159

CHAPTER – 4

Reduction of Aryl Ketones Using Ionic Liquids

160

4.1 Introduction

Hydride reduction of ketones to alcohols is one of the most

important and extensively used chemical transformations. Synthesis

of several biologically active molecules, for example, terfenadine,1

montelukast etc. involve hydride reduction as one of the key synthetic

steps. The discovery of sodium borohydride in 1942 brought a

revolutionary change in procedures for the reductions of functional

groups in organic molecules.2 Hydride reductions are considered

superior in terms of ease of handling and reaction selectivity

compared to classical reduction methods such as dissolving metal

reactions and transfer hydrogenations. The reactivity of the hydride

reagents can be fine tuned to achieve the desired chemical

transformations by changing the substituents. Selective reducing

agents, a variety of acidic hydride reducing agents, such as BH3:L,

BH2Cl:L, BHCl2:L, BH2R, BHR2, AlH3:L, AlHCl2, AlHR2, and basic

reducing agents, such as MBH4, MBH(OR)3, MBHR3, MAlH4,

MAlH(OR)3, and MAlHR3 have become popular in the recent past.

Synthetic chemists can now do many selective reductions of one group

in the presence of another group or viceversa. Sodium borohydride

has found applications in many industries for example in paper and

pharmaceutical industries. Many of these reagents and their modified

variations are now readily available commercially in bulk quantities

and used in process chemistry.

161

The developments in this area led to the discovery of alkyl

borohydrides and later to the discovery of asymmetric

hydroborating/reducing agents such as IpcBH2, Ipc2BH and Ipc2BCl.

There has been a flurry of activity on the synthesis, properties

and applications of several ionic liquids in the last decade culminating

in several publications and reviews. Ionic liquids have no vapor

pressure, and are therefore useful solvents for large scale applications.

They can be devised in such a way as to offer the temperature range of

choice with desired dissolution properties for the substrate and/or the

product of choice. They are also known to enhance the rate of

reaction showing higher selectivity,3-4 to give good yields and to be

easily reused5-6. Room temperature ionic liquids are attracting

interest as environmentally benign reaction media, and have been

found to be excellent solvents for a number of 7-9 such as Friedel-

Crafts reaction,10 Knoevenagel, Michael addition reactions,11

Beckmann rearrangements,12-13 Pechmann condensation,14 Heck

reactions,15-16 Diels-Alder reactions17-19 etc. Ryan and co workers20

have reported the reduction of aldehydes and ketones with NaBH4

using ionic liquid [bmim] PF6 over conventional organic solvents

resulting in moderate to good yields.

There is very limited literature available on the application of

ionic liquids as solvents in hydride reductions. In 2001, Howarth et

al. reported the first sodium borohydride reduction in ionic liquid as a

162

solvent.20 The methodology as been generalized with various

substituted aromatic aldehydes and ketones using [bmim] PF6,21

Scheme-4.1.

R1 R2

O

R1 R2

OHbmim PF6

NaBH4

Yield %

a) R1=R2=Ph 65

b) R1=Ph, R2=H 90

c) R1=Ph, R2=CH(OH)Ph 70

d) R1=Ph, R2=COPh 70

e) R1=m-NO2, R2=H 75

f) Cyclohexanone 55

N

N

Me

n-Bu

PF6

1 2

3

Scheme: 4.1 Reduction of aldehydes and ketones in the recyclable

ionic liquid [bmim] [PF6].

There is good amount of literature available on the reduction of

carbonyl group in presence of ionic liquids using bio transformations

and chiral ligands. Howarth et al. describe a bio-reduction of carbonyl

compounds with immobilized baker’s yeast in a 10:1 [bmim] PF6 ionic

liquid/water mixture to give alcohols with comparable enantio-

selectivities to baker’s yeast reductions in alternative media,22

Scheme-4.2.

Scheme: 4.2 Immobilized baker’s yeast reduction of ketones in IL and

water mix.

163

Another effective method for asymmetric reduction of ketones was

developed using an enzyme in ionic liquids by Matsuda et al.23

Asymmetric reductions of ketones by Geotrichum candidum in ionic

liquids proceeded smoothly with excellent enantio-selectivity when the

cell was immobilized on water-absorbing polymer containing water.

