, and many biologically active compounds. In this context, the
pioneering work of Hirao,[8] Corey,[9] and their coworkers has inspired the research
interests of synthetic organic chemists, and the asymmetric reduction of prochiral
ketones to optically active alcohols using chiral oxazaborolidine catalysts has
become one of the most active research topics.[10]
Received August 1, 2013.
Address correspondence to Yuhan Zhou and Jingping Qu, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian 116024, China. E-mail: zhouyh@dl.cn; qujp@
dlut.edu.cn
1515

1516
Y. ZHOU ET AL.
However, borane itself is a very harmful and unstable gas. Although the
stability of borane is improved by complexing with tetrahydrofuran (THF), SMe2,
or tertiary amines, its storage still needs an inert environment such as dry nitrogen
or argon atmosphere and low temperature.[11] This limitation restricts the use of
borane on large scale. One of the alternative ways to overcome that limit is developing
NaBH4=additive systems to replace borane in organic synthesis.[12] In reported
systems, the additives included chlorotrimethylsilane,[13] iodine,[14] bromine,[15]
catechol,[16] phenylboronic acid,[17] Lewis acids,[18] and so on. Nevertheless, most of
the NaBH4=additive combinations suffered from either poor selectivity or high cost
of the additives. Thus, a safe and low-cost NaBH4=additive system is highly desired.
Recently, we reported a convenient method to generate BH3=THF complex (BTHF)
via the reaction of NaBH4 with Me2SO4 in THF.[19] BTHF prepared in situ is almost
as effective as the commercial one. Herein, we report a novel combination of reagents
NaBH4=Me2SO4 with the chiral oxazaborolidine [(S)-Me-CBS] catalyst that reduces
prochiral ketones with good yield and enantioselectivity under mild conditions.
RESULTS AND DISCUSSION
BTHF (BH3=THF complex) was generated in situ by the reaction of NaBH4
with Me2SO4 in THF following the method established in our laboratory, and it
was applied to reduce prochiral ketones in the presence of (S)-Me-CBS catalyst
directly. To optimize the reaction condition, acetophenone was employed as the
model substrate. 1-Phenylethanol was generated in good yield when acetophenone
was added dropwise into the mixture of BTHF (generated in situ from NaBH4=
Me2SO4) and (S)-Me-CBS catalyst (Table 1, entries 1–5). A little greater enantios-
electivity was achieved at lower temperature (entries 1–3). Less BTHF resulted in
the decrease of both the yield and enantioselectivity (entry 4). The reaction gave
the best results with 10 mol% (S)-Me-CBS catalyst and 0.7 equivalent of BTHF at
ꢀ15 ꢁC (entry 5).
Having established the optimum condition, we applied this method to a
number of prochiral ketones. Good to excellent yield were achieved with high
enantioselectivity (Table 1, entries 6–12). a-Chloro or a-bromo of acetophenone
did not influence the yield and ee value (entries 7 and 8). 4-Chloroacetophenone
and 4-bromoacetophenone gave lower yield (entries 9 and 10). This may be due to
the effect of electron-withdrawing group para to the acetyl group. 2-Acetonaphthone
gave the best enantioselectivity because of the great bulky distinction between the
groups beside the carbonyl group (entry 11). The results were similar with those
reported by Corey et al.,[9b] in which commercial BTHF was used. It indicates that
the BTHF generated in situ by the reaction of NaBH4 with Me2SO4 in THF is as
effective as the commercial one in the enantioselective reduction of prochiral ketones
catalyzed by Me-CBS.
Recently, Soloshonok revealed that some nonracemic enantiomeric alcohols
are prone to an enantiomer self-disproportionation effect (SDE) on achiral silica
gel or via sublimation.[20] We therefore confirmed that the optical purity of the
products do not change after chromatographic purification using achiral silica gel.
The same result was given for nonracemic enantiomeric 1-(phenyl)ethanol while it
was distilled in vacuum.

NaBH4/Me2SO4/(S)-Me-CBS REDUCTION
1517
a
Table 1. Asymmetric reduction of prochiral ketone with NaBH4=Me2SO4 catalyzed by Me-CBS
Catalyst
loading (mol%)
Entry
Ketone
Temp. (ꢁC)
Yieldb (%)
ee (%)c
1
25
0
5
5
98
98
95
72
99
84
86
93
85
96
2
3
ꢀ15
ꢀ15
ꢀ15
5
4d
5
5
10
6
7
8
ꢀ15
ꢀ12
ꢀ12
10
10
10
99
97
98
98
96
98
9
ꢀ10
ꢀ10
10
10
90
80
97
97
10
11
12
ꢀ10
10
10
94
95
99
93
0
aReaction conditions: NaBH4=Me2SO4=ketone ¼ 0.7=0.7=1.
bIsolated yield.
cDetermined by HPLC with a chiral column (Daicel OD).
dNaBH4=Me2SO4=ketone ¼ 0.6=0.6=1.
EXPERIMENTAL
All reactions were performed under a nitrogen atmosphere in oven-dried
glassware with magnetic stirring. Anhydrous solvents were freshly distilled from
sodium and benzophenone. Column chromatography was performed on silica gel

1518
Y. ZHOU ET AL.
(100–200 mesh) using petroleum ether=EtOAc (7:3) as an eluant. NMR spectra were
recorded in CDCl3 at 400 MHz (1H) on a spectrometer. Chemical shift (d) were
reported in parts per million (ppm) relative to the residual solvent signal. (S)-Me-
CBS catalyst was prepared following the procedure described by Corey et al.[9b] Other
reagents were purchased from commercial sources.
Under a nitrogen atmosphere, 27.7 mg (0.7mmol) of NaBH4 (purity: 96%) and
1 mL of anhydrous tetrahydrofuran were introduced into a 10-mL, three-necked
flask equipped with pressure-equalizing addition funnel, a gas inlet pipe, a thermometer,
and magnetic stirring bar. The mixture was added dropwise with 89.3mg of Me2SO4
(0.7mmol) at 0 ꢁC and stirred for 1 h in an icebath and further 4 h at room temperature
until no gas generation was observed. Then 28.2mg of (S)-Me-CBS was added and
stirred at room temperature for 10min. After the reaction mixture was cooled to
desired temperature, a solution of the corresponding prochiral ketone (1 mmol) in
anhydrous THF was added dropwise through a syringe in 1 h. After the addition, the
mixture was stirred for additional 30min; 1 mL of HCl (2mol=L) aqueous solution
was added and stirred for 30min. Then THF was removed on a rotary evaporator.
The residue was extracted with ethyl acetate (3ꢂ 10mL). The organic layers were
combined and washed with saturated sodium bicarbonate (10mL) and brine (10 mL).
The organic layer was then dried over anhydrous sodium sulfate, filtered, concentrated,
and purified by column chromatography on silica gel to give pure products.
Spectroscopic and characterization data of the products are provided in the
Supporting Information, available online.
CONCLUSION
In conclusion, we have developed a convenient and useful method to prepare
asymmetric second aryl alcohols using the combination of NaBH4, Me2SO4, and
Me-CBS. The reagent NaBH4=Me2SO4 can be used as a cheap large-scale resource
of borane in laboratory and industry. The excellent asymmetric selectivity and
yields of the isolated products indicate that this is a useful and convenient method
of asymmetric reduction of prochiral ketones.
FUNDING
We are grateful to the National Natural Science Foundation of China
(No. 20676019), the Fundamental Research Funds for the Central Universities
(No. DUT13LAB03), and the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry for financial support of this
work. We also thank Baomin Wang for valuable discussions.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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