Catalytic asymmetric reduction of prochiral ketones with chiral β-amino alcohol N-Boranes and the corresponding tris(oxazaborolidine) borazines

Article abstract of DOI:10.1055/s-0033-1339943

Chiral β-amino alcohol-derived N-borane catalysts, namely noncyclic (2S)- and (2R)-2-amino-2-phenylethanol N-borane and their corresponding cyclic trimeric borazine derivatives, were synthesized and their catalytic activities in the asymmetric reduction of prochiral ketones were examined. Both the noncyclic and cyclic catalysts successfully catalyzed this reaction, giving the desired secondary alcohols in up to 82% isolated yield and with up to 80% enantioselectivity. The noncyclic catalyst was stable in aqueous and organic solvents, whereas the polycyclic borazine was stable only in nonprotic dry organic solvents. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339943

LETTER
▌2401
lCettaertalytic Asymmetric Reduction of Prochiral Ketones with Chiral β-Amino
Alcohol N-Boranes and the Corresponding Tris(oxazaborolidine)borazines
Chiral Amino Alcohol Borane Catalysts for Ketone Reduction
Afroditi Pinaka,a,b Dimitra Dimotikali,b Bezhan Chankvetadze,c Kyriakos Papadopoulos,*a
Georgios C. Vougioukalakis*a,d
a
Division of Physical Chemistry, NCSR Demokritos, 15310 Athens, Greece
E-mail: kyriakos@chem.demokritos.gr
b
Department of Chemical Engineering, NTU Athens, 15780 Athens, Greece
c
Institute of Physical and Analytical Chemistry, School of Exact and Natural Sciences,Tbilisi State University, 0170 Tbilisi, Georgia
d
Department of Chemistry, University of Athens, 15771 Athens, Greece
Fax +30(210)6511766; E-mail: vougiouk@chem.uoa.gr
Received: 28.08.2013; Accepted after revision: 24.09.2013
Dedicated to Professor Nikos Hadjichristidis on the occasion of his 70th birthday
Abstract: Chiral β-amino alcohol-derived N-borane catalysts,
namely noncyclic (2S)- and (2R)-2-amino-2-phenylethanol
N-borane and their corresponding cyclic trimeric borazine derivatives,
were synthesized and their catalytic activities in the asymmetric re-
duction of prochiral ketones were examined. Both the noncyclic and
cyclic catalysts successfully catalyzed this reaction, giving the de-
sired secondary alcohols in up to 82% isolated yield and with up to
80% enantioselectivity. The noncyclic catalyst was stable in aque-
ous and organic solvents, whereas the polycyclic borazine was sta-
ble only in nonprotic dry organic solvents.
Key words: reductions, catalysis, asymmetric catalysis, asymmet-
ric synthesis, boron, ketones
Afroditi Pinaka was born in Volos, Greece, in 1981 and received
her B.Sc. degree from the University of Ioannina in 2005. In 2008, she
obtained her M.Sc. in bioinorganic chemistry from the same univer-
sity. Currently, she is pursuing her Ph.D. in the field of organocataly-
sis at NCSR Demokritos. The work presented here is part of the
research carried out during her Ph.D. studies.
The catalytic asymmetric reduction of prochiral ketones is
one of the most important methods for the synthesis of
chiral secondary alcohols. Borane catalysts bearing chiral
moieties have been extensively employed in this kind of
transformation.1 Oxazaborolidines, one of the most wide-
ly applied types of chiral borane catalyst, were used for
the first time by Itsuno and co-workers.2 These asymmet-
ric catalysts were further developed by Corey and co-
workers,3 who found that oxazaborolidines having bulky
substituents on the carbinol carbon perform better in terms
Georgios C. Vougioukalakis was born in 1976 on the island of
Crete, Greece. He studied chemistry at the University of Crete and, in
2004, received his Ph.D. under the direction of Professor M.
