Asymmetric reduction of aromatic ketones in pyridinium-based ionic liquids

Article abstract of DOI:10.1016/j.tetasy.2006.03.032

The asymmetric reduction of aromatic ketones has been studied in pyridinium-based room temperature ionic liquids, namely, 1-ethyl-pyridinium tetrafluoroborate, [EtPy]⁺[BF₄]^- and 1-ethyl-pyridinium trifluoroacetate, [EtPy]<

Full text of DOI:10.1016/j.tetasy.2006.03.032

Tetrahedron: Asymmetry 17 (2006) 1062–1065
Asymmetric reduction of aromatic ketones in pyridinium-based
ionic liquids
Ying Xiao and Sanjay V. Malhotra*
Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, Newark, NJ 07102, USA
Received 7 February 2006; accepted 30 March 2006
Available online 27 April 2006
Abstract—The asymmetric reduction of aromatic ketones has been studied in pyridinium-based room temperature ionic liquids, namely,
+
ꢀ
+
ꢀ
1
-ethyl-pyridinium tetrafluoroborate, [EtPy] [BF
4
]
and 1-ethyl-pyridinium trifluoroacetate, [EtPy] [CF COO] . Ionic liquids were
3
employed as solvents, while (R)-BINOL and (R)-BINOL-Br were used as chiral promoters. The effects of solvent, reaction time, temper-
ature, catalyst loading and substituents were investigated. The reduction could be easily carried out in both ionic liquids with lower
catalyst loading. 1-Ethyl-pyridinium tetrafluoroborate was recycled and reused efficiently.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
The increased interest in these solvents is mainly due to
their highly polar, non-coordinating and good solvating
9
Enantioselective reduction of prochiral carbonyl com-
pounds is an important method the for preparation of opti-
properties. Encouraged by earlier successful investigations
1
0
with pyridinium based ionic liquids, we embarked on the
1
+
ꢀ
cally active alcohols. Generally, aldehydes and ketones
study of two ionic liquids, that is, [EtPy] [CF COO] and
3
+
ꢀ
can be reduced to the corresponding alcohols by reduc-
tants, such as alkali metal aluminum hydrides, alkali metal
borohydrides, and metal cyanoborohydride, while the
asymmetric reduction of prochiral ketones to chiral alco-
hols with these metal hydrides can be achieved by the mod-
ification of the reagent with chiral ligands, such as alcohols
[EtPy] [BF ] for the asymmetric reduction of aromatic
4
ketones. Herein, we report the results of our study on the
enantioselective reduction using LiAlH and chiral ligands
4
BINOL and Br-BINOL.
*
*
or amines—R OH or RR NH.
2. Results and discussion
Among commonly used reagents, lithium aluminum hy-
dride (LAH) is a powerful reducing agent with high solubil-
ity in ether solvents. As a hydrogen donor, it is widely
employed for reductions of aldehydes, ketones, esters,
amides, and nitriles. In 1951, Bothner-By modified lithium
0
The aromatic ketones treated with the complex of (R)-1,1 -
0
bi-2-naphthol [(R)-BINOL] or its derivative (R)-6,6 -di-
bromo-1,1 -bi-2-naphthol [(R)-BINOL-Br] and lithium
aluminum hydride were investigated in N-ethyl-pyridinium
tetrafluoroborate [EtPy] [BF ] or N-ethyl-pyridinium tri-
0
+
ꢀ
2
4
aluminum hydride with (+)-camphor, to achieve asym-
+
ꢀ
fluoroacetate [EtPy] [CF COO] , as shown in Figure 1.
3
metric reduction. Since then, a wide variety of chiral
3
4
5
ligands derived from alkaloids, sugars, alcohols,
It has been reported earlier11 that in organic solvents the
reduction with LiAlH is more effective in the presence of
ethanol. In order to study the influence of ethanol in ionic
liquids and also the catalyst loading required, aceto-
phenone was initially used as the representative ketone.
6
7
amines, amino alcohols, etc. have been employed with
4
LAH (LiAlH ) in order to induce asymmetric reduction
4
in various organic solvents.
Recently, much attention has been focused on ionic liquids
The molar ratio of chiral ligand–LiAlH –ethanol, 1:1:1
8
4
for their advantageous applications in organic reactions.
was kept constant and the reaction studied at room tempera-
ture for 24 h. A parallel study was also performed under
the same conditions, but in the absence of ethanol. Results
are summarized in Table 1.
*
Corresponding author. Tel.: +1 973 596 5583; fax: +1 973 596 3586;
e-mail: malhotra@adm.njit.edu
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.032

