Asymmetric reduction of ketones catalyzed by α,α-diphenyl-(L)-prolinol modified with imidazolium ionic liquid and BH3·SMe2 as a recoverable catalyst

Article abstract of DOI:10.1016/j.molcata.2014.12.009

The synthesis of α,α-diphenyl-4-trans-hydroxy-(L)-prolinol modified with imidazolium based ionic liquids was carried out with trans-α,α-diphenyl-4-hydroxy-(L)-prolinol, 5-bromovaleric acid or 1,5-dibromopentane and imidazole. α,α-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic liquid was treated with BH₃·SMe₂ which generate 1,3,2-oxazaborolidine, that acts as a catalyst for asymmetric reduction of prochiral ketones. α,α-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic liquids (PF₆ anion) with BH₃?SMe₂ found to be an efficient catalyst (10 mol%) for the reduction of the acetophenone, gave 99% yield and 87-84% ee. The catalytic method has wide applicability for a variety of substrates. 1,3,2-oxazaborolidine containing ether linkage ionic liquid was recovered and reused up to 4 cycles with 99-91% yields and 87-81% ee's.

Full text of DOI:10.1016/j.molcata.2014.12.009

Journal of Molecular Catalysis A: Chemical 398 (2015) 184–189
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Asymmetric reduction of ketones catalyzed by
␣,␣-diphenyl-(L)-prolinol modified with imidazolium
ionic liquid and BH3·SMe2 as a recoverable catalyst
ManMohan Singh Chauhan, Surendra Singh∗
Department of Chemistry, University of Delhi, Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of ␣,␣-diphenyl-4-trans-hydroxy-(L)-prolinol modified with imidazolium based ionic
liquids was carried out with trans-␣,␣-diphenyl-4-hydroxy-(L)-prolinol, 5-bromovaleric acid or 1,5-
dibromopentane and imidazole. ␣,␣-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic
liquid was treated with BH3·SMe2 which generate 1,3,2-oxazaborolidine, that acts as a catalyst for asym-
metric reduction of prochiral ketones. ␣,␣-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium
ionic liquids (PF6 anion) with BH3·SMe2 found to be an efficient catalyst (10 mol%) for the reduction of the
acetophenone, gave 99% yield and 87–84% ee. The catalytic method has wide applicability for a variety
of substrates. 1,3,2-oxazaborolidine containing ether linkage ionic liquid was recovered and reused up
to 4 cycles with 99–91% yields and 87–81% ee’s.
Received 30 July 2014
Received in revised form
28 November 2014
Accepted 6 December 2014
Available online 10 December 2014
Keywords:
Asymmetric reduction
Ketones
© 2014 Elsevier B.V. All rights reserved.
Oxazaborolidine
Borane dimethyl sulfide complex
␣,␣-diphenyl-4-trans-hydroxy-(L)-prolinol
Imidazolium ionic liquids
1. Introduction
linked dendimers [37], imidazolium-tagged sulfonamide [38], use
of C3-symmetric Tris(␤-hydroxyphosphoramide) [39] and sulfon-
The enantioselective reduction of prochiral ketones is an impor-
tant transformation for the synthesis of chiral secondary alcohols
[1,2]. Enantiopure secondary alcohols are important intermediates
or chiral building blocks for the preparation of natural prod-
ucts, pharmaceuticals and agrochemicals. Alcohol functionality can
be converted to other useful functional groups such as chloride
[3–6], amine [7,8], azide [9] and fluoride [10–12]. Chiral 1,3,2-
oxazaborolidine catalyzed asymmetric reduction of ketones in
conjunction with BH3.THF is one of most popular method which
was developed by Hirao et al. and later improved by Corey and
co-workers [13–20]. Numerous methods for asymmetric reduction
of ketone using chiral 1,3,2-oxazaborolidine have been devel-
oped in homogenous medium at room temperature as well as
higher temperatures [21–35]. Low molecular weight chiral 1,3,2-
oxazaborolidines are difficult to separate from the product, if
modified this can be recoverable and reusable for asymmetric
reduction of ketones. In the recent past several researchers have
been addressed to this issue by using fluorous tags [36], triazole
amide [40], and immobilization by covalent bond on polymer beads
[41–44]. Maltsev et al., have been reported O-TMS-␣,␣-diphenyl-
L-prolinol modified with an ionic liquid moiety for asymmetric
Michael reaction of ␣,␤-enals with dialkyl malonates, nitroalka-
nes and N-protected hydroxylamine [45–47]. Herein, we report
the synthesis of ␣,␣-diphenyl-L-prolinol containing ionic liquids
(ILs) with imidazolium cation, and bromide, hexafluorophosphate
and tetrafluoroborate anions (Fig. 1) with BH3·SMe2 generate 1,3,2-
oxazaborolidine as a catalysts for the asymmetric reduction of
prochiral ketones using BH3·SMe2 as hydride source.
