Ionic liquid/potassium hydroxide catalyzed solvent-free, one-pot synthesis of diarylglycolic acids from aromatic aldehydes under microwave

Article abstract of DOI:10.1016/j.tetlet.2011.03.020

Ionic liquid in conjugation with KOH brings about an efficient, one-pot, green synthesis of α,α-diarylglycolic acids in reasonably high yields from aromatic aldehydes under solvent-free condition using conventional heating as well as microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2011.03.020

Tetrahedron Letters 52 (2011) 2419–2422
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ionic liquid/potassium hydroxide catalyzed solvent-free, one-pot synthesis of
diarylglycolic acids from aromatic aldehydes under microwave
⇑
Neetu Singh, Satish Kumar Singh, R. S. Khanna, Krishna Nand Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Ionic liquid in conjugation with KOH brings about an efficient, one-pot, green synthesis of a,a-diarylgly-
colic acids in reasonably high yields from aromatic aldehydes under solvent-free condition using conven-
tional heating as well as microwave irradiation.
Received 12 January 2011
Revised 2 March 2011
Accepted 4 March 2011
Available online 23 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
One-pot synthesis
Ionic liquid
a,a-Diarylglycolic acid
Green approach
a
-Hydroxycarboxylic acids are an important class of com-
efficient, and environmental friendly synthetic methodologies.
Thus, development of ionic liquid mediated organic transformation
using microwave heating is gaining prominence.12
pounds, which are applied to cure some skin diseases (such as acne
and ichthyosis),1–3 or used as intermediates in the production of
some nonsteroidal anti-inflammatory drugs.4,5 Many substituted
benzilic acids and their esters are known for their analgesic and
physiological activities and have accordingly, been subjected to de-
tailed pharmacological studies particularly in the preparation of
antidepressants, anticholinergics, antispasmodic drug and bron-
chodilators.6–8
Microwave (MW) provides a powerful way to do synthetic
chemistry in the light of current paradigm shift to ‘Green Chemis-
try’. It provides many chemical reactions with attributes such as
enhanced reaction rates, higher yields of pure products, better
selectivity, improved ease of manipulation, rapid optimization of
reactions and several eco-friendly advantages.9 Ionic liquids have
been recognized as versatile and novel reaction catalysts for
organic transformations, and have also found application as
flexible ‘platforms’ to establish highly effective and easily
separable systems.10 Room temperature ionic liquids, especially
those based on the 1,3-dialkylimidazolium cation, have attracted
considerable attention due to their negligible vapour pressure,
nonflammability, reasonable thermal stability, ease of handling,
ability to act as catalyst, and potential for recycling.11 The conjuga-
tion of ionic liquid and microwave irradiation as a nonconventional
heating source has shown evident advantages when compared to
conventional synthetic procedures for the generation of fast,
Preparation of benzilic acid from benzaldehyde is accomplished
by a three-step approach involving conversion of benzaldehyde to
benzoin, oxidation of benzoin to benzil, and finally benzilic acid
rearrangement of benzil to afford the desired product. A multi-step
synthesis of benzilic acid/ester from p-bromotoluene has also been
investigated and described.13 Formation of benzoin from benzalde-
hyde is usually achieved by using cyanide ion,14 or ionic liquids.15
The oxidation of benzoin to benzil has been accomplished by sev-
eral oxidative reagents16 such as bismuth oxide,17 Co(II)/Fe(III)
complexes,18 alumina-supported copper(II) sulfate,19 bismuth ni-
trate/copper acetate,20 trichlorooxyvanadium,21 zeolite,22 TiCl4/
MW (180W), [Bmim]BF4 / KOH
60°C, 20-25 min
(73-81%)
CHO
COOH
C
2
R
1a-j
OH
2a-j
R
R
R = H, CH3, OCH3, Cl, Br, NO2
[Bmim]BF4 / KOH
70°C, 3-4 h
(57-68%)
⇑
Corresponding author. Tel.: +91 542 6702485; fax: +91 542 2368127.
E-mail addresses: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in (K.N. Singh).
Scheme 1. [Bmim]BF4/KOH catalyzed solvent-free synthesis of
acids.
a,a-diarylglycolic
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.020

