Enantioselective reduction of trifluoromethyl ketones using an oxazaborolidine catalyst generated in situ from a chiral lactam alcohol

Article abstract of DOI:10.1016/j.tetasy.2011.08.006

The oxazaborolidine catalyst prepared in situ from the chiral lactam alcohol 2 and borane was found to catalyze the enantioselective reduction of highly reactive trifluoromethyl ketones at room temperature with high enantioselectivities of up to 86% ee.

Full text of DOI:10.1016/j.tetasy.2011.08.006

Tetrahedron: Asymmetry 22 (2011) 1464–1466
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Enantioselective reduction of trifluoromethyl ketones using an
oxazaborolidine catalyst generated in situ from a chiral lactam alcohol
⇑
Yasuhiro Kawanami , Katsuhiro Hoshino, Wataru Tsunoi
Department of Applied Biological Science, Faculty of Agriculture, Kagawa University, Miki-cho, Kagawa 761-0795, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Accepted 1 August 2011
Available online 2 September 2011
The oxazaborolidine catalyst prepared in situ from the chiral lactam alcohol 2 and borane was found to
catalyze the enantioselective reduction of highly reactive trifluoromethyl ketones at room temperature
with high enantioselectivities of up to 86% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
O
Ph
O
Ar
Ph
Ph
Ar
N
The oxazaborolidine-catalyzed asymmetric borane reduction of
prochiral ketones (CBS reduction) has become important in mod-
ern synthetic chemistry since the reports of Itsuno et al.1 and Corey
et al.2 The CBS reduction provides a predictable absolute stereo-
chemistry and high enantiomeric excess (ee) of chiral secondary
alcohols, which are valuable chiral building blocks for the synthesis
of natural products.
N
O
N
H
H
B
B
OH
O
O
R
1a R = H
2 Ar = Ph
3 Ar = 3,5-Me2Ph
1g
1b R = Me
1c R = n-Bu
1d R = OMe
As an alternative method, we have previously reported that the
oxazaborolidine catalyst can be generated in situ from the chiral lac-
tam alcohol 2, (S)-5-(diphenylhydroxymethyl)pyrrolidin-2-one
(Fig. 1), and borane–tetrahydrofuran (BH3–THF) at room tempera-
ture; the resulting oxazaborolidine was found to catalyze the borane
reduction of aromatic ketones with high enantioselectivities of up to
98% ee.3 Moreover, we developed the enantioselective reduction of
aliphatic ketones, which was carried out using the oxazaborolidine
1e generated in situ from the chiral lactam alcohol 3 and 4-
iodophenoxyborane (4-I-PhOBH2).4 Fluorine-containing optically
active alcohols have recently been studied for preparing ferroelec-
tric liquid crystals, but the trifluoromethyl ketones are so reactive
that reduction using the CBS catalyst generally affords the corre-
sponding alcohols with poor enantioselectivity.5 However, Corey
et al.6 reported that the reduction of trifluoroacetophenone with
Bu–CBS 1c and 2 equiv of catecholborane at ꢀ78 °C proceeded with
a 90% ee (R). On the other hand, Stepanenko et al.7 described that the
reduction of trifluoroacetophenone using spiroborate esters 1g and
BH3–Me2S at room temperatureprovided a slightlylower enantiose-
lectivity (82% ee) and the opposite enantioselection (S). Recently,
Korenaga et al.8 also reported that the electronic tuning of the CBS
catalyst 1f could enhance the enantioselectivity up to 90% ee (S).
Herein, we report the practical enantioselective reduction of trifluo-
romethyl ketones using the simple oxazaborolidine 1a, without ste-
1e R = O-4-I-C6H4
1f R = 2,4,6-F3C6H2
Figure 1.
ric and electronic factors, generated in situ from the chiral lactam
alcohol 2 and borane (Scheme 1).
2. Results and discussion
We first examined the effect of borane reagents on the enanti-
oselectivity of the reduction of trifluoroacetophenone. Chiral lac-
tam alcohol 23 or 34 (10 mol %) was added to various borane
reagents, such as BH3–THF, borane–dimethylsulfide (BH3–Me2S),
catecholborane, and 4-I-PhOBH2, at room temperature and stirred
for 10 min, except for 4-I-PhOBH2, which was stirred for 1 h. To the
resulting oxazaborolidine catalyst, a solution of trifluoroacetophe-
none was added slowly over 1 h using a syringe pump, providing
chiral secondary alcohols in good yields. The results are summa-
rized in Table 1. The reduction using 2 and BH3–THF afforded the
(S)-alcohol with a moderate enantioselectivity (52% ee, entry 1),
although the reduction with BH3–Me2S and catecholborane pro-
vided no enantioselectivity (entries 2 and 3).