2. Experimental
2.1. General details
All the ketones and BH3·SMe2 (2M in THF) were used as recieved
from commercial source. Proton and carbon nuclear magnetic res-
onance spectra (1H and 13C NMR, respectively) were recorded on
400 MHz (operating frequencies: 1H, 400.13 MHz; 13C, 100.61 MHz)
Jeol-FT-NMR spectrometers at ambient temperature. The chem-
ical shifts (ı) for all compounds are listed in parts per million
downfield from tetramethylsilane using the NMR solvent as an
∗
Corresponding author. Tel.: +91 11 27667794; fax.: +91 11 27666605.
E-mail address: ssingh1@chemistry.du.ac.in (S. Singh).
http://dx.doi.org/10.1016/j.molcata.2014.12.009
1381-1169/© 2014 Elsevier B.V. All rights reserved.

M.S. Chauhan, S. Singh / Journal of Molecular Catalysis A: Chemical 398 (2015) 184–189
185
2.4. Synthesis of (2S,4R)-tert-butyl 4-((5-bromopentanoyl)
oxy)-2-(hydroxydiphenylmethyl) pyrrolidine-1-carboxylate (10)
HO
Ph
Ph
Ph
OH
Ph
N
H
N
H
5-Bromopentanoic acid (0.81 g, 4.48 mmol) was added to a solu-
tion of N,Nꢀ-dicyclohexylcarbodiimide (DCC) (0.92 g, 4.48 mmol)
and 4-dimethylaminopyridine (DMAP) (0.42 g, 0.1 mmol) in CH2Cl2
(20 mL) at 0 ◦C and then compound 9 (1.29 g, 3.5 mmol) was added
in a 10 min. The reaction mixture was stirred at 0 ◦C for 1 h, later DCC
(0.46 g, 2.24 mmol) and 5-bromopentanoic acid (0.40 g, 2.24 mmol)
were added and the reaction mixture was refluxed for 30 min,
precipitate was filtered off and washed with CH2Cl2 (3 × 25 mL).
Organic filtrate was washed with conc. HCl (1.65 mL), saturated
aqueous NaHCO3 (2 × 15 mL), water (25 mL) and dried over Na2SO4.
The solvent was evaporated by rotavapor and the product was iso-
lated by column chromatography using a mixture of hexane/Et2O
(8:2) to afford brown solid (1.78 g, 96%). Mp = 108.1 ◦C; = + 33.9 (c
0.8, chloroform); 1H NMR (400 MHz, CDCl3): ı = 7.42–7.23 (m, 10H),
5.03 (dd, J = 8.79, 5.86 Hz, 1H), 4.72 (brs, 1H), 3.54 (brs, 1H), 3.38 (t,
J = 6.59 Hz, 2H), 3.01 (brs, 1H), 2.28–2.22 (m, 3H), 2.14–2.11 (m, 1H),
1.87–1.83 (m, 2H), 1.76–1.71 (m, 2H), 1.34 (brs, 9H) ppm; 13C NMR
(100 MHz, CDCl3): ı = 172.7, 145.2, 143.2, 128.1 (2 C), 127.9 (2 C),
127.7 (2 C), 127.4 (2 C), 81.7, 73.0, 65.2, 53.5, 36.2, 33.3, 33.0, 32.0,
28.3, 23.4 ppm; IR (CH2Cl2, film): ꢀ = 3433, 3058, 2963, 1730, 1679,
OH
2
1
O
N
O
Ph
X
N
Ph
OH
N
H
3; X = Br
4; X = BF4
5; X = PF6
Fig. 1. Structures of ␣,␣-diphenyl-L-prolinol and its ionic liquids.
