Asymmetric reduction of aromatic ketones: Importance of the conformation of the aromatic group

Article abstract of DOI:10.1016/S0957-4166(98)00347-4

Some aromatic ketones have been reduced by borane or by catecholborane using oxazaborolidine as a catalyst. It has been found that, when borane is used, the enantiomeric excess of alcohol produced decreases as the substitution on the ortho position of ben

Full text of DOI:10.1016/S0957-4166(98)00347-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3365–3369
Asymmetric reduction of aromatic ketones: importance of the
conformation of the aromatic group
Kavita Manju and Sanjay Trehan ∗
Department of Chemistry, Panjab University, Chandigarh-160 014, India
Received 22 June 1998; accepted 28 August 1998
Abstract
Some aromatic ketones have been reduced by borane or by catecholborane using oxazaborolidine as a catalyst. It
has been found that, when borane is used, the enantiomeric excess of alcohol produced decreases as the substitution
on the ortho position of benzene ring increases. However, for ketones with 2,6-disubstituted aryl substituents the
enantiomeric excess increases when catecholborane is used. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Reduction of a prochiral ketone to an alcohol is a common reaction in organic synthesis. In order
to achieve enantioselective reduction of prochiral ketones, various chiral non-racemic reducing reagents
have been developed.1 In an ongoing project in our laboratory we required various chiral non-racemic
secondary benzylic alcohols. The obvious choice was to reduce the corresponding aromatic ketones with
borane in the presence of oxazaborolidine catalyst2 due to its wide range of applicability and simplicity
of procedure.1d,e
2. Results and discussion
When ketones 1–3 were subjected to CBS2a reduction using B-butyl catalyst 13 and BH3·Me2S as
a reducing agent, the enantiomeric excess (ee) of the resulting alcohols 7–9 decreased as the bulk
of the aromatic group increased (Table 1, entries 1–3). This was contrary to our expectations. It has
been reported that mesityl methyl ketone can be reduced in high ee when catecholborane is used
as the reducing agent.3 In the event, when CBS reduction was carried out using catecholborane as
reducing agent there was no noticeable change in the enantiomeric excess of the alcohols formed from
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00347-4

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Table 1
Asymmetric reduction of aromatic ketones using oxazaborolidine as catalysta
acetophenone and methyl o-tolyl ketone (Table 1, entries 1, 2 and 7, 8) but there was an appreciable
increase in ee in the case of mesityl methyl ketone (Table 1, entries 3 and 9). Similar results were also
obtained when ketones 4–6 were reduced to give alcohols 10–12 under the same conditions (Table 1).
The reduction using CBS catalyst works well when the two groups attached to the carbonyl group to be
reduced have significantly different steric bulk.4 These results clearly indicate that due to the substitution
at the ortho position the aromatic group takes conformation in such a manner that its effective steric
bulk decreases. In order to substantiate this hypothesis, we carried out semi-empirical calculations on
ketones 1–3.5,6 It was found that the dihedral angle abcd for the most stable conformation increases as
the substitution on the ortho position increases (Table 2). In the case of the mesityl group, it is almost
orthogonal to the CO sigma bond. The results obtained in the case of borane reduction can be explained
on the basis of these conformations of the different aryl groups. As the substitution increases, the net steric
bulk of the aryl group moves away from the carbonyl oxygen lone pair which is syn to the aryl group. As
a result, the effective steric differentiation of two groups of the ketone decrease and the ee also decreases
correspondingly. In the case of reduction using catecholborane, the enhancement of the enantiomeric
excess for mesityl ketones 3 and 6 can be explained by considering the interaction of one of the ortho
methyl of mesityl groups with the bulkier catecholborane when it attaches to boron of oxazaborolidine to
give a minor isomer via complex 15 (Scheme 1). Due to the small size of borane, this type of interaction

K. Manju, S. Trehan / Tetrahedron: Asymmetry 9 (1998) 3365–3369
3367
Table 2
Most stable conformation of aromatic ketones as calculated by MM2
will be absent when borane is used as the reducing agent. The molecular models also reveal this fact. On
the other hand, phenyl and o-tolyl groups can avoid interaction with the catecholborane because they can
always place a hydrogen towards catecholborane in complex 15.
Scheme 1.
In conclusion, we have demonstrated that the conformation of the aryl part of the ketone is important
in the outcome of CBS reduction. These results will help in the planning of the synthesis of these types of
molecules. These results also add to a small but growing number of examples where the effective steric
bulk of the aryl group depends on its conformation in the molecule.8
3. Experimental
All the reactions were carried out under a nitrogen atmosphere in flame dried apparatus. Toluene was
distilled over sodium/benzophenone. All the ketones were distilled and stored over 4A molecular sieves.
(S)-(−) α,α-diphenylprolinol was purchased from Aldrich, butyl boronic acid and B-butyl catalyst 13
were prepared using Corey’s procedure.9 All of the alcohols prepared by asymmetric reduction were
characterised by comparing their 1H NMR, IR, TLC and mixed TLC with authentic samples.
3.1. General procedure for asymmetric reduction using BH3·Me2S as reducing agent10
To a solution of catalyst 13 (0.15 mmol) in 1 ml of toluene, BH3·Me2S (2M solution in toluene, 0.6
mmol) was added at −10°C. Neat ketone (1 mmol) was added slowly at the same temperature over a

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period of 15 min. After 30 min the reaction was quenched by adding 2 ml of methanol and the reaction
mixture was stirred for an additional 30 min at room temperature. Solvent was removed under reduced
pressure and the residue was dissolved in ether. The ether solution was washed with dilute HCl, water,
saturated aqueous sodium bicarbonate and finally with brine. The organic layer was dried over anhydrous
Na2SO4, concentrated under vacuum and purified by flash chromatography using 5% ethyl acetate in
hexane as eluent.
3.2. General procedure for asymmetric reduction using catecholborane as reducing agent
To a solution of catalyst 13 (0.15 mmol) in 1 ml of toluene, catecholborane (0.75 ml of 2M in toluene,
1.5 mmol) and ketone (1 mmol) were added at −10°C and the reaction mixture was kept at −10°C for
48 h. The reaction was quenched by adding methanol (2 ml) and solvent was removed under vacuum.
The residue was dissolved in ether (10 ml) and the resulting ethereal solution was washed sequentially
with saturated aqueous sodium hydroxide, water, dilute HCl and finally with brine. The organic layer
was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified using 5% ethyl
acetate in hexane as eluent.
3.3. General procedure for the preparation of Mosher ester11
To a mixture of Mosher acid (0.15 mmol), DCC (0.18 mmol) and DMAP (5 mg) in 1 ml of CH2Cl2, a
solution of alcohol (0.1 mmol) in 0.5 ml of CH2Cl2 was added at room temperature. The reaction mixture
was stirred overnight at room temperature. Ether (5 ml) was added and the precipitates were removed by
filtration. The filtrate was washed sequentially with dilute HCl, water, aqueous sodium bicarbonate and
brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue
was passed through a short pad of silica gel to remove baseline material.
Acknowledgements
We are thankful to CSIR for the financial support for this work. K.M. is also thankful to UGC for a
senior research fellowship.
References
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