Using the more bulky chiral lactam alcohol 3 or 4-I-PhOBH2 did
not increase the enantioselectivity (entries 4 and 5), which is effec-
⇑
Corresponding author.
E-mail address: kawanami@ag.kagawa-u.ac.jp (Y. Kawanami).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.006

Y. Kawanami et al. / Tetrahedron: Asymmetry 22 (2011) 1464–1466
1465
sults are summarized in Table 2. When the reaction temperature
was decreased from 25 to 0 °C and ꢀ40 °C, the ee of the resulting
secondary alcohol greatly decreased to 8% ee and 18% ee, respec-
tively, with the opposite enantioselection (entries 1–3). At
ꢀ78 °C, the reaction did not take place. On the other hand, the
same enantioselectivity was obtained when the reaction was car-
ried out at 40 °C (entry 4). This temperature effect is in accordance
with the reported one8 for the reduction of trifluoroacetophenone
but is quite different from the reduction of acetophenone (97% ee
at ꢀ10 °C).3 At low temperature, the transition state B might be in-
creased due to electronic repulsion between the trifluoromethyl
group and lone pair of the carbonyl group as proposed by Corey
et al.6 and, therefore, the reverse of the sense of enantioselectivity
might be observed. It should be noted that we observed that the
enantioselectivity was susceptible to the balance between the bor-
ane equivalents and catalyst loading. When 1.2 equiv of BH3–THF
was used, the ee was significantly decreased (entry 5). On the other
hand, using 0.8 equiv of BH3–THF increased the enantioselectivity
up to 83% ee (entry 6). In addition, catalyst 1a showed the same
enantioselectivity even with an 8 mol % ligand loading when
0.64 equiv of BH3–THF was used (entry 9).
Ar
Ar
O
N
H
OH
(10 mol%)
CF3
OH
CF3
BH3-THF, rt
O
Scheme 1.
Table 1
Asymmetric reduction of trifluoroacetophenone using chiral lactam alcohol 2 or 3a
Entry Ligand Borane
Solvent
Yieldb (%) % eec Config.d
1
2
3
4
5
6
7
8
9
2
2
2
3
3
2
2
2
2
BH3–THF
BH3–Me2S
THF
THF
89
77
36
90
67
52 (S)
3
2
(R)
(S)
Catecholborane THF
BH3–THF
4-I-PhOBH2
BH3–THF
BH3–THF
BH3–THF
BH3–THF
THF
THF
Toluene 82
CH2Cl2
CHCl3
CCl4
46 (S)
42 (S)
56 (S)
78 (S)
80 (S)
97
90
56
8
(S)
Table 2
The temperature effect and effect of borane equivalents on the enantioselectivity for
a
All reactions were carried out with 10 mol % of 2 or 3 and 1.0 equiv of BH3–THF
at rt for 1 h.
reduction of trifluoroacetophenone using 2a
b
Yieldb
(%)
%eec Config.d
Isolated yield.
Entry Ligand
(mol %)
BH3
(equiv)
Temp
(°C)
c
Determined by HPLC analysis using a Chiralcel OD column.
Determined by comparison of the retention time of commercial (S)-2,2,2-tri-
d
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
8
1.0
1.0
1.0
1.0
1.2
0.8
0.6
0.8
0.64
ꢀ40
0
56
87
90
97
98
96
93
93
90
18
8
(R)
(R)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
fluoro-1-phenylethanol.
25
40
25
25
25
25
25
80
80
74
83
81
82
83
tive for the reduction of aliphatic ketones.4 It should be noted that
a solvent effect was observed during the reduction with 2 and
BH3–THF in various solvents (entries 6–9). Toluene showed a slight
increase in the ee (entry 6), while the polar solvents dichlorometh-
ane (CH2Cl2) and chloroform (CHCl3) afforded higher enantioselec-
tivities (78%, 80% ee, entries 7 and 8, respectively).9 When the less
polar carbon tetrachloride was used as the solvent, the enantiose-
lectivity decreased significantly (entry 9). The stereochemistry of
the resulting secondary alcohol was (S) except in the case of entry
2, which was in agreement with that of the reduction catalyzed by
1f8 and 1g.7 These results suggest that a polar reaction solvent is
crucial to reduce trifluoroacetophenone using 1a with a high
enantioselectivity, probably due to its stabilization of the preferred
transition state A, which is the same for acetophenone (Fig. 2).