internal reference. The reference values used for deuterated chlo-
roform (CDCl3) were 7.26 and 77.00 ppm for 1H and 13C NMR
spectra, respectively. HRMS analysis was carried out using QSTAR
XL Pro system microTOF-Q-II. Infrared spectra were recorded on a
PerkinElmer FT-IR spectrometer. Thin layer chromatography was
carried out using Merck Kieselgel 60 F254 silica gel plates. Col-
umn chromatography separations were performed using silica gel
230–400 mesh. All the new synthesized compounds were charac-
terized by 1H, 13C NMR and HRMS and known compounds were
characterized by 1H and 13C NMR. The experimental procedure
for the known compounds were followed according to literature
reports and given in supporting information (SI). The enantiomeric
excess was determined on Shimadzu LC-2010HT using OD–H and
AD–H chiral columns. The optical rotation was taken using Rudo-
plph digipol polarimeter.
1407, 1259, 1165, 701 cm−1
.
2.5. Synthesis of 3-(5-(((3R,5S)-1-(tert-butoxycarbonyl)-5-
(hydroxydiphenylmethyl) pyrrolidin-3-yl)
oxy)-5-oxopentyl)-1-methyl-1H-imidazol-3-ium bromide (11)
The mixture of compound 10 (1.59 g, 3 mmol) and 1-methyl-1H-
imidazole (0.49 g, 6 mmol) was heated at 100 ◦C for 10 min and then
cooled to room temperature and washed with Et2O (5 × 6 mL) to
separate an excess of 1-methyl-1H-imidazole. The residue was dis-
solved in MeOH (1.5 mL) and Et2O (30 mL) was added, ethereal layer
was separated and the residue was washed with Et2O (5 × 6 mL).
The obtained product was dried under reduced pressure to afford
11 (1.80 g, 98%) as a brown hygroscopic liquid. = + 16.8 (c 1.6, chlo-
roform); 1H NMR (400 MHz, CDCl3): ı = 9.74 (s, 1H), 7.37–6.97 (m,
12H), 4.76–4.75 (m, 1H), 4.04–4.01 (m, 2H), 3.73 (s, 3H), 3.52–3.48
(m, 2H), 2.04–2.01 (m, 3H), 1.87–1.84 (m, 1H), 1.64 (d, J = 5.86 Hz,
2H), 1.33–1.29 (m, 2H), 1.03 (brs, 9H) ppm; 13C NMR (100 MHz,
CDCl3): ı = 172.4, 145.7, 136.5, 127.9 (2C), 126.9 (2C), 126.8 (2C),
126.6 (2C), 126.0, 123.5, 122.1, 80.8, 74.6, 63.5, 53.3, 48.3, 35.7, 32.6,
31.2, 28.7, 27.3, 20.8 ppm; IR (CH2Cl2, film): ꢀ = 3419, 3108, 2929,
2.2. General procedure of asymmetric reduction of ketones
In a schlenk tube, BH3·SMe2 (0.55 mmol, 275 ␮L) was added in
the solution of IL 5 (28 mg, 10 mol%) dissolved in THF (1 mL), under
nitrogen atmosphere. The homogenous mixture was stirred and
heated at 70 ◦C for 30 min. Later, a solution of ketone (0.5 mmol
in THF (0.5 mL)) was added within 30 min. After the addition was
completed, the solvent was evaporated under vacuum. An aqueous
solution of 1M HCl (5 mL) was added and the product was extracted
with DCM. The solvent was dried on anhydrous sodium sulfate
and evaporated under reduced pressure. Crude residue was further
purified by column chromatography on silica gel using hexane-
ethyl acetate as eluent. Enantiomeric excesses of all alcohols were
determined by HPLC analysis using Chiralcel OD–H/AD–H chiral
column, isopropanol-n-hexane as mobile phase and HPLC condi-
tions are given in SI.
1726, 1676, 1409, 1392, 1232, 1167, 701 cm−1
.
