A convenient method for the preparation of oxazaborolidine catalyst in situ using (S)-α,α-diphenylpyrrolidinemethanol, tetrabutylammonium borohydride, and methyl iodide for the asymmetric reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetasy.2006.11.032

An oxazaborolidine catalyst is readily prepared in situ at 25 °C in THF using (S)-α,α-diphenylpyrrolidinemethanol and borane generated from tetrabutylammonium borohydride/CH₃I reagent system. The oxazaborolidine/BH₃ reagent system prepared in this way is useful for the reduction of prochiral ketones to the corresponding alcohols with up to 99% ee.

Full text of DOI:10.1016/j.tetasy.2006.11.032

Tetrahedron: Asymmetry 17 (2006) 3244–3247
A convenient method for the preparation of oxazaborolidine
catalyst in situ using (S)-a,a-diphenylpyrrolidinemethanol,
tetrabutylammonium borohydride, and methyl iodide for
the asymmetric reduction of prochiral ketones
Shaik Anwar and Mariappan Periasamy*
School of Chemistry, University of Hyderabad, Central University P.O., Hyderabad 500 046, India
Received 23 October 2006; accepted 21 November 2006
Available online 4 January 2007
Abstract—An oxazaborolidine catalyst is readily prepared in situ at 25 ꢀC in THF using (S)-a,a-diphenylpyrrolidinemethanol and
borane generated from tetrabutylammonium borohydride/CH I reagent system. The oxazaborolidine/BH reagent system prepared in
3
3
this way is useful for the reduction of prochiral ketones to the corresponding alcohols with up to 99% ee.
2006 Elsevier Ltd. All rights reserved.
ꢁ
1
. Introduction
cially available, these borane carriers suffer from draw-
backs with regards to their commercial application
because of difficulties in handling and transporting these
reagents, especially for large scale applications. We have
reported from this laboratory that borane–THF prepared
in situ using NaBH and I in THF is useful for several
The synthesis of enantiomerically pure compounds has
become an important area of research for pharmaceutical
industries, as often two enantiomers of a chiral drug mole-
1
cule display different biological activities. Asymmetric
4
2
reduction of prochiral ketones is an extremely important
methodology for the synthesis of chiral secondary alcohols.
The oxazaborolidine (CBS reagent)-catalyzed asymmetric
reduction methodology has been extensively used for this
synthetic applications that require borane–THF. Unfortu-
nately, the a,a-diphenylpyrrolidinemethanol and NaBH4/
I combination gave poor results in the asymmetric reduc-
2
1
2
tion of acetophenone. It was thought that a major prob-
2
–4
purpose. Even though the parent catalyst H-CBS 4, pre-
lem in using NaBH is that it is only sparingly soluble in
4
pared in situ using a,a-diphenylpyrrolidinemethanol and
THF. Accordingly, we have undertaken an investigation
þ
ꢀ
BH –THF, has been found to give good results in asym-
to employ the readily accessible R N BH for this pur-
3
4
4
þ
ꢀ
metric reductions, the corresponding B-methyl derivative
is preferred. However, this reduction method is not entirely
satisfactory, particularly for large-scale productions, owing
pose. Herein we report that the R
4
N BH , CH I and
4
3
(S)-a,a-diphenylpyrrolidinemethanol combination is useful
for the asymmetric reduction of aryl alkyl ketones to
obtain the corresponding alcohols in up to 99% ee (Fig. 1).
5
a
to the requirement for trimethyl boroxine or methyl
5
b
boronic acid and the requirement of complete removal
of water from such condensations to avoid undesired
6
effects. The other difficulty is the requirement of the highly
7
8
2. Results and discussion
reactive reagents, such as borane–THF, borane–SMe ,
2
9
10
borane–1,4-thioxane, catecholborane, and N,N-diethyl-
þ
ꢀ
1
1
The R N BH species has been reported to have low
aniline–borane
(DEANB) complexes for the oxaza-
4
4
1
3
reactivity as a reducing agent. This is easily realized by
the fact that it can be recrystallized from either ethyl acet-
ate or even acetone if the operation is carried out rapidly.
This reagent had been known for some time and it has been
used for the reduction of a number of representative car-
bonyl functionalities. However, it has not been employed
borolidine catalyzed asymmetric reduction of ketones.
Although several of these borane complexes are commer-
*
Corresponding author. Tel.: +91 40 23134814; fax: +91 40 23012460;
e-mail: mpsc@uohyd.ernet.in
0957-4166/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.11.032