Orfanopoulos. During his graduate studies, he spent short periods at
the University of Sussex and at the Consiglio Nazionale delle Ri-
cerche in Bologna. After two years of postdoctoral research at the
California Institute of Technology with Professor R. H. Grubbs, and
one year at the University of Athens with Professor N. Hadjichristidis,
of their enantioselectivities. The molecular structures of he joined NCSR Demokritos. In 2010, he was appointed Lecturer in
Organic Chemistry at the University of Athens. In 2012, he visited the
University of California–Irvine as a visiting scholar. His research in-
terests include homogeneous catalysis, organic and organometallic
chemistry, the synthesis of compounds of biological relevance and
the first chiral oxazaborolidine catalysts developed by the
research groups of Itsuno and Corey are shown in Figure
1. In recent decades, a significant number of reports have
been published on the synthesis of oxazaborolidines and
potential applications, as well as the development of nanostructures,
their catalytic efficiencies in asymmetric ketone reduc-
tions.4–6 In these studies, the oxazaborolidine catalyst was
usually formed in situ through the complexation of a
borane with an amino alcohol.
mostly related to energy issues and nanotechnology.
mation of oxazaborolidines with enhanced stabilities and
improved catalytic abilities. In this context, we recently
showed that β-amino alcohol N-boranes can be easily pre-
pared from the corresponding naturally occurring amino
acids in a single step under mild conditions (Scheme 1).7
Chiral β-amino alcohol N-boranes are promising catalysts
for asymmetric reduction reactions, because the combina-
tion of these chiral compounds with a second source of
borane, such as borane–tetrahydrofuran (BH3·THF) or
borane–dimethyl sulfide can, potentially, lead to the for-
A careful review of the literature revealed that there have
been no reports on the catalytic properties of oxazaboro-
lidines synthesized directly from β-amino alcohol N-bo-
ranes. We therefore decided to study the synthesis of a
chiral oxazaborolidine in situ from enantiopure (2R)-2-
amino-2-phenylethanol N-borane and borane–tetrahydro-
furan, and to evaluate its catalytic efficiency in the asym-
SYNLETT 2013, 24, 2401–2406
Advanced online publication: 14.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339943; Art ID: ST-2013-B0829-L
© Georg Thieme Verlag Stuttgart · New York

2402
A. Pinaka et al.
LETTER
O
O
N
B
B
H
N
O
B
N
B
N
O
N
H
B
R
OH
H2N
BH3
O
Figure 1 Chiral oxazaborolidine catalysts developed by Itsuno (left)
and Corey (right) for the asymmetric reduction of prochiral ketones
1
2
R
O
R
R
NaBH4
Figure 2 (2R)-2-amino-2-phenylethanol N-borane catalyst (1) and
the corresponding polycyclic borazine catalyst 2
+
H2SO4, Et2O
NH2
OH
NH2
OH
NH2
BH3
OH
Scheme 1 Sulfuric acid assisted direct reduction of chiral α-amino
acids by sodium borohydride
metric reduction of prochiral ketones. Moreover, we
attempted to modify this β-amino alcohol N-borane cata-
lyst further, with the aim of improving its properties. Ac-
cording to the literature,8 polycyclic borazines with three
adjacent oxazaborolidine moieties can be easily synthe-
sized from β-amino alcohol N-boranes through a relative-
ly simple one-step cyclization process at temperatures
above 140 °C.
Polycyclic borazines were studied extensively during the
1960s, while current interest in them lies mainly in the
fields of inorganic chemistry and ceramics.9 The presence
of three oxazaborolidine rings and three Lewis-base nitro-
gen atoms in the same structure gives polycyclic bora-
zines considerable potential as catalysts for the synthesis
of reduction products with enhanced enantioselectivi-
ties.10 However, the catalytic ability of polycyclic bora-
zines in asymmetric synthesis has not been sufficiently
investigated and, to the best of our knowledge, there have
been only two studies on this subject. Both reported that
the borazine catalysts showed low reactivities, although
this aspect was inadequately documented.8b,9b On this ba-
sis, we decided to synthesize a new polycyclic borazine by
cyclization of chiral 2-amino-2-phenylethanol N-borane,
and to make a detailed study of its catalytic properties in
the asymmetric reduction of prochiral ketones.