2.6. Synthesis of (2R,4R)-tert-butyl4-((5-bromopentyl)
oxy)-2-(hydroxydiphenylmethyl) cyclopentanecarboxylate (12)
Compound
9
(2 g, 5.4 mmol) was dissolved in dry
dichloromethane (50 mL) and triethylamine (0.904 mL, 6.5 mmol)
and 1,5-dibromopentane (0.881 mL, 6.5 mmol) were added and
reaction mixture was allowed to stir at r.t. for 15 min, then
anhydrous KOH (0.151 g, 2.7 mmol) was added. The resulting
heterogeneous reaction mixture was allowed to stir at r.t. for
overnight. The residue was diluted with DCM and washed with
saturated aq. solution of NaHCO3, water and dried over Na2SO4. The
solvent was evaporated by rotavapor and product was purified by
column chromatography with Hexane/EtOAc (80:20). The product
was obtained as light yellowish liquid (1.791 g, 64%).[ = −23.0 (c
1.26, dichloromethane); 1H NMR (400 MHz, CDCl3): ı = 7.33–7.15
(m, 10H), 4.94 (t, 1H J = 7.63 Hz), 3.36–3.28 (t, 3H, J = 6.87 Hz),
3.14–3.09 (m, 3H), 2.03–2.0 (m, 2H), 1.79–1.72 (m, 2H,), 1.45–1.24
(m, 13H) ppm; 13C NMR (100 MHz, CDCl3): ı = 145.9, 143.3, 127.8
2.3. Procedure for recycling of catalyst
After the fresh catalytic cycle, the solvent was removed under
vaccum and hexane:diethyl ether (5 mL, 1:1) was added. The 1,3,2-
oxazaborolidine of IL 5 or IL 15 was precipited out as viscous liquid
and the product was in the solvent which was removed by syringe.
The recovered catalyst was dissolved in THF (1 mL) and BH3·SMe2
(250 ␮L, 0.50 mmol) was added, and resulting mixture was heated
at 70 ◦C for 30 min. A solution of acetophenone (0.5 mmol in THF
(0.5 mL)) was added within 30 min, after the addition was com-
pleted, the reaction progress was checked on TLC, and the solvent
was evaporated under vacuum. Similar procedure was also fol-
lowed for next catalytic run.

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M.S. Chauhan, S. Singh / Journal of Molecular Catalysis A: Chemical 398 (2015) 184–189
(2C), 127.4 (2C), 127.1 (2C), 127.08 (2C), 81.5, 80.6, 68.5, 64.6, 52.7,
36.3, 33.6, 32.4, 28.7, 28.1, 24.7 ppm.
under inert atmosphere. The reaction mixture was allowed to stir
for 4 h at r.t. The solvent was evaporated by rotavapor and crude
product was washed with diethyl ether (5 mL). The product 14 was
obtained as light yellowish liquid (0.730 g, 88%). [ = −11.5 (c 0.68,
dichloromethane); 1H NMR (400 MHz, CDCl3): ı = 10.21 (s, 1H),
7.54 (d, 2H, J = 7.63 Hz), 7.38–7.21 (m, 10H), 4.80 (dd, 1H, J = 12.21,
6.10 Hz), 4.24 (t, 2H, J = 6.87 Hz), 4.02–3.93 (m, 5H), 3.34–3.28 (m,
2H), 3.16 (d, 1H, J = 12.21 Hz), 1.92–1.81 (m, 2H), 1.63–1.55 (m, 2H),
1.43–1.35 (m, 2H), 1.25 (brs, 2H), 1.18–1.10 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3): ı = 143.1, 139.9, 128.6 (2C), 128.4 (2C), 127.7,
125.9 (2C), 125.3 (2C), 123.4, 122.0, 85.9, 78.8, 68.6, 67.4, 53.4, 49.9,
35.8, 29.5, 28.8, 22.7 ppm.
