Tetrahedron Letters 52 (2011) 2419–2422

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Tetrahedron Letters

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Ionic liquid/potassium hydroxide catalyzed solvent-free, one-pot synthesis ofdiarylglycolic 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

Article history:Received 12 January 2011Revised 2 March 2011Accepted 4 March 2011Available online 23 March 2011

Keywords:MicrowaveOne-pot synthesisIonic liquida,a-Diarylglycolic acidGreen approach

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.03.020

⇑ Corresponding author. Tel.: +91 542 6702485; faxE-mail addresses: knsingh@bhu.ac.in, knsinghbhu@

a b s t r a c t

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.

� 2011 Elsevier Ltd. All rights reserved.

CHO

C

COOH

OH

2

[Bmim]BF4 / KOH

RRR

MW (180W), [Bmim]BF4 / KOH

60°C, 20-25 min

70°C, 3-4 h

1a-j2a-j

(73-81%)

R = H, CH3, OCH3, Cl, Br, NO2

a-Hydroxycarboxylic acids are an important class of com-pounds, which are applied to cure some skin diseases (such as acneand ichthyosis),1–3 or used as intermediates in the production ofsome nonsteroidal anti-inflammatory drugs.4,5 Many substitutedbenzilic acids and their esters are known for their analgesic andphysiological activities and have accordingly, been subjected to de-tailed pharmacological studies particularly in the preparation ofantidepressants, anticholinergics, antispasmodic drug and bron-chodilators.6–8

Microwave (MW) provides a powerful way to do syntheticchemistry in the light of current paradigm shift to ‘Green Chemis-try’. It provides many chemical reactions with attributes such asenhanced reaction rates, higher yields of pure products, betterselectivity, improved ease of manipulation, rapid optimization ofreactions and several eco-friendly advantages.9 Ionic liquids havebeen recognized as versatile and novel reaction catalysts fororganic transformations, and have also found application asflexible ‘platforms’ to establish highly effective and easilyseparable systems.10 Room temperature ionic liquids, especiallythose based on the 1,3-dialkylimidazolium cation, have attractedconsiderable 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 nonconventionalheating source has shown evident advantages when compared toconventional synthetic procedures for the generation of fast,

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efficient, and environmental friendly synthetic methodologies.Thus, development of ionic liquid mediated organic transformationusing microwave heating is gaining prominence.12

Preparation of benzilic acid from benzaldehyde is accomplishedby a three-step approach involving conversion of benzaldehyde tobenzoin, oxidation of benzoin to benzil, and finally benzilic acidrearrangement of benzil to afford the desired product. A multi-stepsynthesis of benzilic acid/ester from p-bromotoluene has also beeninvestigated 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/

(57-68%)

Scheme 1. [Bmim]BF4/KOH catalyzed solvent-free synthesis of a,a-diarylglycolicacids.

Table 1Optimization of reaction conditions using compound 1a as reference

Entry Ionic liquids (mol %) Base (mmol) Reaction conditions

Conventional Microwave

Temp (�C) Time (h) Yield (%) Power (W) Temp (�C) Time (min) Yield (%)

1 — KOH 80 10 Nil 220 100 30 Nil2 [Bmim]BF4 (10) — 80 10 Nil 220 100 30 Nil3 [Bmim]BF4 (20) — 100 10 Nil 220 100 30 Nil4 [Bmim]BF4 (20) Basic alumina 80 6 20 120 60 30 355 [Bmim]BF4 (20) Basic alumina 100 6 20 180 60 30 406 [Bmim]BF4 (20) KOH (1.0) 70 4 57 180 60 25 747 [Bmim]PF6 (20) KOH (1.0) 70 4 45 180 60 30 588 [Bmim]BF4 (10) KOH (1.0) 60 5 46 180 60 30 519 [Bmim]BF4 (20) KOH (0.5) 60 5 48 180 60 30 52

10 [Bmim]BF4 (25) KOH (1.0) 70 4 56 180 60 25 7311 [Bmim]BF4 (20) KOH (1.5) 70 4 57 180 60 25 7412 [Bmim]BF4 (20) KOH (1.0) 60 5 53 120 60 30 6313 [Bmim]BF4 (20) KOH (1.0) 65 4 55 120 80 30 6414 [Bmim]BF4 (20) KOH (1.0) — — — 140 60 30 6615 [Bmim]BF4 (20) KOH (1.0) — — — 200 60 25 7316 [Bmim]BF4 (20) KOH (1.0) — — — 180 70 25 71

Table 2[Bmim]BF4/OH� catalyzed one-pot, solvent-free synthesis of a,a-diarylglycolic acids

Entry Aldehyde Product Conventional Microwavea

Time (h) Yieldb (%) Time (min) Yieldb (%)