8
a
All reactions were carried out with 10 mol % of 2 and BH3–THF in CHCl3 for 1 h
except for entry 1, in which the reaction was carried out for 4 h.
b
Isolated yield.
c
Determined by HPLC analysis using a Chiralcel OD column.
Determined by comparison of the retention time with commercial (S)-2,2,2-
d
trifluoro-1-phenylethanol.
Finally, we carried out the catalytic reduction of 4-methoxy-40-
(trifluoroacetyl)biphenyl, which is a potentially interesting precur-
sor for the preparation of ferroelectronic liquid crystals.10 As shown
in Scheme 2, the more sterically hindered biphenyl trifluoromethyl
ketones were reduced under the optimized reaction conditions
(BH3–THF, CHCl3, 25 °C) with a higher enantioselectivity (86% ee)
than trifluoroacetophenone in 87% yield, which is the same enanti-
oselectivity as the reduction with Bu–CBS 1c or the oxazaborolidine
Ph
Ph
Ph
Ph
derived from L-threonine and catecholborane in CH2Cl2–toluene at
N
N
O
H
O
H
H
H
H
H
ꢀ90 °C, but with an opposite (S)-configuration.10
B
B
B
B
O
O
H
H
3. Conclusion
F3C
Ph
In conclusion, we have demonstrated that a simple oxazaboroli-
dine catalyst11 generated in situ from the chiral lactam alcohol 2 and
BH3–THF catalyzed the enantioselective reduction of trifluoro-
methyl ketones in CHCl3 at room temperature with high enantiose-
lectivity. It is interesting to note that the polar halogenated organic
solvent, CHCl3, is the optimal solvent for achieving high enantiose-
lectivities of the reactive trifluoromethyl ketones, because CH2Cl2
has generally been reported to afford a somewhat lower ee than
THF and toluene for the asymmetric reduction of typical ketones.
Thus, this method offers an excellent alternative for the asymmetric
reduction of trifluoromethyl ketones. Moreover, this practical meth-
odology has many advantages that include stability toward air and
CF3
Ph
A
B
Figure 2. Proposed transition state models.
To further improve the enantioselectivity of trifluoroacetophe-
none reduction, we investigated the temperature effect, the effect
of borane equivalents and catalyst loading on the enantioselectiv-
ity. The reduction was carried out with BH3–THF in CHCl3. The re-

1466
Y. Kawanami et al. / Tetrahedron: Asymmetry 22 (2011) 1464–1466
MeO
Ph
MeO
Ph
O
N
H
OH
CF3
CF3
(10 mol%)
O
OH
BH3-THF, rt
86% ee
Scheme 2. Enantioselective reduction of 4-methoxy-40-(trifluoroacetyl)biphenyl using 2.
moisture and the requirement of mild reaction conditions compared
to the reported methods for trifluoromethyl ketones.6–8 Further
applications of this asymmetric catalytic reduction of para-substi-
tuted biphenyl trifluoromethyl ketones are currently in progress.
be 86% by HPLC analysis using a Chiralcel OD column, hexane/i-
PrOH = 90:10, 1.0 ml/min [retention times = 12 and 20 min for (S)
and (R), respectively].10 Mp 130–132 °C. 1H NMR (600 MHz,
CDCl3): d 2.69 (br s, 1H), 3.86 (s, 3H), 5.07 (q, J = 6.90 Hz, 1H),
6.99 (d, J = 8.28 Hz, 2H), 7.49–7.55 (m, 4H), 7.60 (d, J = 8.28 Hz,
2H). 13C NMR (150 MHz, CDCl3): d 55.4, 72.5 (q, J = 50.3 Hz),
114.3, 124.3 (q, J = 281.5 Hz), 126.9, 127.8, 128.2, 132.1, 132.8,
141.2, 159.5.
4. Experimental
4.1. General
The 1H NMR and 13C NMR spectra were recorded at 600 and
150 MHz using a JNM-ECA600 spectrometer, respectively. The
mass spectra were recorded by a JEOL JMS-SX102A mass spectrom-
eter. Optical rotations were taken with a JASCO P-1010 polarime-
ter. HPLC analysis was carried out using a DAICEL Chiralcel OD
column (0.46 ꢁ 25 cm) with a Shimadzu LC6A. THF and toluene
were dried over benzophenone ketyl before use. CH2Cl2 and CHCl3
were dried over P2O5 before use. TLC was carried out on Merck
glass plates precoated with Silica Gel 60F-254 (0.25 mm), and col-
umn chromatography was performed using Merck 23–400 mesh
silica gel. BH3–THF was purchased from Toyo Kasei Kogyo Co.
and BH3–Me2S and catecholborane were purchased from Aldrich
Chemical. All other reagents were purchased from the Wako
Chemical Co.