Y. Xiao, S. V. Malhotra / Tetrahedron: Asymmetry 17 (2006) 1062–1065
1063
O
OH
*
selectivity (Table 2). The results were marginally better in
+
ꢀ
[
EtPy] [CF COO] .
3
Chiral ligand with LiAlH4
Pyridinium IL
R
R
The reaction procedure developed with acetophenone was
employed further for the reduction of other aromatic
a: R = CH3
b: R = C2H5
c: R = n-C3H7
d: R = CH(CH3)2
e: R = n-C4H9
Br
Br
ketones. Since better results were seen in the reductio+n
of acetophenone under different conditions in [EtPy]
OH
OH
OH
OH
ꢀ
+
ꢀ
4
[CF COO] , compared to that in [EtPy] [BF ] , rest of
3
+
ꢀ
the studies was carried out in [EtPy] [CF COO] only.
3
f : R = CH2CH(CH3)2
g: R = C(CH3)3
These reactions were also studied at lower temperature
with the hope of improving enantioselectivity. It should
(
R)-BINOL
(R)-BINOL-Br
+
ꢀ
be noted that in the case of [EtPy] [BF ] as solvent,
4
Figure 1. Asymmetric reduction of aromatic ketones.
decreasing the temperature to 0 °C solidified the reaction
mixture and it could not be used as solvent. Similarly, in
+
ꢀ
the case of [EtPy] [CF COO] , decreasing the reaction
3
Table 1. Asymmetric reduction of acetophenone with various amount of
catalyst
temperature below ꢀ30 °C, solidified the reaction mixture.
Therefore, reduction at 0 °C and ꢀ30 °C were studied in
+
ꢀ
[
EtPy] [CF COO] only. The results are summarized in
3
Solvents
Dosage of
catalyst (equiv)
Yield/ee (%)
a
Table 3.
With
Without
ethanol
ethanol
Table 3. Asymmetric reduction of ketones catalyzed by BINOL–LAH in
b
THF
2.0
0.5
95–100/64
—
+
ꢀ
3
[EtPy] [CF COO]
+
ꢀ
[
EtPy] [CF
3
COO]
78/58
96/66
99/66
99/68
99/68
99/69
91/63
99/68
99/68
99/68
99/68
99/68
Entry Ketone
Yield/ee (%)
1
1
2
2
3
.0
.5
.0
.5
.0
rt (4 h) 0 °C (24 h) ꢀ30 °C (24 h)
1
2
3
4
5
6
7
C H COCH
3
6
5
99/69
99/69
98/70
97/69
96/69
97/68
95/59
91/75
93/80
91/79
85/78
87/79
82/74
79/64
85/84
86/85
83/84
79/82
80/84
76/78
71/70
C H COCH CH
3
6
5
2
C H CO(CH ) CH
6
6
6
6
6
5
5
5
5
5
2 2
3
3
+
ꢀ
C
C
C
C
H
H
H
H
3 2
COCH(CH )
[
EtPy] [BF
4
]
0.5
76/54
97/63
99/64
99/65
99/66
99/66
86/59
99/66
99/66
99/66
99/66
99/66
CO(CH
COCH
3 3
COC(CH )
2 3
) CH
1
1
2
2
3
.0
.5
.0
.5
.0
2 3 2
CH(CH )
As expected, a decrease in the reaction temperature to
30 °C, resulted in a significant increase in the product
a
1
equiv is counted on the basis of acetophenone (2 mmol).
Reported by Noyori et al., 1979.
ꢀ
b
enantioselectivities for all ketones (Table 3). However,
the overall yields decreased even with prolonged reaction
period. Also due to steric hindrance, lower selectivity and
yields are obtained in the reduction of phenyl-t-butyl
ketone, as compared with other ketones.
As the data show, 2 or more equivalents of the catalyst
complex were needed when ethanol was used in the reac-
tion, where as only 1 equiv of the catalyst complex was suf-
ficient in the absence of ethanol. This indicates that ethanol
does not have the same effect on the reagent efficiency in
ionic liquids, as it does in organic solvents. This is because
in organic solvents, ethanol forms an alkoxy complex with
We noticed that in the case of acetophenone, a homo-
geneous reaction mixture was formed, while solubility
decreased with increase in the size of the alkyl substituent
on ketone, and two phases were obtained in the case of
phenyl-t-butyl ketone. This was overcome by stirring the
reaction mixture at 250 rpm. As the data in Table 3 show,
higher yields and enantioselectivity were seen in the case
of ketones a–f (entries 1–6). Both yield and selectivity
decreased with bulky t-Bu substituent (entry 7).
LiAlH –BINOL mixture, leaving one hydrogen for reduc-
4
tion.1 On the other hand, anion of the ionic liquid could
induce a similar effect on the reagent, thereby eliminating
the need for ethanol. In both ionic liquids, optimal
results were obtained in 4 h. Continuation of the reac-
tion beyond this time did not improve the enantio-
1
0
Further investigations were carried out with (R)-6,6 -di-
0
bromo-1,1 -bi-2-naphthol [(R)-BINOL-Br], to see if an
Table 2. Reaction time effect of asymmetric reduction of acetophenone
electron withdrawing substituent on the chiral ligand, for
example, bromine has any influence on product selectivity.
Therefore, reductions were carried out under identical con-
ditions as before, except using Br-BINOL in place of BI-
NOL as chiral ligand. Results are summarized in Table 4.
We saw an improved enantioselectivity in the reduction
of all ketones, clearly indicating better influence of an elec-
Reaction time (h)
Yield/ee (%)
+
ꢀ
+
ꢀ
[
EtPy] [CF
3
COO]
[EtPy] [BF
4
]
1
2
4
8
73/71
96/70
99/69
99/68
99/68
99/68
76/68
97/67
99/67
99/66
99/66
99/66
1
2
2
4
0
tron withdrawing group at the 6,6 -position of BINOL,
and an enhanced effect on selectivity.