2.7. Synthesis of 3-(6-((3R,5S)-1-(tert-butoxycarbonyl)-5-
(hydroxydiphenylmethyl) pyrrolidin-3-yl)
hexyl)-1-methyl-1H-imidazol-3-ium bromide (13)
Compound 12 (1.034 g, 2 mmol) and 1-methyl imidazole (1.2eq,
0.191 mL, 2.4 mmol) was heated at 100 ◦C for 30 min, cooled to
room temperature and washed with diethyl ether (5 × 5 mL) to
remove excess 1-methyl imidazole. The obtained product was
dried under reduced pressure to afford light yellowish solid (1.15 g,
96%). [ = −67.2 (c 2.2, dichloromethane); 1H NMR (400 MHz, CDCl3):
ı = 9.59 (s, 1H), 7.38–7.25 (m, 12H), 4.95 (s, 1H), 4.13 (brs, 2H),
3.90 (brs, 4H), 3.49–3.47 (m, 2H), 3.21–3.19 (m, 2H), 2.07 (brs, 2H),
1.82 (brs, 2H), 1.48–1.19 (m, 13H) ppm. 13C NMR (100 MHz, CDCl3):
ı = 145.3, 143.2, 137.4, 129.6 (2C), 127.9 (2C), 127.5 (2C), 127.1 (2C),
123.8, 122.06, 81.8, 80.9, 67.8, 65.6, 52.8, 49.5, 36.3, 36.1, 29.8, 28.8,
28.2, 22.8 ppm.
2.9. Synthesis of 3-(6-((3R,5S)-5-(hydroxydiphenylmethyl)
pyrrolidin-3-yl) hexyl)-1-methyl-1H-imidazol-3-ium
hexaflourophosphate (15)
Compound 14 (0.500 g, 1 mmol) was dissolved in the mixture of
methanol (7 mL) and water (20 mL). An aqueous solution of KPF6
(0.36 g, 2 mmol, 10 mL) was added to the above solution. MeOH
was removed at reduced pressure by rotavapor to give transparent
solution. The aqueous phase was decanted off and the residue was
dissolved in CH2Cl2 (35 mL), washed with 0.1 M solution of KPF6
(2 × 10 mL) and dried over Na2SO4. The solvent was evaporated
and residue was dried under reduced pressure to afford compound
15 (0.463 g, 82% yield). [ = −18.5 (c 0.3, dichloromethane); 1H NMR
2.8. Synthesis of 3-(6-((3R,5S)-5-(hydroxydiphenylmethyl)
pyrrolidin-3-yl) hexyl)-1-methyl-1H-imidazol-3-ium
bromide (14)
Compound 13 (1.0 g, 1.67 mmol) was dissolved in dry
dichloromethane (7.5 mL), trifluoroacetic acid (1.5 mL) was added
HO
b
HO
HO
a
COOH
CO2Et
.HCl
N
H
N
H
OH
.HCl
N
H
6
8
7
c
Br
HO
O
d
O
N
Boc
N
Boc
OH
OH
10
9
e
N
N
N
N
O
O
Br
f
Br
O
O
N
H
OH
N
Boc
OH
3
11
g
N
N
O
X
O
N
H
OH
4; X = BF4
5; X = PF6
Scheme 1. (a) SOCl2, ethanol, reflux, 4 h, 94%, (b) PhMgBr, Et2O, reflux, 5 h, 70%, (c) (Boc)2O, Et3N, CH2Cl2, reflux, 1 h, 94%, (d) DCC, DMAP, 5-bromovalleric acid, CH2Cl2,
reflux, 1.5 h, 96%, (e) 1-Methyl imidazole, 100 ◦C, 10 min, 98%, (f) TFA, CH2Cl2, 2 h, 85%, (g) KPF6, MeOH/H2O, 80%, and (h) NaBF4, H2O, 90%.