Acknowledgment
This research was financially supported by the Tosoh Co., Japan.
References
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1981, 315; Itsuno, S.; Hirao, A.; Nakahama, S.; Yamazaki, N. J. Chem. Soc., Perkin
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1984, 49, 555; Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.;
Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985, 2039.
2. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551; For
review, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
3. Kawanami, Y.; Murao, S.; Ohga, T.; Kobayashi, N. Tetrahedron 2003, 59, 8411.
4. Kawanami, Y.; Mikami, Y.; Hoshino, K.; Suzue, M.; Kajihara, I. Chem. Lett. 2009,
38, 722.
5. Goushi, S.; Funabiki, K.; Ohta, M.; Hatano, K.; Matsui, M. Tetrahedron 2007, 63,
4061.
6. Corey, E. J.; Cheng, X.; Cimprich, K. A.; Sarshar, S. Tetrahedron Lett. 1991, 32,
6835; Corey, E. J.; Link, J. O.; Bakshi, D. K. Tetrahedron Lett. 1992, 33, 7107.
7. Stepanenko, V.; Jesus, M. D.; Correa, W.; Guzman, I.; Vazquez, C.; Cruz, W.;
Ortiz-Marciales, M.; Barnes, C. L. Tetrahedron Lett. 2007, 48, 5799.
8. Korenaga, T.; Nomura, K.; Onoue, K.; Sakai, T. Chem. Commun. 2010, 46, 8624.
9. The reduction using commercially available Me–CBS (1 M in toluene) under the
same reaction conditions (BH3–THF, CHCl3, rt) afforded a low enantioselectivity
(20–29% ee) with the opposite enantioselection (R), which was irreproducible
over prolonged storage maybe due to some decomposition caused by
atmospheric moisture.
10. Fujisawa, T.; Onogawa, Y.; Shimizu, M. Tetrahedron Lett. 1998, 39, 6019.
11. Garrett et al. reported that the catalyst 1a formed in situ from (S)-diphenyl-2-
pyrrolidinemethanol was the most effective catalyst for the reduction of 20-
fluoroacetophenone among the catalysts 1a, 1b, and 1d,13 although catalyst 1a
can form a dimer and other species which can change the nature of the
catalyst14; Garret, C. E.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron:
Asymmetry 2002, 13, 1347.
4.2. Typical procedure for the reduction of a trifluoromethyl
ketone
To a solution of chiral lactam alcohol 2 (10.7 mg, 0.04 mmol,
10 mol %) in CHCl3 (0.8 ml) was added a 1 M BH3–THF solution
(0.48 ml, 0.48 mmol). The mixture was stirred under Ar at room
temperature for 10 min.
A solution of trifluoroacetophenone
(56 l, 0.4 mmol) in CHCl3 (0.6 ml) was added dropwise over 1 h
l
using a syringe pump. The reaction mixture was stirred until the
ketone disappeared based on TLC (1 h). The reaction was quenched
with MeOH (200 ll), extracted with ether and dried over MgSO4.
Flash-chromatography of the crude mixture (hexane/AcOEt, 5:1)
gave (S)-2,2,2-trifluoro-1-phenylethanol (63.4 mg, 90%). The ee
was determined to be 83% by HPLC analysis using a Chiralcel OD
column, hexane/i-PrOH = 97:3, 1.0 ml/min, and the absolute con-
figuration was established by comparing the retention time of
the commercially available (S)-2,2,2-trifluoro-1-phenylethanol
[retention times = 22 and 27 min for (S) and (R), respectively].
12. Fujisawa, T.; Onogawa, Y.; Sato, A.; Mitsuya, T.; Shimizu, M. Tetrahedron 1998,
54, 4267.
13. Matsui, M.; Shioiri, T. Synlett 1997, 273.
14. Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carrol, J. D.;
Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 5, 165.
4.3. (S)-2,2,2-Trifluoro-1-(4-methoxy-40-biphenyl)ethanol
Yield 87%, ½a 2D5
ꢂ
¼ þ22:7 (c 0.08, CHCl3) {lit.12
½
a 2D3
ꢂ
¼ þ26:0 (c
0.19, CHCl3), 98% ee for the (S)-form}. The ee was determined to