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N. Singh et al. / Tetrahedron Letters 52 (2011) 2419–2422
Table 1
Optimization of reaction conditions using compound 1a as reference
Entry
Ionic liquids (mol %)
Base (mmol)
Reaction conditions
Power (W)
Conventional
Time (h)
Microwave
Temp (°C)
Yield (%)
Temp (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
—
KOH
—
—
80
80
100
80
100
70
70
60
60
70
70
60
65
—
10
10
10
6
6
4
4
5
5
4
4
5
4
—
—
—
Nil
Nil
Nil
20
20
57
45
46
48
56
57
53
55
—
220
220
220
120
180
180
180
180
180
180
180
120
120
140
200
180
100
100
100
60
60
60
60
60
60
60
60
60
80
60
60
70
30
30
30
30
30
25
30
30
30
25
25
30
30
30
25
25
Nil
Nil
Nil
35
40
74
58
51
52
73
74
63
64
66
73
71
[Bmim]BF4 (10)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]PF6 (20)
[Bmim]BF4 (10)
[Bmim]BF4 (20)
[Bmim]BF4 (25)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
[Bmim]BF4 (20)
Basic alumina
Basic alumina
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (0.5)
KOH (1.0)
KOH (1.5)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
KOH (1.0)
—
—
—
—
Table 2
[Bmim]BF4/OHÀ catalyzed one-pot, solvent-free synthesis of
a,a-diarylglycolic acids
Entry
Aldehyde
Product
Conventional
Microwavea
Time (min)
Yieldb (%)
Time (h)
Yieldb (%)
COOH
C
CHO
1
1a
4
57
25
25
25
74
OH
2a
COOH
H3C
CHO
H3C
H3CO
Cl
C
CH3
2
3
1b
3.5
3.5
62
62
78
76
OH
2b
COOH
H3CO
CHO
C
OCH3
1c
OH
2c
COOH
Cl
CHO
C
Cl
1d
4
5
6
7
3
3
3
4
65
64
68
62
20
20
20
25
80
78
81
77
OH
2d
COOH
Br
CHO
Br
C
Br
1e
1f
OH
2e
COOH
O2N
Cl
CHO
O2N
Cl
C
NO2
OH
2f
COOH
C
CHO
OH
2g
1g
Cl