M.S. Chauhan, S. Singh / Journal of Molecular Catalysis A: Chemical 398 (2015) 184–189
187
Table 1
(400 MHz, CDCl3): ı = 8.54 (s, 1H), 7.52 (d, 2H, J = 7.63 Hz), 7.37–7.20
Optimization of reaction conditions for asymmetric reduction of acetophenone.a
(m, 11H), 4.79 (dd, 1H, J = 10.68, 4.58 Hz), 4.10 (t, 2H, J = 6.87 Hz),
4.02–3.99 (t, 1H, J = 5.34 Hz), 3.92 (dd, 1H, J = 12.21, 5.34 Hz), 3.84
(s, 3H), 3.37–3.28 (m, 2H), 3.15 (d, 1H, J = 12.21 Hz), 1.87–1.81 (m,
2H), 1.57–1.52 (m, 2H), 1.41–1.34 (m, 2H), 1.25 (brs, 2H), 1.15–1.08
(m, 1H) ppm. 13C NMR (100 MHz, CDCl3): ı = 143.0, 139.9, 128.6
(2C), 128.4 (2C), 127.7, 125.9 (2C), 125.3 (2C), 123.4, 122.0, 85.9,
78.8, 68.6, 67.4, 53.4, 49.9, 35.8, 29.5, 28.8, 22.7 ppm.
Entry
Ligand
Solvent
T (◦C)
Yield (%)b
Ee (%)c,d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1
2
3
4
5
5
5
5
5
5
5
5
5
5
5
5
THF
THF
THF
THF
THF
Neat
Hexane
Diethyl ether
Dichloromethane
Toluene
THF
THF
THF
THF
THF
70
70
70
70
70
70
70
Refluxing
Refluxing
110
25
40
50
60
70
70
96
94
85
92
99
90
79
75
95
97
75
80
87
85
94
99
91
91
53
60
84
53
35
13
43
61
3
13
20
43
65e
86f
3. Results and discussion
The ␣,␣-diphenyl-(L)-prolinol modified with imidazolium ionic
liquids (ILs) with tetrafluoroborate and hexafluorophosphate
anions (4 and 5) were synthesized in a 80–90% yields by the
reaction of ␣,␣-diphenyl-(L)-prolinol @ IL imidazolium bromide
(3) with NaBF4 and KPF6 (Scheme 1). The ␣,␣-diphenyl-(L) pro-
linol @ IL imidazolium bromide (3) was obtained in a 83.3%
yield in a two steps by the reaction of (2S,4R)-tert-butyl-4-((5-
bromopentanoyl) oxy)-2-(hydroxydiphenylmethyl) pyrrolidine-1-
carboxylate (10) and 1-methyl imidazole at 100 ◦C and followed
by N-Boc deprotection using trifluoroacetic acid (TFA). The
THF
a
Ligands 1–5 (10 mol%) was taken in Schlenk tube, solvent (1 mL), BH3·SMe2
(0.55 mmol) were added and heated or refluxed for specified temperature for 30 min,
solution of acetophenone (0.5 mmol in THF (0.5 mL)) was added within 30 min.
ester (10) was synthesized in
a 95% yield by the reac-
b
Isolated yield after purification by column chromatography.
The ee was determined by HPLC using Chiralcel OD–H column.
The absolute configuration was determined by comparing the optical rotation
tion of (2S,4R)-tert-butyl-4-hydroxy-2-(hydroxydiphenylmethyl)
pyrrolidine-1-carboxylate (9) and 5-bromopentanoic acid in the
presence of DCC/DMAP in CH2Cl2. (2S,4R)-tert-butyl 4-hydroxy-
2-(hydroxydiphenylmethyl) pyrrolidine-1-carboxylate (9) was
synthesized from trans-4-hydroxy-L-proline in sequence reac-
tion, first trans-4-hydroxy-(L)-proline was converted to its ethyl
ester (7) and then react with phenylmagnesium bromide to give
(3R,5S)-5-(hydroxydiphenylmethyl) pyrrolidin-3-ol hydrochloride
(8) [48]. Later, the amino group was protected as N-Boc by
using di-tert-butyl dicarbonate and triethylamine. The total
yield for the ␣,␣-diphenylprolinol modified with ionic liq-
uids (IL) 3–5 were 39.5–49%, starting from trans-4-hydroxy-(L)-
proline.
c
d
with literature and found to be (R).
e
IL 5 (5 mol%) was used.
