In situ NMR study of asymmetric borane reduction reaction - An abnormal factor in the temperature effect on the bis-oxazaborolidine catalyst and the relationship between the catalyst structure and selectivity

Article abstract of DOI:10.1016/S0957-4166(00)00306-2

The relationship between the structure of the catalyst and the selectivity in the asymmetric borane reduction reaction of prochiral ketones is discussed. The variation of the catalyst itself at low temperature is observed by the in situ NMR method and the origin of the temperature effect of the reaction is proposed. It is concluded that the amount of the effective component of the catalyst present has an important effect on the enantioselectivity. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00306-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3351–3359
In situ NMR study of asymmetric borane reduction
reaction—an abnormal factor in the temperature effect on
the bis-oxazaborolidine catalyst and the relationship between
the catalyst structure and selectivity
Jinkai Zhao,a Xinhe Bao,a,* Xiumei Liu,a Boshun Wan,a Xiuwen Han,a Caiguang Yang,b
Jiangfeng Hang,b Yan Fengb and Biao Jiangb
aState Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China
bShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received 4 July 2000; accepted 25 July 2000
Abstract
The relationship between the structure of the catalyst and the selectivity in the asymmetric borane
reduction reaction of prochiral ketones is discussed. The variation of the catalyst itself at low temperature
is observed by the in situ NMR method and the origin of the temperature effect of the reaction is
proposed. It is concluded that the amount of the effective component of the catalyst present has an
important effect on the enantioselectivity. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The enantioselective reduction of prochiral ketones is an important method for the synthesis
of optically active secondary alcohols, which are key intermediates for medicines and pesticides,
etc. Some of the best enantioselectivities have been achieved with systems derived from chiral
vicinal amino alcohols, which were pioneered by Itsuno,1 and then developed by Corey’s group2
and are well known as the CBS reduction. Comparing the numerous attempts to improve the
enantiomeric excess, few papers have concentrated on the mechanistic aspects of the catalytic
reaction, and many phenomena are still difficult to explain.
* Corresponding author. Tel: 0086-0411-4686637; fax: 0086-0411-4694447; e-mail: xhbao@ms.dicp.ac.cn
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00306-2

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J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
During the course of studies of borane reductions of ketones catalyzed by oxazaborolidine,
many papers have reported the effect of temperature on selectivity.3 In one of the first paper
concerning this reaction, Corey and co-workers2 stated that enantioselectivity often decreases
somewhat with decreasing temperature. Stone studied this effect in detail and improved the
selectivity by adjusting the temperature that was dependent on the substrate.4 Corey summarized
this effect in his recent comprehensive review5 and stated that the coordination of Me2S, THF
etc. to borane generally did not affect the level of enantioselection except at temperatures below
243 K. They attributed this effect to the alteration of the equilibrium between borane, the
coordinated ligand, the oxazaboralidine catalyst and the ketone at this temperature, and this
allowed the intervention of the competing reduction pathways. It has been observed that certain
catalysts exist in a temperature dependent equilibrium with their dimeric form. Buono et al.6
reported that with increasing temperature the equilibrium was shifted towards the monomeric
form. The dimer is certainly less active as a catalyst due to more steric hindrance and a
decreased reactivity of B towards the ketone because of the strong donation of O and N. Thus
the amount of catalyst dimer present has a negative effect on the selectivity. These elucidations
may be reasonable but there are still no definite conclusion and convincing proof, so we tried to
study the temperature effect with our bis-oxazaborolidine catalyst by in situ NMR method in
the hope of gaining insight into the effect.
Recently, good enantioselectivities of the C2-symmetric ligand 1 applied in the asymmetric
borane reduction of prochiral ketones have been found and the important intermediate
responsible for the enantioselectivity was shown to be 2 by in situ NMR method.7
During the study of the asymmetric borane reduction of ketones catalyzed by the ligand 1, a
dramatic temperature effect on enantioselectivity was observed (Table 1). With the increase of
the temperature from 243 to 308 K, the chemical yield and the enantioselectivities were greatly
improved (Fig. 1).
These results stimulated our interest to study the ‘equilibrium’ described by Corey et al.
Another problem that concerned us most is why so simple and less rigid a molecule (compound
1) can induce so high an enantioselectivity? Herein we try to provide some evidence for this
problem.