N. Singh et al. / Tetrahedron Letters 52 (2011) 2419–2422
2421
Table 2 (continued)
Entry
Aldehyde
Product
Conventional
Time (h)
Yieldb (%)
Microwavea
Time (min)
Yieldb (%)
Br
COOH
C
Br
CHO
8
9
4
61
5
75
76
1h
OH
2h
Br
CH3
CHO
CH3
COOH
C
3.5
3.5
61
60
25
OH
1i
H3C
2i
OCH3
CHO
OCH3
COOH
C
10
25
73
1j
OH
H3CO
2j
a
Microwave heating performed on 180 W at 60 °C using aromatic aldehydes (1 mmol), [Bmim]BF4 (20 mol %) and KOH (1 mmol).
Isolated yield.
b
Et3N,23 and alumina.24 The rearrangement of benzil to benzilic acid
assumed to proceed via benzoin and its subsequent oxidation to
benzil, whose intermediacy was proved by their presence during
the course of reaction. With the progress of the reaction, the
appearance and disappearance of both benzoin and benzil were
noticed on the TLC.
Potassium hydroxide was chosen as the base so as to remove
the C-2 hydrogen of imidazolium to form the catalyst imidazoli-
um-2-ylide.15d All the products were fully characterized based on
their melting points, elemental analyses and spectral data (IR, 1H
NMR, 13C NMR).
In conclusion, we have developed a facile and efficient one-pot
methodology for the eco-compatible preparation of a,a-diarylgly-
colic acids using ionic liquid as a green catalyst in solvent-free con-
ditions. The mildness of the conversion, experimental simplicity,
compatibility with various functional groups, high product yield,
shorter reaction time, and the easy work-up procedure make this
has been effected by base.25 Scanning of literature reveals that
there exists no report on one-pot direct conversion of aromatic
aldehydes to a,a-diarylglycolic acids. In view of the above, we re-
port herein a one-pot, green protocol for the synthesis of diarylgly-
colic acids from aldehydes using [Bmim]BF4/KOH combination as
an efficient catalyst under controlled microwave irradiation in sol-
vent-free conditions.
Due to our interest in microwave assisted organic reactions,26
we have investigated a [Bmim]BF4/KOH catalyzed, one-pot, simple
and efficient procedure for the rapid construction of diarylglycolic
acids from aromatic aldehydes in solvent-free conditions in rea-
sonably good yields under conventional heating (57–68%) as well
as under controlled microwave irradiation (73–81%) (Scheme 1).
To screen the experimental conditions, a typical reaction of
benzaldehyde (1a, 1 mmol) was carried out both by conventional
as well as by microwave heating at different power (Watt), tem-
perature and time under solvent-free conditions (Table 1). It is evi-
dent from the Table that no anticipated product is formed when
the reaction is carried out in the presence of ionic liquid or base
alone (Table 1, entries 1–3). However, a combination of different
ionic liquids and base gives rise to variable yields of the desired
product (entries 4–7), the best being achieved with [Bmim]BF4
and KOH combination (entry 6). It was imperative to observe the
effect of molar proportion of [Bmim]BF4 and KOH, MW power,
temperature and time. Decreasing the molar proportion of
[Bmim]BF4 or KOH decreases the yield of the product considerably
(Table 1, entries 8 and 9); however, an increase in the molar pro-
portion of [Bmim]BF4 or KOH does not improve the product yield
further (Table 1, entries 10 and 11). Compared to optimum MW
power and temperature (180 W at 60 °C), further change in MW
power and temperature did not improve the product yield (entries
12–16). Thus, the use of [Bmim]BF4 (20 mol %) and KOH (1 mmol)
combination was concluded to afford the optimum yield of the
product (74%) in short reaction time under controlled MW irradia-
tion (180 W, 60 °C) (Table 1, entry 6).
approach more attractive in synthesizing
derivatives.
a variety of such
Acknowledgment
The authors are thankful to the Department of Biotechnology,
New Delhi for financial assistance.
References and notes
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27. General conventional procedure: A mixture of [Bmim]BF4 (20 mol %), KOH
(1 mmol), and aromatic aldehyde (1 mmol) was placed in 10 mL round bottom
flask and heated at 70 °C with stirring for 3–4 h under aerobic conditions till
the completion of the reaction (TLC). The reaction mixture was cooled to room
temperature and poured into ice-cold water. The mixture was then acidified
with concentrated HCl and the precipitate obtained was extracted with diethyl
ether (3 Â 5 mL). The combined organic phase was dried over anhydrous
Na2SO4, filtered, evaporated and recrystallized from hot water to give the pure
product 2a–j.
28. General MW procedure: A mixture of [Bmim]BF4 (20 mol %), KOH (1 mmol), and
aromatic aldehyde (1 mmol) was placed in a sealed pressure regulation 10 mL
pressurized vial with ‘snap-on’ cap under aerobic conditions and was
irradiated in the single-mode microwave synthesis system at 180 W at 60 °C
for 20–25 min. After completion of reaction (TLC), the reaction mixture was
cooled to room temperature, poured into ice-cold water and then acidified
with concentrated HCl. The precipitate obtained was extracted with diethyl
ether (3 Â 5 mL) and the combined organic phase was dried over anhydrous
Na2SO4, filtered and evaporated. The residue was recrystallized from hot water
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