However the reaction did not proceed in the absence of the polymer,

Scheme-4.3.

Scheme: 4.3 Asymmetric reduction of ketone and recycling of coenzyme catalyzed by Geotrichum candidum dried cell

containing alcohol dehydrogenases.

The asymmetric reduction of aromatic ketones has been

reported in pyridinium-based room temperature ionic liquids, namely,

1-ethyl-pyridinium tetrafluoroborate and 1-ethyl pyridinium

trifluoroacetate as solvents, while (R)-BINOL and (R)-BINOL-Br were

used as chiral promoters.24 Several parameters like the effect of

solvent, reaction time, temperature, catalyst loading and substituents

164

were investigated. The ionic liquids could be recycled and reused.

The aromatic ketones treated with the complex of (R)-1,1’-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]+[BF4]- or N-

ethyl-pyridinium trifluoroacetate [EtPy]+ [CF3COO]-, as shown in

Scheme-4.4.

R

O

R

OH

*Chiral ligand with LiAlH4

Pyridinium IL

OH

OH

OH

OH

Br

Br

(R)-BINOL (R)-BINOL-Br

a: R=CH3b: R=C2H5c: R=n-C3H7d: R=CH(CH3)2e: R=n-C4H9f: R=CH2CH(CH3)2g: R=C(CH3)3

10 11

12 13

Scheme: 4.4 Asymmetric reductions of aromatic ketones.

In 2007, Kroutil et al. have reported bi and monophasic ionic

liquid/buffer systems for the biocatalytic reduction of ketones

catalyzed by the alcohol dehydrogenase via hydrogen transfer.25 The

use of these solvents allowed highly stereo-selective enzymatic

carbonyl reductions at substrate concentration from 1.2-1.5 M,

Scheme-4.5.

165

Scheme: 4.5 Ionic liquid/buffer as reaction medium for the 'coupled

substrate' approach in the ADH-'A' catalysed reduction

of ketones.

Despite the rapid design of new chiral ionic liquids, successful

applications remained hidden for some time. The first successful

application of chiral ionic liquid, with enantiomeric excess of greater

than 90% was published after a decade of its synthesis. So far, there

are no reports in the literature on the use of chiral ionic liquids as

solvents to reduce carbonyl group into alcohols using sodium

borohydride. Herein, we attempt to develop a protocol for the

reduction of ketones to alcohols in ionic liquids as solvents. We also

attempt to use a chiral ionic liquid (21), synthesized in our laboratory,

for the asymmetric reduction of aromatic ketones to alcohols.

Raju et al. have reported chiral ionic liquid 1-[(1R)-1-

ethoxymethylpropyl]-1-methylpyrrolidinium iodide, in 2008.26 This

chiral ionic liquid was prepared by prepared by treatment of (R) -2-

aminobutnol (18) with 1-bromo-4-chlorobutane in the presence of

triethylamine in dichloromethane to yield the corresponding

166

pyrrolidine alcohol 2 (R) 2-(1-Pyrrolidine) butane-1-ol (19), which was

further treated with diethyl sulphate using sodium hydroxide as base

in a mixture of toluene and N-methylpyrrolidine as solvent to give the

corresponding (R)-2-(1-Pyrrolidine) butyl ethyl ether (20). Further

treatment of the ether 20 with methyl iodide in acetonitrile medium

gave the respective chiral ionic liquid (21), Scheme-4.6.

NO

NO

NO+

I-

NO+

I-

NOH

NOH

H2NOH

a b

c

a) 1-Bromo-4-chlorobutane, TEA, DCM, RT

b) Diethyl sulphate, NaOH, toluene, NMP, 10-25 °C.

c ) MeI, Acetonitrile, RT

19

21

18 20

Scheme: 4.6 Synthetic pathway of pyrrolidine-based chiral ionic

liquid.

X. Lijin et al. have reported ionic liquid 1-n-butyl-3-

methylimidazolium bromide (23), in 2000.27 Ionic liquid [bmim] [Br]

was prepared by addition of n-bromobutane to a stirred solution of N-

methylimidazole (22) in acetonitrile by allowing the reaction mixture

to stir overnight at room temperature and by the evaporation of the

solvent under reduced pressure to afford the corresponding ionic

liquid (23), Scheme-4.7.

