(2S)-2-Anilinomethylpyrrolidine: an efficient in situ recyclable chiral catalytic source for the borane-mediated asymmetric reduction of prochiral ketones in refluxing toluene

Article abstract of DOI:10.1016/j.tetasy.2006.03.021

(2S)-2-Anilinomethylpyrrolidine was successfully utilized as a chiral catalytic source in the borane-mediated asymmetric reduction of prochiral ketones in refluxing toluene to provide the corresponding secondary alcohols with enantiomeric excesses up to 91%. The potential of (2S)-2-anilinomethylpyrrolidine as an in situ recyclable chiral catalytic source in the borane-mediated chiral reduction processes has also been demonstrated.

Full text of DOI:10.1016/j.tetasy.2006.03.021

Tetrahedron: Asymmetry 17 (2006) 1041–1044
(2S)-2-Anilinomethylpyrrolidine: an efficient in situ recyclable
chiral catalytic source for the borane-mediated asymmetric
reduction of prochiral ketones in refluxing toluene
Deevi Basavaiah,* Kalapala Venkateswara Rao and Bhavanam Sekhara Reddy
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 16 March 2006; accepted 23 March 2006
Available online 27 April 2006
Abstract—(2S)-2-Anilinomethylpyrrolidine was successfully utilized as a chiral catalytic source in the borane-mediated asymmetric
reduction of prochiral ketones in refluxing toluene to provide the corresponding secondary alcohols with enantiomeric excesses up to
91%. The potential of (2S)-2-anilinomethylpyrrolidine as an in situ recyclable chiral catalytic source in the borane-mediated chiral reduc-
tion processes has also been demonstrated.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
chiral guanidine, that is, (5S)-1,3-diaza-2-imino-3-phenyl-
bicyclo[3.3.0]octane 1 built on the (2S)-2-anilinomethyl-
pyrrolidine 2 framework, as an in situ recyclable catalytic
source, we observed a remarkable reversal of stereoselectiv-
ity from room temperature (ꢀ30 °C) to high temperature
(110 °C), probably due to two different catalytic species
actually involved in the transition state of the reduction
process. We also observed interesting temperature depen-
dent levels of stereoselectivity from the same catalytic spe-
cies due to the different pathways involved in the reduction
process.1 This temperature dependent direction and levels
of stereoselectivity have attracted our attention, and based
on this fact it occurred to us that (2S)-2-anilinomethylpyrr-
olidine7 itself might offer promising enantioselectivities at
higher temperature, that is, at 110 °C in toluene. Asami
et al.8,9 reported during their elegant work on the applica-
tions of various chiral diamines as possible catalysts for the
borane- mediated asymmetric reduction of prochiral keot-
nes that chiral diamine 3, as a catalyst, provides high
enantioselectivities in the reduction of prochiral ketones
at room temperature and at low temperatures (up-to
ꢁ15 °C) (they studied up-to ꢁ30 °C), while catalyst 2 pro-
vides inferior selectivities (14% ee) at room temperature in
the reduction of acetophenone. However, to the best of our
knowledge, they did not examine the effect of high temper-
ature on the enantioselectivity using those chiral diamines,
and also there is no report in the literature in this regard.
In the preceding paper, we described the application of
(5S)-1,3-diaza-2-imino-3-phenylbicyclo[3.3.0]octane 1 as
the first example of guanidine based chiral catalytic source
for the borane-mediated asymmetric reduction of represen-
tative prochiral ketones.1 In continuation of our studies2–6
in the search for suitable, practical and recyclable chiral
catalysts for the borane-mediated asymmetric reduction
processes, we herein report (2S)-2-anilinomethylpyrrolidine
2 as an efficient in situ recyclable chiral catalytic source for
the asymmetric reduction of prochiral ketones in refluxing
toluene, thus providing the desired secondary alcohols in
high enantioselectivities.
H
H
H
N
N
N
N
H
H
HN
HN
CF3
HN
1
2
3
2. Results and discussion
During our work on the borane-mediated asymmetric
reduction of representative prochiral ketones using the
*
Accordingly, we have performed the reduction of phenacyl
Corresponding author. Tel.: +91 40 23134812; fax: +91 40 23012460;
e-mail: dbsc@uohyd.ernet.in
bromide 4a using 5 mol % (2S)-2-anilinomethylpyrrolidine
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.021