1064
Y. Xiao, S. V. Malhotra / Tetrahedron: Asymmetry 17 (2006) 1062–1065
0
0
Table 4. Asymmetric reduction of ketones catalyzed by BINOL-Br–LAH
or (R)-6,6 -dibromo-1,1 -bi-2-naphthol (2 mmol, 1 equiv)
was added to 2 ml of ionic liquid. The mixture was heated
to 45 °C and stirred until the solid dissolved. Lithium alu-
minum hydride (2 mmol, 1 equiv) was slowly added to the
mixture, which produced a very small amount of suspen-
sion. Furthermore, in this step, we noticed that some bub-
bles were generated. The mixture was stirred (250 rpm) for
+
ꢀ
3
COO]
in [EtPy] [CF
Entry Ketones
Yield/ee (%)
rt (4 h) 0 °C (24 h) ꢀ30 °C (24 h)
1
2
3
4
5
6
7
C
6
C
6
C
6
C
6
C
6
C
6
C
6
H
5
H
5
H
5
H
5
H
5
H
5
H
5
COCH
COCH
CO(CH
3
99/70
99/73
99/74
97/70
96/73
96/71
93/62
91/79
91/83
83/90
85/80
86/82
80/79
75/68
86/88
90/82
82/90
80/87
78/89
75/81
68/74
2
CH
CH
COCH(CH
CO(CH CH
COCH
COC(CH
3
2
)
2
3
3
0 min at the specified reaction temperature, and the aro-
3 2
)
matic ketone (2 mmol, 1 equiv) was added dropwise. The
reaction mixture was stirred (250 rpm) at this temperature
for the desired time period. Finally, 2 M HCl (5 ml), was
added to quench the reaction mixture, which was then
brought to room temperature. The organic compound
was extracted by diethyl ether (5 ml), washed first with
saturated sodium bicarbonate (5 ml) followed by brine
2 3
)
3
2
CH(CH
)
3 3
3
)
2
The reusability of ionic liquids was also tested in the asym-
metric reduction of acetophenone catalyzed by using (R)-
BINOL–LAH complex. Therefore, after completion of
the reaction, the organics were extracted into diethyl ether,
and the ionic liquid was decanted and residual products
distilled off. The ionic liquid was passed through a chro-
matographic column, washed with distilled water and dried
under vacuum at 65 °C overnight before reuse. Table 5
shows the results with recycled and reused ionic liquids in
the reduction of acetophenone.
(
5 ml). Evaporation under reduced pressure yielded the
concentrated organic mixture, which was further purified
by flash chromatography (acetone/hexanes 1:7) to give
purified products.
4. Conclusion
This is the first study demonstrating that the pyridinium
+
ꢀ
+
ꢀ
4
based ionic liquids [EtPy] [CF COO] and [EtPy] [BF ]
3
Table 5. Recycling and reuse of ionic liquids
can be used efficiently in the asymmetric reduction of aro-
matic ketones. High yield and ee have been achieved with
low dosages of catalysis complex. Higher selectivity was
+
ꢀ
+
ꢀ
COO]
Recycling #
[EtPy] [BF
Recovered
wt %)
4
]
[EtPy] [CF
3
Yield/ee
(%)
Recovered
(wt %)
Yield/ee
(%)
+
ꢀ
obtained with Br-BINOL in [EtPy] [CF COO] when
3
(
+
ꢀ
compared to BINOL and/or [EtPy] [BF ] . We have also
shown that [EtPy] [BF ] could be recycled and reused
4
0
1
2
3
—
93
92
90
99/67
97/64
98/65
98/63
—
87
76
68
99/68
98/51
99/43
99/37
+
ꢀ
4
efficiently.
References
+
ꢀ
Ionic liquid [EtPy] [BF ] could be recovered efficiently
4
1
2
. Seyden-Penne, J. Reduction by the Alumino- and Borohydrides