Figure 3 13C NMR spectra of (2R)-2-amino-2-phenylethanol,
(2R)-2-amino-2-phenylethanol N-borane, and the corresponding
polycyclic borazine
O
OH
R-configured catalyst 1 or 2
reducing reagent, THF
Scheme 2 Asymmetric reduction of acetophenone, utilizing cata-
lysts 1 and 2 in conjunction with various reducing reagents
tetrahydrofuran, dichloromethane, or dimethyl sulfoxide.
In all other cases, decomposition to the corresponding
β-amino alcohol is observed.
(2R)-2-Amino-2-phenylethanol N-borane (1; Figure 2)
was synthesized by the sulfuric acid-assisted direct reduc-
tion of (2R)-(–)-2-phenylglycine with sodium borohy-
dride.7 The corresponding borazine 2 was obtained by
heating borane 1 under a continuous argon flow in a tube
furnace.8,11
We evaluated chiral catalysts 1 and 2 in the asymmetric
reduction of a series of prochiral ketones. To determine
the optimal conditions for the reaction, we initially tested
a series of reducing agents for the asymmetric reduction
of acetophenone (Scheme 2).
The use of lithium aluminum hydride, sodium borohy-
dride, or sodium borohydride in combination with
diiodine5 gave racemic products in moderate to good iso-
lated yields (Table 1, entries 1–3, 8, and 9). The enantio-
selectivity was significantly improved when borane–
tetrahydrofuran was used as the source of borane (entries
4–6 and 10–13), and there was also an increase in the yield
of the isolated product. When catalyst 1 was used in the
absence of a reducing agent, low yields and no enantio-
selectivity were observed.
The structure of the novel polycyclic borazine catalyst
was determined by 1H and 13C NMR spectroscopy (Figure
3), Fourier-transform IR spectroscopy, elemental analy-
sis, and high-resolution electrospray-ionization mass
spectrometry (HRMS).12 Although we were unable to de-
tect the molecular ion of catalyst 2 in its HRMS spectrum,
certain fragments might well originate from it. Despite re-
peated attempts, we were unable to obtain single crystals
of adequate quality for X-ray analysis. Catalyst 2 is stable
only in dry, degassed, nonprotic organic solvents such as
Synlett 2013, 24, 2401–2406
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Amino Alcohol Borane Catalysts for Ketone Reduction
2403
Having determined the most efficient reducing agent, we noncatalyzed reduction of the ketone by the free borane or
examined the effects of various catalyst loadings. Chang- reduced levels of dimerization of the oxazaborolidine cat-
ing the catalyst loading from 20% to 100% did not result alyst at elevated temperatures.13c
in significant changes in the yield or enantioselectivity
with catalyst 1 (entries 4 and 5). In the case of borazine 2,
however, reduction in the catalyst loading from 33 to 10%
We also studied the effect of the rate of addition of the bo-
rane–tetrahydrofuran to the reaction solution. Under the
optimized conditions, the borane–tetrahydrofuran solu-
decreased the enantioselectivity by 10% (entries 10–13);
tion was added to the reaction flask at a rate of 1 mL per
the corresponding decrease in the isolated yield was rela-
hour. When we tried a faster addition rate (4.8 mL per
tively low (6%).