J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
3353
Table 1
Asymmetric stoichiometric borane reduction of prochiral ketones by ligand 1 at different temperatures
Entry
R1
R2
Temperature (K)
Yield (%)
Ee (%)a
Configurationb
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
CH2Cl
CH2Br
Me
243
303
308
318
308
308
308
55
95
95
94
92
91
95
33.8
60.6
65.5
64.8
84.7
88.1
69.6
S
S
S
S
R
R
S
b-Naphthyl
a Values of % ee were obtained by a HPLC chiral column OD, OJ.
b Configurations of the products [h]D were gained by comparing with the standard compound.
Figure 1. Plot of temperature versus yield and % ee of the asymmetric borane reduction of acetophenone (Table 1,
entry 1–4)
2. Experimental
2.1. Sample preparation
Compound 1 was synthesized from
L
-tartaric acid, as described elsewhere.3 Ligand 3 and
another compound 4 were prepared from the reduction products of their corresponding amino
acids by LiAlH4.
For preparing the coordinated compounds, 50 mg of the ligand (1R,4R,2S,3S)-1,4-dibenzyldi-
amino-2,3-butanediol 1 (0.17 mmol) was put in the pretreated NMR sample tube, and 0.3 ml of
2 M borane (0.6 mmol) in THF was dropped in at 203 K, and the temperature was increased
gradually to 308 K. The sample tube was sealed and kept for more than 12 h at 308 K, when
compound 2 was the main component in the system.
Other samples with different ligand concentrations were also prepared by this method.

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J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3559
2.2. NMR experiments
NMR experiments were performed on a Bruker DRX 400 spectrometer with a 5 mm BBI
1
probehead. H, 13C and 11B NMR experiments were carried out at room temperature or at a
1
predetermined temperature. H, 13C and 11B NMR spectra were recorded at 400.1, 100.6 and
1
128.4 MHz, respectively. The 90° pulses for H, 13C and 11B NMR spectra were 10, 10.1 and 10
ms, respectively. Their spectral widths were 4807.7, 25062.7 and 25641.0 Hz with data points at
16, 16 and 8 K, respectively.
The 11B NMR background from the probehead was deducted from the 11B NMR spectrum
and the peak at l −20 for BH3·Me2S was chosen as the internal standard in order to eliminate
the effect of temperature on the chemical shift.
2.3. In situ NMR tests
An in situ NMR method was employed to decide the structure of the coordinated catalysts.
The NMR sample tube was evacuated and filled with argon gas before the sample was
introduced, and a small tube filled with D2O or acetone-d6 was put in the NMR sample tube as
the lock signal. The sample was transferred from the reaction system to the NMR sample tube
under an argon atmosphere, then the tube was sealed and moved to the magnet for continuous
NMR detection immediately.
3. Results and discussion
Study of the catalyst 2 at different temperatures disclosed some abnormal information (Fig.
2). With a decrease in temperature the component of the catalytic system changes. The broad
peaks at l ꢀ29 and l ꢀ1.6 in Fig. 2(a) are assigned to the monomer and dimer (NꢀBꢀO in the
ring) of ligand 1, respectively. The peak at l ꢀ5.6 is the incompletely transformed catalyst
(ꢀOꢀBꢀOꢀ) according to our previous work.7 The upfield peaks from l −10 to −30 came from
the solution of borane complex such as BH3·Me2S and BH3·THF, etc. When the catalyst was
investigated from 308 to 223 K (Fig. 2(a–h)), the broad peak at l 29 decreased greatly and
another broad peak at l 16 appeared gradually from 263 to 223 K. These two peaks in the 11B
NMR spectrum (Fig. 2(f)) can be well resolved by deconvolution using the Bruker software
WINNMR, as shown in Fig. 3. The other 11B NMR spectra in Fig. 2 were also deconvoluted
and the data are collected in Table 2.
These results show that with a decrease in temperature the peak at l 29 was still the main
component, in spite of the fact that the other peaks at l 19 and l 16 were formed (Fig. 4). When
the sample was diluted with 0.5 ml deuterated THF this variation became dramatic. As indicated
in Fig. 5, three peaks in the spectrum detected at 223 K (Fig. 5, (1)) can be well resolved by
deconvolution and the ratio of the three peaks is 49/36/14. Generally, as it becomes more dilute
in the real catalytic system, it can be reasonably assumed that the transformations would
become more dramatic.
Considering the mechanism proposed by Corey2 and the reaction results, which were greatly
affected by the temperature, it could be concluded that component ‘a’ at l 29 in Fig. 3 was the
effective catalyst for the borane reduction reaction, and the chiral induction ability for
components b and c were not so satisfactory. Components b and c were assumed to be the