in Organic Synthesis, 2nd ed.; John Wiley and Sons: New
York, 1997; p 37.
and reused up to three times with negligible loss of activity
+
ꢀ
and selectivity. However, [EtPy] [CF COO] could not
3
be easily recovered on subsequent reuse. This could be
. Bothner-By, A. A. J. Am. Chem. Soc. 1951, 73, 846.
because a stronger complex was formed with LiAlH and
3. (a) Cervinka, O. Chem. Commun. 1965, 30, 1684; (b)
Cervinka, O.; Belovsky, O. Chem. Commun. 1967, 32,
3897.
4
ꢀ
CF COO , which is also evident from the dark color of
3
the ionic liquid after each subsequent recycling. Therefore,
selectivity of the reduced products also dropped
significantly.
4
. (a) Landor, S. R.; Miller, B. J.; Tatchell, A. R. J. Chem. Soc.
966, 20, 1822; (b) Landor, S. R.; Miller, B. J.; Tatchell, A. R.
1
J. Chem. Soc. 1967, 3, 197; (c) Cervinka, O.; Fabryova, A.
Tetrahedron Lett. 1967, 13, 1179.
5
6
. (a) Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc.
3
. Experimental
1
979, 101, 3129; (b) Noyori, R. Pure Appl. Chem. 1981, 53,
2
315.
All analyses were carried out by HP 1050 HPLC equipped
with chiralcel OD-H column (hexanes/2-propa-
nol = 75:25). Product formation was also conformed by
H NMR (500 MHz, in CDCl ). Aromatic ketones were
purchased from Sigma Aldrich Co. and used as received.
Ionic liquids were prepared following the procedure
. (a) Asami, M.; Mukaiyama, T. Heterocycles 1979, 12, 499; (b)
Mukaiyama, T.; Asami, M.; Hanna, J.; Kobayashi, S. Chem.
Lett. 1977, 7, 783.
a
1
7. (a) Yamaguchi, S.; Mosher, H. S.; Pohland, A. J. Am. Chem.
Soc. 1972, 94, 9254; (b) Yamaguchi, S.; Mosher, H. S. J. Org.
Chem. 1973, 38, 1870; (c) Jacquet, I.; Vigneron, J. P.
Tetrahedron Lett. 1974, 24, 2065; (d) Vigneron, J. P.; Jacquet,
I. Tetrahedron 1976, 32, 939; (e) Terashima, S.; Tanno, N.;
Koga, K. Chem. Lett. 1980, 8, 981.
3
1
2
reported earlier.
3
.1. General procedure for reduction
8
. (a) Zhao, D.; Wu, M.; Kou, Y.; Min, E. Catalysis Today
002, 74, 157; (b) Zhao, H.; Malhotra, S. V. Aldrichimica
2
Reactions were carried out under a moisture free N atmo-
sphere. Ionic liquids were dried overnight in an oven at
0 °C before each use. Chiral ligand (R)-1,1 -bi-2-naphthol
2
Acta 2002, 35, 75; (c) Olivier-Bourbigou, H.; Magna, L.
J. Mol. Catal A: Chem. 2002, 182, 419; (d) Gordon, C. M.
Appl. Catal. A: General 2001, 222, 101.
0
7

Y. Xiao, S. V. Malhotra / Tetrahedron: Asymmetry 17 (2006) 1062–1065
1065
9
. Wasserscheid, P.; Welton, T. Ionic Liquids in Synthesis;
Wiley-VCH Verlag GmbH: Germany, 2003; Chapter 3.
11. Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
7816.
1
0. (a) Xiao, Y.; Malhotra, S. V. Tetrahedron Lett. 2004, 45,
12. (a) Holbrey, J. D.; Seddon, K. R. J. Chem. Soc.,
Dalton Trans. Inorg. Chem. 1999, 13, 2133; (b) Zhao, H.;
Malhotra, S. V.; Luo, R. Phys. Chem. Liq. 2003, 41,
487.
8
2
339; (b) Xiao, Y.; Malhotra, S. V. J. Mol. Catal. A: Chem.
005, 230, 129; (c) Xiao, Y.; Malhotra, S. V. J Organomet.
Chem. 2005, 15, 3609.