hour), the enantioselectivity fell by 15% (Table 1, entries
A rather unexpected result was observed upon studying 10 and 17). With regard to the effects of various solvents
the temperature dependence of the enantioselectivity. For on the stereoselectivity, the best results were obtained by
both catalysts, the highest enantiomeric excesses were ob- using tetrahydrofuran. Moreover, as expected, when we
served at room temperature (entries 4, 5, and 10). In other used the S-configured catalyst, we obtained an excess of
words, lowering the reaction temperatures did not lead to the R-enantiomer of 1-phenylethanol (entries 4, 12, and
improved enantioselectivity, as we had expected. Similar 14), whereas S-enantiomers dominated when the R-con-
effects have been reported by Prasad and Joshi,13a as well figured catalysts were used (entries 5, 10, 11, 13, and 15–
as by Xu and co-workers13b,c in other oxazaborolidine-cat- 17).
alyzed asymmetric reductions of ketones. For example,
one of the oxazaborolidines studied by Xu showed its
Having identified the optimal reaction conditions (20%
and 33% catalyst loadings for catalysts 1 and 2, respec-
highest enantioselectivity at about 50 °C, whereas the en-
tively; r.t.; 1 M BH3–THF as the borane source added at a
antioselectivity of another increased linearly with the re-
rate of 1 mL/h), we examined the asymmetric reduction of
action temperature up to 110 °C.13c Rationalizations
a series of prochiral ketones (Scheme 3).14,15 The results
offered for these abnormal effects include competitive
Table 1 Asymmetric Reduction of Acetophenone with Catalyst 1 or 2 and Various Reducing Agents at Various Temperatures and Catalyst
Loadings
Entry
Reducing agent
Catalyst
Catalyst loading Temp
Yielda
(%)
eeb
(%)
Configurationc
(%)
(°C)
1
2
LiAlH4
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
100
100
100
100
20
10
20
33
33
33
15
10
8
0
r.t.
0
55
42
63
80
70
64
30
71
50
78
67
72
66
56
57
61
40
0
0
–
NaBH4
–
3
NaBH4–I2
BH3·THF
BH3·THF
BH3·THF
BH3·THF
NaBH4–I2
NaBH4
0
–
4
r.t.
r.t.
r.t.
–78
0
46
45
38
0
Rd
S
5
6
S
7
–
8
–
–
9
r.t.
r.t.
r.t.
r.t.
r.t.
–78
–20
50
–
–
10
11
12
13
14
15
16
17
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
46
39
36
36
3
S
S
Rd
S
33
33
33
33
Rd
S
13
22
31
S
r.t.
S
a Yield of isolated product after column chromatography.
b Determined by chiral HPLC.
c Determined by comparison of the + or – sign with the absolute configuration of commercial 1-phenylethanol.
d The S-configured catalyst was used.
e The reducing reagent was added at a rate of 5.0 mL/h.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2401–2406

2404
A. Pinaka et al.
LETTER
from these studies are summarized in Table 2. In most spectroscopy. Both catalysts gave similar reaction mix-
cases, the isolated yields were good to high, with full con- tures that contained amino alcohol–borane adducts.
versions of the ketone in all cases.
In summary, we evaluated the catalytic activity of both the
chiral (2R)-2-amino-2-phenylethanol N-borane catalyst 1
O
OH
R2
4a–h
and the corresponding polycyclic borazine 2 in the asym-
metric reduction of prochiral ketones. Both 1 and 2 are
new, easily handled, chiral compounds that can be readily
synthesized and isolated by one-step procedures in pure
form, without the need for elaborate purification proce-
dures. Both catalysts afforded reduction products in good
to high yields and enantioselectivities of up to 80%. This
is the first report of a detailed study on the catalytic poten-
tial of a polycyclic borazine (2). Catalyst 1 is stable in
aqueous as well as organic solvents, whereas borazine 2 is
stable only in nonprotic dry organic solvents. The catalyt-
ic ability of both catalysts in other asymmetric reduction
reactions, such as those of imines, oximes, and hydra-
zones, remains to be investigated.
R-configured catalyst 1 or 2
BH3⋅THF, THF
R1
R2
R1
3a–h
Scheme 3 Asymmetric reduction of a series of prochiral ketones by
using catalysts 1 and 2
The corresponding enantioselectivities were low to high.