S. Anwar, M. Periasamy / Tetrahedron: Asymmetry 17 (2006) 3244–3247
3245
BH4
BH3
H
N
N
N
H
O
OH
N
B
H
1
TEAB
2 TBAB
3
(
S)-DPP
4
Figure 1.
in an asymmetric reduction in combination with chiral a,a-
diphenylpyrrolidinemethanol. We have observed that the
none remained unaffected. Upon the addition of CH3I,
evolution of CH was noticed, indicating that the forma-
4
tetrabutylammonium borohydride (TBAB 2)/CH I reagent
tion of BH ÆTHF in situ from tetraalkylammonium
3
3
system in the presence of (S)-a,a-diphenylpyrrolidinemeth-
anol (5 mol %) affords a very easy and simple preparation
borohydride is essential for the reduction. Chiral
aminoalcohol 3 can be used in 5 mol % in THF to give
maximum selectivity (Table 1, entries 5–9).
of the oxazaborolidine catalyst 4, as well as the BH spe-
3
cies, which effectively reduces acetophenone within about
3
0 min at 25 ꢀC (Scheme 1, Table 1).
With a view to extend the scope and to understand the
applicability of this reagent system, we examined the reduc-
tion of representative class of aryl alkyl ketones using
5
mol % catalyst 3 and obtained the secondary alcohols
O
OH
CH3
3
, R NBH /CH I
4 4 3
6b–k in 41–96% ee (Scheme 2, Table 2).
Ph
CH3
Ph
solvent
5a
6a
OH
O
Scheme 1.
(
0.8 equiv. TBAB/0.8 equiv. CH3I)/3 (5 mol%)
Ar
R
Ar
R
o
THF, 25 C, 30 min
Initially, we examined the reduction of acetophenone using
the tetraethylammonium borohydride (TEAB 1)/CH3I
combination under the influence of (S)-a,a-diphenylpyrr-
olidinemethanol 3 (20 mol %) in DCM at 0 ꢀC. In this case,
the desired alcohol was obtained in quantitative yields with
6b-6j
5
b-5j
O
OH
(0.8 equiv. TBAB/0.8 equiv. CH3I)/3 (5 mol%)
6
3% ee (Table 1, entry 1). Surprisingly, at 25 ꢀC, the ketone
o
THF, 25 C, 30 min
remained unreacted. The same result was observed when
THF was used as a solvent, as the TEAB 1 is insoluble
in THF at room temperature. Fortunately, the more solu-
ble TBAB 2 gave better results. We observed that the
6k
5
k
Scheme 2.
TBAB 2/CH I reagent system in the presence of catalyst
3
3
1
(20 mol %) yielded the desired alcohol in 97% ee (Table
, entry 2). The use of I in place of CH I, or a change
The para-substituted acetophenones are reduced to give
93–96% ee as observed in the reductions using the B-methyl
2
3
6
of solvent led to a decreased ee (Table 1, entries 3 and 4).
In the absence of additives (CH I and I ), the acetophe-
CBS catalyst system. The ee’s are not affected significantly
by alkyl groups of the acetophenone and electron donating
3
2
a
Table 1. Enantioselective reduction of acetophenone 5a at various conditions
b
c
d
Entry
Reagent (equiv)
Additive (equiv)
Catalyst 3 (mol %)
Solvent
CH Cl
THF
THF
Toluene
THF
THF
Temperature (ꢀC)
Yield (%)
Conf.
ee (%)
1
2
3
4
5
6
7
8
9
TEAB 1 (1)
TBAB 2 (1)
TBAB 2 (1)
TBAB 2 (1)
TBAB 2 (1)
TBAB 2 (1)
TBAB 2 (0.8)
TBAB 2 (0.8)
TBAB 2 (0.8)
CH
CH
3
I (1)
I (1)
20
20
20
20
5
5
2
1
5
2
2
0
25
25
25
25
25
25
25
25
76
86
78
68
87
85
88
86
89
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
63
97
89
47
96
84
97
87
>99
3
I
2
(0.5)
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
I (1)
I (1)
I (1)
I (0.8)
I (0.8)
I (0.8)
THF
THF
THF
a
3
All reactions were carried out using 5 mmol of (TEAB 1 or TBAB 2), 5 mmol of CH I, 5 mmol of ketone in 25 mL of solvent except for entries 7–9 where
4
mmol of TBAB 2, 4 mmol of CH I, and 5 mmol of ketone were used.
3
b
1
13
The yields are of the isolated products after purification by column chromatography. The products were identified by spectral data (IR, H NMR and
NMR) and physical constant data.
Absolute configuration was assigned by the comparison of the sign of the specific rotation with that of a literature value.
Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
C
c
d