IL 5 (15 mol%) was used.
f
We screened the different IL’s 3–5 (10 mol%) for asymmetric
reduction of acetophenone with BH3·SMe2 (2M in THF) at 70 ◦C
under inert atmosphere. 1,3,2-Oxazaborolidine of IL 5 gave an
excellent yield (99%) and 84% enantiomeric excess (ee) compared
to the other IL’s (4) and (3) which have corresponding tetrafluorob-
orate and bromide anions (Table 1, entries 3–5). We have also used
␣,␣-diphenyl-(L)-prolinol (1) and trans-␣,␣-diphenyl-4-hydroxy-
Br
a
HO
O
N
Boc
OH
N
Boc
OH
b
9
12
N
c
N
N
N
O
O
Br
Br
N
H
OH
d
N
Boc
OH
14
13
N
N
O
PF6
N
OH
H
15
Scheme 2. Synthesis of (L)-prolinol modified with ether linker ionic liquid. (a) TEA, Dry DCM, 1,5dibromopentane, KOH, 65%, (b) 1-Methyl imidazole, 100 ◦C, 30 min, 96%,
(c) TFA, CH2Cl2, 4 h, 88%, and (d) KPF6, MeOH/H2O, 82%.

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M.S. Chauhan, S. Singh / Journal of Molecular Catalysis A: Chemical 398 (2015) 184–189
Table 2
(L)-prolinol (2) under similar reaction conditions, gave 94–96%
yields and 91% enantiomeric excesses (ee’s) (Table 1, entries 1and
2). Screening of the different solvents for asymmetric reduction
of acetophenone using IL 5 (10 mol%) with BH3·SMe2 at 70 ◦C or
reflux temperature. Asymmetric reduction of acetophenone in hex-
ane, diethyl ether and dichloromethane, afforded poor ee’s (Table 1,
entries 7–9) and moderate ee (61%) was observed in case of toluene
as solvent (Table 1, entry 10). The best solvent system for reduction
was found to be THF. Effect of temperature on asymmetric reduc-
tion was also studied, the reaction temperature varied in range
70–25 ◦C and ee’s were dropped from 86% to 3% (Table 1, entries
5 and 11–14). We have also varied the loading of IL 5 (5–15 mol%),
increasing the catalyst loading improved the ee of the product
(Table 1, entries 5, 15 and 16).
The asymmetric reduction of a variety of prochiral ketones were
carried out using IL 5 (10 mol%) and BH3·SMe2 in THF at 70 ◦C
under inert atmosphere and the results were given in Table 2. The
asymmetric reduction of 2-methoxy, 3-methoxy and 4-methoxy
acetophenone gave corresponding products in 81–92% yields and
69–86% ee’s (Table 2, entries 1–3). Substrate 2-nitro acetophenone
gave poor ee (40%) compared to the 4-nitro acetophenone (81%
ee) (Table 2, entries 4 and 5). 2-Bromo, 3-bromo and 4-bromo ace-
tophenone afforded 91–94% yields and 64–88% ee’s (Table 2, entries
6–8). Substrates 2-fluoro and 4-fluoro acetophenone gave corre-
sponding products in a 90–92% yields and 78–81% ee’s (Table 2,
entries 9 and 10). These results indicate that 4-substituent on ace-
tophenone provides better ee compared to the other acetophenone
derivatives. Asymmetric reduction of propiophenone gave 92%
yield with 81% ee (Table 2, entry 11). We have also investigated the
asymmetric reduction of aliphatic ketones like cyclopropyl methyl
ketone and methyl ethyl ketone afforded 88–91% yields and 48–62%
ee’s (Table 2, entries 12 and 13).
Asymmetric reduction of a variety of prochiral ketones using IL 5 and BH3·SMe2.a
Entry
1
Substrates
Products
Yield (%)b
Eec,d
88
79
2
81
69
3
4
5
92
84
93
86
40
81
6
7
8
94
91
92
64
84
88
9
90
81
The recycling and reusability of 1,3,2-oxazaborolidine of IL 5 was
carried out for the asymmetric reduction of acetophenone. After
completion of fresh catalytic cycle, the solvent (THF) was removed
under reduced pressure and a mixture of diethyl ether and hexane
(5 mL, 1:1) was added and 1,3,2-oxazaborolidine of IL 5 was pre-
cipitated as viscous oil and the product was removed by syringe.