The best results for catalyst 1 were obtained in the asym-
metric reduction of 1-(2-naphthyl)ethanone (Table 2, en-
try 7; 75% isolated yield, 80% ee). 1-(2-Naphthyl)-
ethanone was also the best substrate for catalyst 2 (entry
8; 82% isolated yield, 49% ee). In all cases, the S-enantio-
mer of the reduced products was obtained in excess with
the R-configured catalysts 1 and 2. As a general observa-
tion, both catalysts gave products with enantioselectivities
in the same range when used in asymmetric reductions of
the various ketones, with the exception of 1-(2-naph-
thyl)ethanone, where a 31% loss in ee was observed when
catalyst 2 was used (entries 7 and 8). Experiments were
also carried out in the absence of a substrate to permit the
observation of possible reactive intermediates by NMR
HPLC Data for the Chiral and Racemic Reduction Products
4a–h
(1S)-1-Phenylethanol (4a)16
HPLC: Lux Cellulose-1, hexane–i-PrOH (98:2); flow rate: 1.0
mL/min, λ = 254 nm; tR (R) = 18.5 min, tR (S) = 24.7 min; ee 45%
(catalyst A); 46% (catalyst B).
Table 2 Asymmetric Reduction of a Series of Prochiral Ketones in the Presence of Catalyst 1 or 2
Entry
Catalyst
R1
Ph
R2
Ketone
Product
Yielda (%)
eeb (%)
1
2
3
4
5
1
2
1
2
1
Me
3a
4a
70
78
57
40
73
45
46
5
2-pyridyl
Me
3b
3c
4b
4c
5
36
6
7
2
1
2
1
2
1
2
1
2
1
2
81
75
82
52
60
55
52
58
62
60
53
46
80
49
22
10
5
2-naphthyl
2-anthryl
4-ClC6H4
(CH2)5Me
Bn
Me
Me
Ph
3d
3e
3f
4d
4e
4f
8
9
10
11
12
13
14
15
16
4
Me
Me
3g
3h
4g
4h
n.d.c
n.d.
13
10
a Isolated yield after column chromatography.
b Determined by HPLC. All the products were S-configured.
c n.d. = not determined.
Synlett 2013, 24, 2401–2406
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Amino Alcohol Borane Catalysts for Ketone Reduction
2405
(1S)-1-Pyridin-2-ylethanol (4b)17
HPLC: Lux Cellulose-1, hexane–i-PrOH (90:10); flow rate: 1.0
mL/min, λ = 254 nm; tR (R) = 7.4 min, tR (S) = 7.9 min; ee 5% (cat-
alyst A); 5% (catalyst B).
(e) Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Pericàs, M.
A.; Riera, A. J. Org. Chem. 1999, 64, 7902. (f) Rao, M.;
Santhi, V. Tetrahedron: Asymmetry 2000, 11, 3553.
(g) Zhou, H.-B.; Zhang, J.; Lü, S.-M.; Xie, R.-J.; Zhou, Z.-
Y.; Choi, M. C. K.; Chan, A. S. C.; Yang, T.-K. Tetrahedron
2001, 57, 9325. (h) Gilmore, N. J.; Jones, S.; Muldowney,
M. P. Org. Lett. 2004, 6, 2805. (i) Zou, H.-H.; Hu, J.; Zhang,
J.; You, J.-S.; Ma, D.; Lü, D.; Xie, R.-G. J. Mol. Catal. A:
Chem. 2005, 242, 57. (j) Korenaga, T.; Kobayashi, F.;
Nomura, K.; Nagao, S.; Sakai, T. J. Fluorine Chem. 2007,
128, 1153. (k) Zhou, Y.; Wang, Y.-W.; Dou, W.; Zhang, D.;
Liu, W.-S. Chirality 2009, 21, 657. (l) Cimarelli, C.; Fratoni,
D.; Palmieri, G. Chirality 2010, 22, 655. (m) Li, D. R.; He,
A.; Falck, J. R. Org. Lett. 2010, 12, 1756.