J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
3355
Figure 2. 11B NMR spectra with decoupling of the coordinated compound of ligand 1 with borane at different
temperatures
complex of the catalyst and the solvent. As the flexibility of the solvent decreases at low
temperatures, so it is easy to interact with the catalyst. It has been proved that components b
and c have the ability to interact with the substrate. Furthermore, they can affect the reaction.8
The complexes are certainly less active as catalysts due to more steric hindrance and a decreased
reactivity of B towards the ketone, caused by strong donation of O (THF) or S (Me2S) in the
solvent molecule.
As indicated in Figs. 2 and 3, the temperature-dependent equilibrium of the catalysts with
their dimeric forms was not obviously observed. But several novel species were found at low
temperatures and the catalytic system at low temperatures became a more complicated mixed
system, thus the amount of effective catalyst was decreased. From our point of view the
decreased amount of effective catalyst (oxazaborolidine) was the main reason for the diminished
enantioselectivity and this was in accord with the conclusions of the literature.

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J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
Figure 3. 11B NMR and their partly deconvoluted spectra of catalyst 1 at 243 K in Fig. 2(f) (a and b are the
deconvoluted peaks and the integration of the peaks a and b equals 2). (1) The original spectrum; (2) the
deconvoluted spectrum
Besides the temperature effect on the novel catalyst, another interesting phenomenon was also
noticed. The structure of compound 1 can be regarded as a combination of two molecules of
compound 3, but the efficiency of compound 3 was proven to be not so satisfactory and only
a 37% ee was obtained in the quantitative reaction1 (Scheme 1).
However, a 63.9% ee can be obtained using only a catalytic amount of ligand 1 (0.1 equiv.)
in the same reaction. This means that the chiral induction ability of ligand 1 was greatly
improved after the combination of two molecules in ligand 3.
Table 2
Variation of the catalyst monomer at different temperatures
Temperature (K)
% ee
%
l 29
l 19
l 16
308
303
273
263
253
243
233
223
65.5
60.6
100
100
100
0
0
0
3.5
6.9
13.0
15.0
20.4
0
0
0
0
0
0
0
2.0
96.5
93.1
87.0
85.0
77.6
33.8

J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
3357
Figure 4. A plot of temperature versus variation of the catalyst monomer. (a) The peak at l 29; (b) the peak at l 19;
(c) the peak at l 16
The primary reaction product of amino alcohol with borane would be the oxazaborolidines
(2, 5 and 6, respectively), which was the key intermediate for the enantioselective borane
reduction. Due to the similarity of the structure, compound 4 was chosen for comparison of the
spectroscopic properties of compound 3 after coordination with borane.
The existence of 2 was detected in our previous work (Fig. 2(a and b)), but similar
experiments for 3 and 4 give a surprising result. The in situ NMR test of the coordinated
compounds of 3 and 4 with borane showed that the systems of the two coordinated ligands are
quite complicated and there were several boron compounds in the mixture (Fig. 6). The 11B
NMR spectra of the coordinated system of 3 and 4 are quite similar, which indicates a similar
reactivity of the two amino alcohols with borane.
Figure 5. 11B NMR and their partly deconvoluted spectra of the diluted catalyst 1 at 223 K in Fig. 2(f) (a, b and c
are the deconvoluted peaks and the integration of the peaks a, b and c equals 2)