167

a) n-Butylbromide, Acetonitrile, RT-over night

NN

NN+

Br-

a

22 23

Scheme: 4.7 Synthetic pathway of [bmim] [Br]

Trihexyl(tetradecyl)phosphonium tris(pentafluoroethyl) trifluoro-

phosphate (24) ionic liquid was procured from Merck. The structures

of these three ionic liquids are given below, Chart-4.1.

Chart - 4.1: Structures of the ionic liquids.

168

4.2 Results and Discussion

Herein, we report the study of hydride reductions on ketones,

particularly substituted acetophenones, using ionic liquids as reaction

media. The representative acetophenones chosen for the study

include electron-releasing, electron-withdrawing and neutral

substituents on aromatic ring 25a-f. The reductions are carried out

in two different ionic liquids trihexyl (tetradecyl) phosphonium tris

(pentafluoroethyl) trifluorophosphate (A) and [bmim] [Br] (B), Chart-1

at ambient temperatures using sodium borohydride. Reaction of

substituted acetophenones 25a-f with sodium borohydride in both the

selected ionic liquids is found to be high yielding as compared to the

reactions using methanol as solvent, Scheme-4.8.

O HOH

R R

R1

R2

R1

R2

25a-f 26a-f

Ionic Liquid A (or) B

Yield %

IL-A IL- B MeOH

26a 79 82 70

26b 81 84 73

26c 80 87 76

26d 88 92 85

26e 80 83 80

26f 85 87 81

R R1 R2

25a OCH3 H H

25b CH3 H H

25c H OCH3 OCH3

25d Cl H H

25e H H H

25f CN H H

NaBH4

Scheme: 4.8 Synthetic pathway of reduction of substituted

acetophenones.

169

Compound 26a was confirmed from the 1H NMR study. The

peak at δ 7.2-7.3 (m, 2H), δ 6.8-6.9 (m, 2H) corresponds to aromatic

ring protons, δ 4.8-4.9 (q, 1H) corresponds to achiral proton, singlet at

δ 3.8 of methoxy group and doublet at δ 1.4-1.5 (d, 3H) corresponds to

the -CH3 group. The broad singlet at δ1.8 is assigned to be the –OH

proton.

The recovery and reusability of ionic liquids in the same

chemical transformations has been studied with p-

chloroacetophenone using pyrrolidine based ionic liquid (C). After the

completion of the reaction, the product is extracted with di-isopropyl

ether and the ionic liquid layer is used for the same reaction. It is

observed that the ionic liquid layer can be successfully used for five

reaction cycles with p-chloroacetophenone (25d) without

compromising on the yield, Scheme-4.9. However, it is difficult to

study the reusability and recyclability of trihexyl (tetradecyl)

phosphonium tris (pentafluoroethyl) trifluorophosphate ionic liquid (A)

due to its solubility in both aqueous and organic media under the

reaction conditions.

170

O

HOH

Cl Cl

Ionic liquid C

NaBH4

Yield %

1st cycle 90

2nd cycle 85

3rd cycle 88

4th cycle 84

5th cycle 85

4-chloroacetophenone 4-chloro-1-phenyl ethanol

25 d 26 d

Scheme: 4.9 Recovery and reusability of pyrrolidine-based ionic liquid (C).

The ketones, substituted acetophenones, 25a-f are also

considered suitable for enantio-selective reductions in the presence of

chiral ionic liquid. The chiral ionic liquid 1-[(1R)-1-

ethoxymethylpropyl]-1-methylpyrrolidinium iodide (C), prepared in our

laboratory was considered for the study. Reaction of the substituted

acetophenones 25a-f with sodium borohydride in the presence of the

chiral ionic liquid C gave the product in good yields comparable to the

ionic liquids A & B, Scheme-4.10. However, chiral HPLC analysis of

the products did not show significant enantio-selectivity. The

observations are in line with the earlier review on enantio-selectivity

using chiral ionic liquids. All the products obtained were subjected to

purification by column chromatography and characterized using

spectral data.