3246
S. Anwar, M. Periasamy / Tetrahedron: Asymmetry 17 (2006) 3244–3247
a
Table 2. Asymmetric reduction of representative ketones
b
c
Substrate
Ar
R
Product
Yield (%)
Conf.
ee (%)
d
5
b
4-Methylphenyl
4-Nitrophenyl
4-Bromophenyl
4-Chlorophenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
CH
CH
CH
CH
3
3
3
3
6b
6c
6d
6e
6f
88
82
89
89
87
89
79
76
78
76
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(R)
96
e
5
c
93
d
5
d
95
d
5
e
96
f
5
f
C
C
2
H
H
5
91
g
5
5
g
h
3
7
6g
6h
6i
94
f
CH
CH
2
Cl
Br
82
f
5
5
i
j
2
76
h
C(Ph)
2
OH
6j
6k
41
f
5k
a-Tetralone
All reactions were carried out using 4 mmol of TBAB 2, 4 mmol of CH
0 min and stirred at 25 ꢀC.
67
a
3
I, and 5 mmol of ketone in the presence of 3 (5 mol %) in THF (25 mL) for
3
b
1
The yields are of the isolated products after purification by column chromatography. The products were identified by spectral data (IR, H NMR, and
1
3
C NMR) and physical constant data.
c
d
e
f
Absolute configuration was assigned by comparison of the sign of the specific rotation with that of a literature value.
Determined by HPLC analysis using the chiral column, Chiralcel-OJ-H.
14
25
Based on reported maximum ½aꢁ ¼ þ31:0 (c 1.22, MeOH) for (R)-isomer.
D
Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
g
15
25
Based on reported maximum ½aꢁ ¼ þ45:2 (c 3.0, benzene) for (R)-isomer.
D
25
h
16
Based on reported maximum ½aꢁ ¼ þ223:6 (c 1.32, CHCl
3
) for (R)-isomer.
D
or withdrawing nature of the aromatic substituent (Table 2,
ketones 5b–g). a-Haloketones were reduced with moderate
to good enantioselectivities (Table 2, ketones 5h and 5i).
However, asymmetric induction was low for the reduction
of the cyclic ketone 5k. This was presumably due to com-
peting uncatalyzed reduction. This was similar to ketone
the solvent was evaporated to give a yellow residue. The
residue was purified on a silica gel column to obtain the
(R)-1-phenylethanol using hexane/ethyl acetate (97:3) as
eluent.
4.2. Procedure utilizing TBAB 2/I reagent system
2
5
j possessing steric bulk around the prochiral carbonyl
group, which therefore may find it difficult to anchor onto
the oxazaborolidine catalyst.
3
Tetrabutylammonium borohydride 2 (1.02 g, 4 mmol) and
S)-a,a-diphenylpyrrolidinemethanol (0.06 g, 0.25 mmol)
(
in THF (12 mL) were taken in a two neck RB flask. The
contents were stirred at 25 ꢀC for 5 min under an N atmo-
2
3. Conclusion
sphere. I (0.50 g, 2 mmol) dissolved in THF (12 mL) was
2
added slowly for about 15–20 min through a pressure
In conclusion, the asymmetric reduction of prochiral
equalizer at 0 ꢀC under an N atmosphere and the reaction
2
ketones using TBAB 2/CH I reagent system gave the
3
mixture was allowed to stir at 0 ꢀC for about 30 min. The
reaction mixture was then slowly brought to 25 ꢀC and
corresponding chiral secondary alcohol in good selectivity.
This method offers a relatively simple and inexpensive
approach to this widely used transformation in syntheses.
was stirred for about 10 min under an N atmosphere. Aceto-
2
phenone (0.60 g, 0.58 mL, 5 mmol) in THF (15 mL) was
added dropwise through a pressure equalizer for about
3
0 min. The reaction mixture was stirred until the ketone
had disappeared. The mixture was carefully quenched with
M HCl (10 mL). The organic layer was extracted with
4
. Experimental
3
4.1. General procedure for the asymmetric reduction of
acetophenone utilizing the TBAB 2/CH I reagent system
ether (3 · 30 mL). The combined organic extract was
washed with brine (30 mL), dried over anhydrous Na SO ,
3
2
4
and the solvent was evaporated to give a yellow residue.
The residue was purified on a silica gel column chromato-
graphy to obtain the (R)-1-phenylethanol using hexane/
ethyl acetate (97:3) as eluent.
Tetrabutylammonium borohydride 2 (1.02 g, 4 mmol) and
(
S)-a,a-diphenylpyrrolidinemethanol (0.06 g, 0.25 mmol)
in THF (12 mL) were taken in a two neck RB flask. The
contents were stirred at 25 ꢀC for 15 min under an N
2
atmosphere. Methyl iodide (0.56 g, 0.25 mL, 4 mmol) was
added using a syringe and the reaction mixture was stirred
for about 30 min. Acetophenone (0.60 g, 0.58 mL, 5 mmol)
in THF (12 mL) was added dropwise through a pressure
Acknowledgements
equalizer for about 30 min under an N atmosphere. The
We are thankful to the DST and CSIR for financial sup-
port and research fellowships. The DST for support under
FIST programme for the 400 MHz NMR is gratefully
acknowledged. Support of the UGC under the University
of Potential for Excellence Program is also gratefully
acknowledged.
2
reaction mixture was stirred until the ketone had dis-
appeared. The mixture was carefully quenched with 3 M
HCl (10 mL). The organic layer was extracted with ether
(
3 · 30 mL). The combined organic extract was washed
with brine (30 mL), dried over anhydrous Na SO , and
2
4

S. Anwar, M. Periasamy / Tetrahedron: Asymmetry 17 (2006) 3244–3247
3247
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