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J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
Scheme 1. Asymmetric borane reduction of phenylacetone
Figure 6. 11B NMR spectra with decoupling of the coordinated ligands 3 and 4 at room temperature. (1)
Coordination of 4 with borane; (2) coordination of 3 with borane
The peak at about l 28 is assigned to the monomer of the catalyst, which was intermediate
6, but the dimer is difficult to assign as there are three peaks in the range of l 1–10 (Fig. 6, (2)).
The spectrum for the coordinated compound 4 with borane is relatively sophisticated and the
small peak at about 28 is assumed to be the intermediate 5. From Fig. 6 it is easy to deduce that
1
the amount of intermediate 5 or 6 at l 28 is quite low. The H and 13C NMR spectra (not
shown) of the two ligands and their coordinated compounds also manifested a mixed system
after coordination. The chemical shift of the spectral line of the carbon connected to the amino
group proceeds downfield to about 6 ppm. About 3 ppm upfield shift for the spectral line of the
carbon connected to the hydroxyl group was found in the 13C NMR spectra after coordination
of 3 and 4 with borane. These results show that the main component of ligands 3 and 4
coordinated with borane were the complexes of their amino group with borane. Their hydroxyl
group may be surrounded by the solvent molecules, thus hampering the combination of borane
with the hydroxyl group. Combining the real reaction conditions and the above results, it can
be concluded that the amount of effective components of the catalyst (5 and 6), which are
responsible for the enantioselectivities, is relatively low, thus causing a low efficiency of the
catalysts. Of course, another unnegligible factor accounting for the high enantioselectivity of 1
is the C2 symmetric properties of the ligand and the catalyst, which has been discussed earlier7
and did not exist in compound 3.

J. Zhao et al. / Tetrahedron: Asymmetry 11 (2000) 3351–3359
3359
At the beginning of the study of the CBS reduction, the importance of the preparation of
chiral oxazaborolidines in pure form was realized, as catalyst purity is essential for the
attainment of high enantioselectivity and reproducibility in the reduction of ketones. Consider-
able effort has been extended towards the development of effective procedures for the generation
of pure oxazaborolidines without the need of a purification step.9 However, it is realized now
that the catalyst itself can be transformed into other species under appropriate conditions. It is
possible to find proper ways to obtain pure catalyst, but it is not easy to limit the transformation
of the catalyst itself in the system under some conditions. Thus it is possible to find an optimum
condition for every catalyst such that the catalyst can be used to the utmost extent.
Although the effect of temperature on the selectivity has been described many times in the
literature, no complete explanation has been reported. It is difficult to provide a straightforward
explanation, as the selectivity of this reduction is likely to be a result of many complex factors.
Our observations just add another aspect of the reaction and hope to gain insight into the origin
of temperature effects on the borane reduction reaction catalyzed by dual-centered oxazaboro-
lidines.
References
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2. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551.
3. (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611–614. (b) Corey, E. J.; Link, J. O. Tetrahedron Lett.
1989, 30, 6275–6278.
4. Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465–472.
5. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
6. Brunel, J. M.; Maffei, M.; Buono, G. Tetrahedron: Asymmetry 1993, 4, 2255.
7. Zhao, J.; Han, X.; Liu, X.; Bao, X.; Hang, J.; Jiang, B. Sci. China, Ser. B 2000, 43, 40–50.
8. Zhao, J.; Liu, X.; Han, X., Wan, B., Bao, X.; Hang, J.; Jiang B. International Laboratory 2000, 30, 10–17.
9. (a) Masui, M.; Shioiri, T. Synlett 1997, 273–274. (b) Prasad, K. R. K.; Joshi, N. N. Tetrahedron: Asymmetry 1996,
7, 3147–3152. (c) Quallich, G. J.; Woodall, T. M. Synlett 1993, 929–930.
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