171

Scheme: 4.10 Synthetic path-way of aryl keto reduction.

172

4.3 Conclusion

In summary, reduction of substituted acetophenones using

sodium borohydride to the corresponding alcohols has been studied in

ionic liquid media. The reactions can be performed at room

temperature and the yields of the reactions are very high in all three

ionic liquids used in the study. The recovery and reusability of the

ionic liquids has been studied and demonstrated for five consecutive

cycles without compromising on the yields. This methodology reduces

the generation of wastes and also avoids safety-related problems.

Further, recycle of the non-volatile ionic liquid are the remarkable

feature of the present method and it is expected to address the

problem of environmental concerns.

173

4.4 Experimental Section

All the chemicals and reagents of LR grade were used. 1H NMR

spectra were obtained on a Varian Gemini 2000 model 200 MHz

instrument (Chemical shifts in ppm) with TMS as internal standard

and mass spectrum run on HP5989 spectrometer.

General procedure for the synthesis of alcohols:

Conventional method:

Sodium borohydride (2.0 eq) was added to the keto compound

(1.0 eq) in methanol (3.0 vol) at 25 oC. The reaction mass was stirred

for overnight at 20-25 oC and completion of the reaction was checked

by TLC. Then water (5 vol) was added and the products were

extracted with ethyl acetate (twice). The combined extracts were dried

over Na2SO4 and the solvent was removed under reduced pressure to

yield the corresponding alcohol.

With ionic liquid method:

Sodium borohydride (2.0 eq) was added to the mixture of keto

compound (1.0 eq) in ionic liquid (1.0 vol) at room temperature. The

reaction was left to stir for overnight at room temperature and then

extracted with di-isopropyl ether (thrice). The combined extracts were

dried over Na2SO4 and the solvent was removed under reduced

pressure to yield the corresponding alcohol.

174

Recycling of the ionic liquid:

After completion of the reaction, di-isopropyl ether or ethyl

acetate (twice) was added to the reaction mixture with vigorous

stirring for 5 min. The mixture was allowed to stand for further 5 min

and the clear supernatant liquid was decanted. The combined solvent

was concentrated under reduced pressure to afford the crude, which

was purified by column chromatography using ethyl acetate and

petroleum ether as an eluent to get the corresponding alcohol. The

ionic liquid was further washed with ether, volatile materials were

evaporated under reduced pressure and nitrogen gas was purged into

the ionic liquid to make it dry before reuse. The recycled ionic liquid

was used in subsequent runs and the reaction profile was studied

with recycled ionic liquid upto 5 cycles on 4-chloroacetophenone (25d)

reduction reaction. The same reaction profile was observed for each

subsequent cycle as with the first one performed with fresh ionic

liquid, however, after 5 cycles ionic liquid transformed to a thick mass

due to reagent residuals.

Preparation of 1-[(1R)-1-ethoxymethylpropyl]-1-methyl

pyrrolidinium iodide (21): (R)-2-aminobutanol (18) (25 g, 280 mmol)

was treated with 1-bromo-4-chlorobutane (53 g, 309 mmol) in the

presence of triethylamine (11.3 g, 1120 mmol) in dichloromethane

(250 mL) as solvent to yield 36.5 g (90%) of the corresponding

pyrrolidine alcohol 2 (R) 2-(1-Pyrrolidine) butane-1-ol (19) in good

yield. Compound (19) (20 g, 138 mmol) was reacted with diethyl

sulphate (54 g, 340 mmol) using sodium hydroxide (28 g, 698 mmol)

175

as base and toluene (100 mL) and N-methylpyrrolidine (40 mL) as

solvent mixture to give 18 g (75%) of the corresponding (R)-2-(1-

Pyrrolidine) butyl ethyl ether (20) in good yield. The compound (20)

(10 g, 58 mmol) was further treated with methyl iodide (1.3 g, 87

mmol) in acetonitrile (100 mL) medium to give 15 g (82%) of the

corresponding ionic liquid (21). 1H NMR (200 MHz, CDCl3): δ 3.9-4.2

(m, 4H, -(CH2)-O), 3.6 (m, 1H, chiral), 3.5-3.7 (m, 4H, -(CH2)-N), 3.10

(s, 3H, -CH3(N)), 2.3-2.5 (m, 4H, -(CH2)-CH2), 1.8-2.2 (m, 2H, -CH2

chiral), 1.2-1.22 (t, 3H, -CH3-CH2 chiral), 1.1-1.2 (t, 3H, -CH3-CH2O).