1042
D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1041–1044
in the presence of BH3ÆSMe2 at 110 °C. The reduction went
to completion within 15 min, and more interestingly the de-
sired secondary alcohol 5a was obtained in 91% enantio-
meric excess. As a result, we thought it would be
appropriate to investigate the minimum levels of the cata-
lyst required for the reduction process to achieve maximum
possible induction. We, therefore, performed the reduction
of phenacyl bromide using different quantities of catalyst
(from 0.25 to 10 mol %), and noticed that 2 mol % catalyst
also offers almost the same selectivity as that of 3, 4, 5 and
10 mol % catalyst (Eq. 1, Table 1).10
In order to understand the generality of this methodology,
we have then carried out the reduction of representative
prochiral a-halo ketones 4b–f using 2 mol % catalyst to
provide the resulting secondary alcohols 5b–f in 84–90%
enantiomeric excesses (Eq. 2, Table 2).
With a view to extend the scope of the application of
this catalyst, we have also examined the reduction of repre-
sentative class of aryl alkyl ketones 4g–k using 2 mol %
(2S)-2-anilinomethylpyrrolidine 2. The resulting secondary
alcohols 5g–k were obtained in 74–78% enantiomeric
excesses (Eq. 3, Table 3).
Table 1. Asymmetric reduction of phenacyl bromide with different
quantities of the catalysta
OH
O
Br
Br
1.0 eq. BH3.SMe2
/ 2 (cat.)
2.1. Towards understanding the nature of the catalytic
species
Toluene, 110 oC, 15 min
5a
4a
In order to understand the effect of temperature on the
enantioselectivity, we examined the efficiency of this di-
amine 2 (2 mol %) as a chiral source in the asymmetric
reduction of phenacyl bromide 4a with BH3ÆSMe2 at room
temperature (ꢀ30 °C) for 7 h and obtained the resulting
secondary alcohol 5a in 8% enantiomeric excess. In an
attempt to understand the nature of the catalyst/catalytic
species generated in situ, we carried out the reaction be-
tween 2 (0.2 mM, 4 mL, 0.05 M solution in toluene) and
BH3ÆSMe2 (10 mM, 10 mL, 1 M solution in toluene) in
refluxing toluene (40 mL) for 15 min (in the ratio of 1:50
as in the case of reaction conditions), and recorded the
11B NMR spectrum of this crude mixture (after removal
of excess BH3ÆSMe2 and toluene under vacuum) and ob-
served a broad peak at d 33.2 ppm16 [in addition to other
peaks between d ꢁ10 and ꢁ30 ppm, arising most likely
due to tetra-coordinated boron species (ate-complexes)].
This probably indicates the presence of diazaborolidine
moiety in the catalyst/catalytic species. However, we did
ð1Þ
Entry
Catalyst 2
(mol %)
Yieldb
(%) 5a
Enantiomeric
Configurationd
excessc (%) 5a
1
2
3
4
5
6
7
8
0.25
0.5
1
82
80
82
82
80
78
79
82
69
86
86
91
90
91
91
89
S
S
S
S
S
S
S
S
2
3
4
5
10
a All reactions were carried out on 1 mM scale of phenacyl bromide with
1 mM of BH3ÆSMe2 in the presence of 2 in toluene for 15 min at 110 °C.
b Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
c Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
d Absolute configuration was assigned by comparison of the sign of the
specific rotation with that reported.11
Table 2. Asymmetric reduction of prochiral a-halo ketonesa
O
OH
2 (2 mol%)
/
1.0 eq. BH3.SMe2
X
X
Ar
Toluene, 110 oC, 15 min
Ar
ð2Þ
4a-f
X = Cl, Br
5a-f
Ar = phenyl, 4-methylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-nitrophenyl
25
Substrate
Ar
X
Product
Yieldb (%)
½aꢂD
Conf.c
ee (%)
4a
4b
4c
4d
4e
4f
Phenyl
Phenyl
4-Methylphenyl
4-Bromophenyl
4-Chlorophenyl
4-Nitrophenyl
Br
Cl
Cl
Br
Br
Br
5a
5b
5c
5d
5e
5f
82
80
88
85
83
84
+39.8 (c 1.2, CHCl3)
+43.8 (c 1.0, C6H12)
+43.1 (c 0.8, CHCl3)
+30.5 (c 1.0, CHCl3)
+38.9 (c 0.9, CHCl3)
+29.9 (c 0.8, CHCl3)
S11
S11
S6
S12
S6
S5
91d
87d
84d
90e
90e
86f
a All reactions were carried out on 1 mM scale of a-halo ketone with 1 mM of BH3ÆSMe2 in the presence of 2 (2 mol %) in toluene for 15 min at 110 °C.
b Isolated yields of alcohols after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
c Absolute configuration was assigned by comparison of the sign of specific rotation with that reported.
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
e Determined by HPLC analyses using the chiral column, Chiralcel-OJ-H.
f Determined by HPLC analysis of the corresponding acetate using the chiral column, Chiralcel-OD-H.