1

CHO

1a C

COOH

2a OH

4 57 25 74

2

CHOH3C

1b C

OH

COOH

H3C CH3

2b

3.5 62 25 78

3

CHOH3CO

1c C

OH

COOH

H3CO OCH3

2c

3.5 62 25 76

4

CHOCl

1d C

OH

COOH

Cl Cl

2d

3 65 20 80

5

CHOBr

1e C

OH

COOH

Br Br

2e

3 64 20 78

6

CHOO2N

1f C

OH

COOH

O2N NO2

2f

3 68 20 81

7CHO

Cl

1g

C

OH

COOHCl

Cl2g

4 62 25 77

2420 N. Singh et al. / Tetrahedron Letters 52 (2011) 2419–2422

Table 2 (continued)

Entry Aldehyde Product Conventional Microwavea

Time (h) Yieldb (%) Time (min) Yieldb (%)

8CHO

Br

1h C

OH

COOHBr

2h Br

4 61 5 75

9CHO

CH3

1i COH

COOHCH3

H3C2i

3.5 61 25 76

10CHO

OCH3

1j COH

COOHOCH3

H3CO2j

3.5 60 25 73

a Microwave heating performed on 180 W at 60 �C using aromatic aldehydes (1 mmol), [Bmim]BF4 (20 mol %) and KOH (1 mmol).b Isolated yield.

N. Singh et al. / Tetrahedron Letters 52 (2011) 2419–2422 2421

Et3N,23 and alumina.24 The rearrangement of benzil to benzilic acidhas been effected by base.25 Scanning of literature reveals thatthere exists no report on one-pot direct conversion of aromaticaldehydes 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 asan 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, simpleand efficient procedure for the rapid construction of diarylglycolicacids from aromatic aldehydes in solvent-free conditions in rea-sonably good yields under conventional heating (57–68%) as wellas under controlled microwave irradiation (73–81%) (Scheme 1).

To screen the experimental conditions, a typical reaction ofbenzaldehyde (1a, 1 mmol) was carried out both by conventionalas 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 whenthe reaction is carried out in the presence of ionic liquid or basealone (Table 1, entries 1–3). However, a combination of differentionic liquids and base gives rise to variable yields of the desiredproduct (entries 4–7), the best being achieved with [Bmim]BF4

and KOH combination (entry 6). It was imperative to observe theeffect 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 yieldfurther (Table 1, entries 10 and 11). Compared to optimum MWpower and temperature (180 W at 60 �C), further change in MWpower and temperature did not improve the product yield (entries12–16). Thus, the use of [Bmim]BF4 (20 mol %) and KOH (1 mmol)combination was concluded to afford the optimum yield of theproduct (74%) in short reaction time under controlled MW irradia-tion (180 W, 60 �C) (Table 1, entry 6).

Under the optimized set of reaction conditions, a number ofaromatic aldehydes 1a–j were readily transformed to diarylglycolicacids 2a–j under solvent-free conditions by conventional heating(70 �C) as well as by microwave (180 W, 60 �C) irradiation.27,28

The results are given in Table 2, which works well for electron-richas well as for electron-deficient aromatic aldehydes. The reaction is

assumed to proceed via benzoin and its subsequent oxidation tobenzil, whose intermediacy was proved by their presence duringthe course of reaction. With the progress of the reaction, theappearance and disappearance of both benzoin and benzil werenoticed on the TLC.

Potassium hydroxide was chosen as the base so as to removethe C-2 hydrogen of imidazolium to form the catalyst imidazoli-um-2-ylide.15d All the products were fully characterized based ontheir melting points, elemental analyses and spectral data (IR, 1HNMR, 13C NMR).

In conclusion, we have developed a facile and efficient one-potmethodology 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 thisapproach more attractive in synthesizing a variety of suchderivatives.

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 bottomflask and heated at 70 �C with stirring for 3–4 h under aerobic conditions tillthe completion of the reaction (TLC). The reaction mixture was cooled to roomtemperature and poured into ice-cold water. The mixture was then acidifiedwith concentrated HCl and the precipitate obtained was extracted with diethylether (3 � 5 mL). The combined organic phase was dried over anhydrousNa2SO4, filtered, evaporated and recrystallized from hot water to give the pureproduct 2a–j.

28. General MW procedure: A mixture of [Bmim]BF4 (20 mol %), KOH (1 mmol), andaromatic aldehyde (1 mmol) was placed in a sealed pressure regulation 10 mLpressurized vial with ‘snap-on’ cap under aerobic conditions and wasirradiated in the single-mode microwave synthesis system at 180 W at 60 �Cfor 20–25 min. After completion of reaction (TLC), the reaction mixture wascooled to room temperature, poured into ice-cold water and then acidifiedwith concentrated HCl. The precipitate obtained was extracted with diethylether (3 � 5 mL) and the combined organic phase was dried over anhydrousNa2SO4, filtered and evaporated. The residue was recrystallized from hot waterto afford the pure product 2a–j.