MS: M+H 314.

Preparation of 1-n-butyl-3-methylimidazolium bromide (23): To a

stirred solution of N-methylimidazole (22) (10 mL, 0.125 mmol) in

acetonitrile (20 mL), n-bromobutane (16 mL, 0.15 mmol) was added

and the reaction mixture was left to stir overnight at room

temperature. The solvent was evaporated under reduced pressure to

afford the corresponding ionic liquid (23) as a brown-colored liquid.

1H NMR (200 MHz, CDCl3): δ 10.40-10.41 (s, 1H, -CH(N)2), 7.80-7.81

(s, 1H, -CH-N(CH)3), 7.60-7.61 (s, 1H, -CH-N(CH)2), 4.4-4.41 (t, 2H, -

CH2-N), 4.2-4.21 (s, 3H, -CH3-N), 1.8-2.0 (m, 2H, -CH2-(CH2)2), 1.3-1.5

(m, 2H, -CH2-CH3), 0.98-0.99 (t, 3H, -CH3-CH2). MS: M+H 139.

1-(4-methoxyphenyl)-1-ethanol (26a): Sodium borohydride (6.6

mmol) was added to the mixture of 4-methoxy acetophenone 25a (3.3

mmol) in ionic liquid (21) (1.0 vol) at room temperature. The reaction

was left to stir for overnight at room temperature and then extracted

with di-isopropyl ether (thrice). The combined extracts were

176

evaporated under reduced pressure, the resulting crude was subjected

to column chromatography using a mixture of ethyl acetate and pet

ether as an eluent to afford the desired product 1-(4-methoxyphenyl)-

1-ethanol, (26a) in 85% yield. 1H NMR (200 MHz, CDCl3): δ 7.2-7.4

(m, 2H, Ar-H), 6.8-7.0 (m, 2H, Ar-H), 4.8-5.0 (q, 1H, -CH-C), 3.8 (s,

3H, Ph-OCH3), 1.7-1.9 (brd s, 1H, -OH), 1.4-1.5 (d, J=6.2 Hz, 3H, -

CH3). MS: M-1 151.

1-(4-methylphenyl)-1-ethanol (26b): Sodium borohydride (7.4 mmol)

was added to the mixture of 4-methyl acetophenone 25b (3.7 mmol) in

ionic liquid (21) (1.0 vol) at room temperature. The reaction was left

to stir for overnight at room temperature and then extracted with di-

isopropyl ether (thrice). The combined extracts were evaporated under

reduced pressure, the resulting crude was subjected to column

chromatography using a mixture of ethyl acetate and pet ether as an

eluent to afford the desired product 1-(4-methylphenyl)-1-ethanol

(26b), in 89% yield. 1H NMR (200 MHz, CDCl3): δ 7.0-7.3 (m, 4H, Ar-

H), 4.8-5.0 (q, 1H, -CH-OH), 2.4 (s, 3H, Ph-CH3), 1.7-1.9 (brd s, 1H, -

OH), 1.4 (d, J=6.2 Hz, 3H, -CH3). MS: M+H 137.

1-(3,5-dimethoxyphenyl)-1-ethanol (26c): Sodium borohydride (5.5

mmol) was added to the mixture of dimethoxy acetophenone 25c (2.7

mmol) in ionic liquid (21) (1.0 vol) at room temperature. The reaction

was left to stir for overnight at room temperature and then extracted

with di-isopropyl ether (thrice). The combined extracts were

evaporated under reduced pressure, the resulting crude was subjected

to column chromatography using a mixture of ethyl acetate and pet

177

ether as an eluent to afford the desired product 1-(3,5-

dimethoxyphenyl)-1-ethanol (26c) in 87% yield. 1H NMR (200 MHz,

CDCl3): δ 6.8-7.0 (m, 3H, Ar-H), 4.8-5.0 (q, 1H, -CH-OH), 3.9 (s, 3H,

Ph-OCH3), 3.8 (s, 3H, Ph-OCH3), 1.7-1.9 (brd s, 1H, -OH), 1.4 (d, 3H, -

CH3). MS: M+H 183.