The recovered catalyst was used for next catalytic run. The conver-
sions of the products were comparable but enantiomeric excesses
(ee’s) gradually decreased (Table 3). 1H NMR of IL 5, its 1,3,2-
oxazaborolidine and recovered 1,3,2-oxazaborolidine (SI, Figure 6)
show that the peak at 2.35 ppm ( CH2 COO) was disappeared and
new peak appears at 3.33 ppm for CH2OH due to reduction of
ester linkage to alcohol. The reduction of ester in IL 5 was also con-
firmed by HRMS, show peak at 270.1493 [M + H]+ and 169.1336
[M]+ corresponding to (L)-prolinol (2) and hydroxyl ionic liquid (SI,
Scheme 1).
To enhance the stability of catalyst, IL 15 with ether linker was
synthesized according to Scheme 2. N-boc-trans-4-hydroxy-(L)-
prolinamide (9) was reacted with 1,5-dibromopentane in presence
of KOH at room temperature gave the compound 12 in a 65% yield.
The compound 12 was further reacted with 1-methylimidazol at
100 C for 30 min yielded compound 13 and Boc deprotection by
trifluroacetic acid gave the IL 14 with bromide anion. The anion
exchange of compound 14 by using KPF6 gave ionic liquid 15. The
ionic liquid 15 was tested for the catalytic asymmetric reduction of
acetophenone and recovered and reused up to 4 cycles with reten-
tion of conversions of product and slightly decrease in ee’s (87–81%)
were observed (Table 3). The 1H NMR of fresh 1,3,2-oxazaborolidine
of IL 15 and recovered 1,3,2-oxazaborolidine of IL 15 were found to
be similar, indicated that complex is stable during the reaction. The
HRMS data of the recovered ionic liquid 15 was also similar to the
fresh ionic liquid 15 (SI, Figs. 7 and 8)
10
92
92
78
81
11
12
88
91
62
48
13
a
The IL 5 (10 mol%) was taken in Schlenk tube, THF (1 mL), BH3·SMe2 (0.55 mmol)
were added and heated at 70 ◦C for 30 min, solution of acetophenone derivatives
(0.5 mmol in THF (0.5 mL)) was added to it within 30 min.
b
Isolated yield after purification by column chromatography.
The ee was determined by HPLC using Chiralcel OD–H/AD–H column.
The absolute configuration was determined by comparing the optical rotation
c
d
with literature and found to be R.
Table 3
Recycling of the catalyst generated from IL 5 and BH3·SMe2 for asymmetric reduction
of acetophenone.a
Entry
Cyclesa
Yieldb
Eec
1 (2)
3 (4)
5 (6)
7 (8)
9 (10)
0
1
2
3
4
99 (99)
95 (99)
95 (96)
91 (94)
90 (94)
84 (87)d
73 (85)
73 (82)
60 (81)
55 (81)
a
Recycling procedure are given in experimental.
b
c
Isolated yield after purification by column chromatography.
The ee was determined by HPLC using Chiralcel OD–H column.
Results in parenthesis were given for IL 15.
d

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In conclusion we have developed 1,3,2-oxazaborolidine from
␣,␣-diphenyl-4-hydroxy-(L)-prolinol modified with ionic liquids
and BH3·SMe2 as a recoverable and reusable catalyst for the asym-
metric reduction of prochiral ketones. The asymmetric reduction of
acetophenone and its derivatives gave excellent yields of the prod-
ucts and good to moderate ee’s except 2-nitro acetophenone. The
reduction of aliphatic ketones afforded good yields of the products
with moderate ee’s. The 1,3,2-oxazaborolidine of ␣,␣-diphenyl-
4-hydroxy-(L)-prolinol modified with ionic liquids having ether
linkage found to be stable compared to ester linkage in presence of
BH3.SMe2 during the asymmetric reduction. 1,3,2-oxazaborolidine
of ionic liquid with ether linkage was recovered and reused up
to 4 cycles for the reduction of acetophenone and conversions of
the products were comparable and also enantiomeric excess (ee’s)
slightly decreased.
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Acknowledgements
SS acknowledges the financial assistance from Science and
Engineering Research Board (SERB), Department of Science and
technology (DST), India, under scheme Fast Track Young Scien-
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Center (USIC), University of Delhi, India for analytical data. MSC
is thankful to University Grant Commission (UGC), New Delhi for
providing SRF.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata
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