(1S)-1,2,3,4-Tetrahydronaphth-1-ol (4c)16
HPLC: Lux Cellulose-1, hexane–i-PrOH (95:5); flow rate: 1.0
mL/min, λ = 254 nm; tR (S) = 9.8 min, tR (R) = 10.7 min; ee 36%
(catalyst A); 46% (catalyst B).
(1S)-1-(2-Naphthyl)ethanol (4d)16
HPLC: Lux Cellulose-1, hexane–i-PrOH (95:5); flow rate: 1.0
mL/min, λ = 254 nm; tR (S) = 20.5 min, tR (R) = 21.9 min; ee 80%
(catalyst A); 49% (catalyst B).
(1S)-1-(2-Anthryl)ethanol(4e)18
HPLC: Lux Cellulose-1, hexane–i-PrOH (90:10); flow rate: 1.0
mL/min, λ = 254 nm; tR (S) = 12.7 min, tR (R) = 21.3 min; ee 22%
(catalyst A); 10% (catalyst B).
(5) Periasamy, M.; Kanth, J. N. B.; Prasad, A. S. B. Tetrahedron
1994, 50, 6411.
(6) For some related reviews, see: (a) Corey, E. J.; Helal, C. J.
Angew. Chem. Int. Ed. 1998, 37, 1986. (b) Glushkov, V. A.;
Tolstikov, A. G. Russ. Chem. Rev. (Engl. Transl.) 2004, 73,
581. (c) Cho, B. T. Tetrahedron 2006, 62, 7621. (d) Cho, B.
T. Chem. Soc. Rev. 2009, 38, 443.
(7) (a) Pinaka, A.; Vougioukalakis, G. C.; Dimotikali, D.;
Psyharis, V.; Papadopoulos, K. Synthesis 2012, 44, 1057.
(b) Pinaka, A.; Vougioukalakis, G. C.; Dimotikali, D.;
Yannakopoulou, E.; Chankvetadze, B.; Papadopoulos, K.
Chirality 2013, 25, 119.
(8) (a) Framery, E.; Vaultier, M. Heteroat. Chem. 2000, 11, 218.
(b) Stepanenko, V.; Ortiz-Marciales, M.; Barnes, C. E.;
Garcia, C. Tetrahedron Lett. 2006, 47, 7603.
(9) (a) Harris, J. J.; Rudner, B. J. Org. Chem. 1962, 27, 3848.
(b) Baum, O.; Goldberg, I.; Srebnik, M. J. Organomet.
Chem. 2006, 691, 1993.
(10) Bridgeman, A. J. Polyhedron 1998, 17, 2279.
(11) Catalyst 1 was heated from 25 to 120 °C over 30 min then
kept at 120 °C for 1 h. Subsequently, the temperature was
raised to 170 °C over 15 min and kept at 170 °C for 1 h to
give borazine catalyst 2 in pure form as a transparent, glass-
like material.
(12) (3S,8S,13S)-3,8,13-Triphenylhexahydrotris[1,3,2]-
oxazaborolo[3,2-a:3′,2′-c:3′′,2′′-e][1,3,5,2,4,6]-
triazatriborinine (2)
(S)-(4-Chlorophenyl)(phenyl)methanol (4f)19
HPLC: Lux Cellulose-1, hexane–i-PrOH (98:2); flow rate: 1.0
mL/min, λ = 254 nm; tR (R) = 47.1 min, tR (S) = 49.5 min; ee 5%
(catalyst A); 4% (catalyst B).
(2S)-1-Phenylpropan-2-ol (4h)20
HPLC: Lux Cellulose-1, hexane–i-PrOH (90:10); flow rate: 1.0
mL/min, λ = 254 nm; tR (R) = 6.0 min, tR (S) = 6.5 min; ee 13%
(catalyst A); 10% (catalyst B).