D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1041–1044
Table 3. Asymmetric reduction of aryl alkyl ketonesa
1043
O
OH
CH3
5g-k
2 (2 mol%)
/
1.0 eq. BH3.SMe2
Ar
CH3
Toluene, 110 oC, 15 min
Ar
ð3Þ
4g-k
Ar = phenyl, 4-methylphenyl, 4-bromophenyl, 4-chlorophenyl, 4-nitrophenyl
25
Substrate
Ar
Product
Yieldb (%)
½aꢂD
Conf.c
ee (%)
4g
4h
4i
Phenyl
5g
5h
5i
79
79
87
78
83
+35.2 (c 0.9, MeOH)
+33.1 (c 0.7, MeOH)
+30.6 (c 1.0, CHCl3)
+37.5 (c 0.7, Et2O)
+22.2 (c 0.5, EtOH)
R13
R14
R14
R14
R15
76d
74e
78e
77e
78f
4-Methylphenyl
4-Bromophenyl
4-Chlorophenyl
4-Nitrophenyl
4j
4k
5j
5k
a All reactions were carried out on 1 mM scale of aryl alkyl ketone with 1 mM of BH3ÆSMe2 in the presence of 2 (2 mol %) in toluene for 15 min at 110 °C.
b Isolated yields of alcohols after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
c Absolute configuration was assigned by comparison of the sign of specific rotation with that reported.
d Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
e Determined by HPLC analyses using the chiral column, Chiralcel-OJ-H.
f Determined by HPLC analysis of the corresponding acetate using the chiral column, Chiralcel-OD-H.
not observe any peak in the region d 20–40 ppm [but con-
tains peaks between d ꢁ10 and ꢁ30 ppm, probably due to
tetra-coordinated boron species (ate-complexes), that is,
due to complexation of borane with diamine] in the 11B
NMR spectrum of the crude compound, when a similar
reaction was carried out at room temperature (ꢀ30 °C)
(Scheme 1). These results suggest the formation of diaz-
aborolidine species at 110 °C, while such a species is not
formed at room temperature.
(110 °C) and at room temperature with the same catalytic
species. We are now, in fact, in the process of understand-
ing these aspects.
2.2. Recyclable potential of in situ generated catalyst/
catalytic species
With a view to understand the in situ recyclable nature of
the catalytic species I, we have first performed the reduc-
tion of phenacyl bromide (1 mM scale) in the usual way
at 110 °C (run 1). To this reaction flask (without work-
up), BH3ÆSMe2 (1 mM) (for run 2) was added and heated
at 110 °C for 15 min, and then a solution of phenacyl bro-
mide (1 mM) in toluene was slowly added dropwise and
stirring was continued at 110 °C for further 15 min as usual
(run 2). We were pleased to obtain the resulting secondary
alcohol (after work-up and purification as usual) in almost
the same enantioselectivity. In a similar way, we examined
the recyclable ability of this catalyst for two more times
(total four times) and noticed that the enantioselectivity
remained almost the same (Table 4).
In order to understand the potential of the diazaborolidine
species as a catalyst at room temperature, we performed
the asymmetric reduction of phenacyl bromide under the
influence of catalytic species I (2 mol %) (generated
in situ by the reaction of diamine 2 with BH3ÆSMe2 at reflux
temperature and cooling back to room temperature) at
room temperature for 6 h and obtained the resulting (S)-
2-bromo-1-phenylethanol with 33% ee (Scheme 2).
These results possibly suggest that different pathways of
reduction processes may be operating at high temperature
H
H
Toluene
N
Toluene
110 oC, 15 min
N
No diazaborolidine
species
+
BH3.SMe2
B
N
H
rt, 15 min
HN
I
2
Scheme 1.
O
Br
(1 mM)
OH
Ph
H
(in toluene)
Br
Toluene
110 oC, 15 min
Ph
N
+
BH3.SMe2
rt, 6 h
80%
H
5a
HN
33% ee
2
Scheme 2.