1-(4-chlorophenyl)-1-ethanol (26d): Sodium borohydride (6.4 mmol)

was added to the mixture of 4-chloro acetophenone 25d (3.2 mmol) in

ionic liquid (21) (1.0 vol) at room temperature. The reaction was left

to stir overnight at room temperature and then extracted with di-

isopropyl ether (thrice). The combined extracts were evaporated under

reduced pressure, the resulting crude was subjected to column

chromatography using a mixture of ethyl acetate and pet ether as an

eluent to afford the desired product 1-(4-chlorophenyl)-1-ethanol

(26d) in 92% yield. 1H NMR (200 MHz, CDCl3): δ 7.3-7.4 (m, 4H, Ar-

H), 4.8-5.0 (q, 1H, -CH-OH), 1.7-1.9 (brd s, 1H, -OH), 1.4-1.5 (d, J=6.8

Hz, 3H, -CH3). MS: M-1 155.

1-Phenyl-1-ethanol (26e): Sodium borohydride (8.3 mmol) was added

to the mixture of acetophenone 25e (4.1 mmol) in ionic liquid (21) (1.0

vol) at room temperature. The reaction was left to stir for overnight at

room temperature and then extracted with di-isopropyl ether (thrice).

The combined extracts were evaporated under reduced pressure, the

resulting crude was subjected to column chromatography using a

mixture of ethyl acetate and pet ether as an eluent to afford the

desired product 1-phenyl-1-ethanol (26e), in 85% yield. 1H NMR (200

178

MHz, CDCl3): δ 7.2-7.4 (m, 5H, Ar-H), 4.8-5.0 (s, 1H, -CH-OH), 1.7-1.9

(brd s, 1H, -OH), 1.4-1.5 (d, J=6.6 Hz, 3H, -CH3). MS: M+H 123.

4-(1-hydroxyethyl)phenyl cyanide (26f): Sodium borohydride (6.8

mmol) was added to the mixture of 4-cyano acetophenone 25f (3.4

mmol) in ionic liquid (21) (1.0 vol) at room temperature. The reaction

was left to stir overnight at room temperature and then extracted with

di-isopropyl ether (thrice). The combined extracts were evaporated

under reduced pressure, the resulting crude was subjected to column

chromatography using a mixture of ethyl acetate and pet ether as an

eluent to yield 90% of the desired product 4-(1-hydroxyethyl)phenyl

cyanide (26f). 1H NMR (200 MHz, CDCl3): δ 7.6-7.7 (m, 2H, Ar-H),

7.4-7.5 (m, 2H, -Ar.), 4.8-5.0 (q, 1H, -CH-OH), 1.7-1.9 (brd s, 1H, -

OH), 1.4-1.5 (d, J=6.6 Hz, 3H, -CH3). MS: M+H 147.

179

4.5 Spectral data

NO+

I-

21

1H NMR spectrum (400MHz, CDCl3) of compound 21:

Mass spectrum of compound 21:

180

OH

H3CO

26a

1H NMR spectrum (200MHz, CDCl3) of compound 26a:

Mass spectrum of compound 26a:

181

OH

H3C

26b

OH

H3CO

OCH3

26c

1H NMR spectrum (200MHz, CDCl3) of compound 26b:

1H NMR spectrum (200MHz, CDCl3) of compound 26c:

182

OH

Cl

26d

1H NMR spectrum (200MHz, CDCl3) of compound 26d:

Mass spectrum of compound 26c:

183

OH

26e

1H NMR spectrum (200MHz, CDCl3) of compound 26e:

Mass spectrum of compound 26d:

184

OH

NC

26f

1H NMR spectrum (200MHz, CDCl3) of compound 26f:

Mass spectrum of compound 26e:

185

Mass spectrum of compound 26f:

186

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