Acknowledgment
The authors thank NCSR Demokritos, the National Technical Uni-
versity of Athens, and the John S. Latsis Public Benefit Foundation
for financial support. A.P. is grateful to NCSR Demokritos for a
Ph.D. fellowship. The Foundation for Education and European Cul-
ture is also acknowledged for providing a scholarship to G.C.V.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
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ungIifoop
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N), 1242 (w, C–N), 1072 (s, B–N), 1007 (m, C–O), 912 (s),
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Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109,
7925. (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Am.
Chem. Soc. 1988, 53, 2861.
(13) (a) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem. 1996, 61,
3888. (b) Xu, J.; Wei, T.; Zhang, Q. J. Org. Chem. 2003, 68,
10146. (c) Xu, J.; Wei, T.; Lin, S.-S.; Zhang, Q. Helv. Chim.
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(14) Asymmetric Reduction of Acetophenone with Catalyst 1;
Typical Procedure
A 100 mL, flame-dried, two-necked, round-bottomed flask
equipped with a magnetic stirrer bar, was charged with
catalyst 1 (0.4 mmol) and anhyd THF (4 mL). BH3·THF (2.4
mmol, 1.2 equiv) was added under argon from a syringe. A
soln of PhCOMe (2 mmol, 0.22 mL) in anhyd THF (2 mL)
was added dropwise at 1 mL/h and the solution was then
stirred at r.t. under argon for 18 h. When the reaction was
complete, the mixture was hydrolyzed by the addition of
MeOH (5 mL) and 1 M aq HCl (5 mL) and stirred for 30 min.
The mixture was then extracted with Et2O (3 × 50 mL), and
(4) (a) Brunel, J. M.; Maffei, M.; Buono, G. Tetrahedron:
Asymmetry 1993, 4, 2255. (b) Quallich, G. J.; Woodall, T.
M. Tetrahedron Lett. 1993, 34, 785. (c) Hulst, R.; Heres, H.;
Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron:
Asymmetry 1996, 7, 1373. (d) Le Toumelin, J.-B.;
Babouléne, M. Tetrahedron: Asymmetry 1997, 8, 1259.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2401–2406

2406
A. Pinaka et al.
LETTER
When the reaction was complete, the mixture was
hydrolyzed by addition of MeOH (5 mL) and 1 M aq HCl (5
mL). Workup as described in ref. 14 gave enantiomerically
enriched 1-phenylethanol as a colorless oil; yield: 0.19 g
(78%).
the combined organic extracts were dried (MgSO4) and
concentrated under reduced pressure. The residual crude
product was purified by column chromatography [silica gel,
EtOAc–hexanes (1:3)] to give enantiomerically enriched
1-phenylethanol as a colorless oil; yield: 0.17 g (70%).
(15) Asymmetric Reduction of Acetophenone with Catalyst 2;
Typical Procedure
(16) Bouzemi, N.; Aribi-Zouioueche, L.; Fiaud, J.-C.
Tetrahedron: Asymmetry 2006, 17, 797.
(17) Pal, M.; Srivastana, G.; Moon, L. S.; Jolly, R. S. Bioresour.
Technol. 2012, 118, 306.
(18) Ito, J.; Ujiie, S.; Nishiyama, H. Organometallics 2009, 28,
630.
(19) Wu, X.; Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2005,
16, 2299.
(20) http://www.sigmaaldrich.com
A 100 mL, flame-dried, two-necked, round-bottomed flask
equipped with a magnetic stirrer bar was charged with
catalyst 2 (0.66 mmol) and anhyd THF (4 mL). PhCOMe (2
mmol, 0.22 mL) was then added under argon from a syringe.
Subsequently, BH3·THF (2.4 mmol, 1.2 equiv) was added
dropwise with the aid of a syringe pump at a rate of 1 mL/h,
and the solution was then stirred at r.t. under argon for 18 h.
Synlett 2013, 24, 2401–2406
© Georg Thieme Verlag Stuttgart · New York

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