1044
D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1041–1044
Table 4. Recyclable ability of catalyst I in the asymmetric reduction of
phenacyl bromide 4a
Chemistry as a ‘Center for Advanced Studies in Chemistry’
and providing some instrumental facilities. K.V.R. and
B.S.R. thank CSIR (New Delhi), for their research
fellowships.
Number of runs
Enantiomeric purity (%)a 5a
1
2
3
4
91
89
88
88
References
a Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
1. Basavaiah, D.; Venkateswara Rao, K.; Sekhara Reddy, B.
Tetrahedron: Asymmetry, preceding paper, doi:10.1016/j.
tetasy.2006.03.020.
2. Basavaiah, D.; Chandrashekar, V.; Das, U.; Jayapal Reddy,
G. Tetrahedron: Asymmetry 2005, 16, 3955–3962.
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7. (2S)-2-Anilinomethylpyrrolidine was prepared following the
literature procedure. (Iriuchijima, S. Synthesis 1978, 684–
685).
In order to examine (rule out) the possible auto-catalytic
potential of the alkoxyborane, generated in the reaction
medium, in inducing the chirality in the asymmetric reduc-
tion of phenacyl bromide, we have conducted the reduction
of phenacyl bromide with BH3ÆSMe2 (1 equiv and also with
2 equiv) under the influence of (S)-2-bromo-1-phenyletha-
nol (1 equiv, 84% ee) (for 30 and 15 min, respectively). In
both cases, we obtained (S)-2-bromo-1-phenylethanol in
42% enantiomeric purity (i.e., enantiomeric purity of the
alcohol obtained by the reduction is ꢀ0%). These experi-
ments clearly indicate that there is no auto-catalysis, and
(S)-2-bromo-1-phenylethanol (as boron species) has no
role in the chiral induction process. Thus, these experi-
ments clearly demonstrate the recyclable potential of the
diamine as the chiral catalytic source in the asymmetric
reduction processes.
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10. Asymmetric reduction of phenacyl bromide 4a: Synthesis of
(S)-2-bromo-1-phenylethanol 5a: Representative procedure:
To a stirred solution of (2S)-2-anilinomethylpyrrolidine 2
(0.02 mM, 0.4 mL, 0.05 M solution in toluene) in toluene
(4 mL) was added BH3ÆSMe2 (1 mM, 1 mL, 1 M solution in
toluene) at room temperature and the reaction mixture heated
under reflux for 15 min. A solution of phenacyl bromide 4a
(1 mM, 199 mg), in toluene (2 mL), was then added slowly,
dropwise and heated under reflux for a further 15 min. The
reaction mixture was cooled to room temperature and
quenched with MeOH. The solvent was removed under
reduced pressure and the residue thus obtained was purified
by column chromatography (silica gel, 5% ethyl acetate in
hexanes) to provide the desired (S)-2-bromo-1-phenylethanol
5a in 82% (165 mg) yield as a colourless oil.
3. Conclusion
In conclusion, we have developed a simple, convenient and
practical methodology for the borane-mediated asymmetric
reduction of prochiral ketones employing (2S)-2-anilino-
methylpyrrolidine 2 as an efficient in situ recyclable chiral
catalytic source in refluxing toluene, thus providing the sec-
ondary alcohols with high enantiomeric purities. Although
our methodology did not provide 100% enantioselectivities,
this study has shown the hidden potential of chiral diamines
in directing the enantioselective processes in the borane-
mediated asymmetric reduction of prochiral ketones at high
temperature, and also emphasizes the need for the design
of appropriate chiral diamines for achieving 100% enantio-
selectivities. Work towards the design of different chiral
diamines in achieving complete enantioselectivities is
currently underway in our laboratory.
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We thank CSIR (New Delhi), for funding this project.
We thank the UGC (New Delhi), for recognizing our
University of Hyderabad as ‘University with Potential for
Excellence (UPE)’ and also recognizing the School of