Microwave-assisted synthesis of a-hydroxy aromatic ketones

from a-bromo aromatic ketones in water

Xiang Liu a,*, Hai Bo Chen a, Zheng Guang Pan a, Jian He Xu b, He Xing Li c

a School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Chinab State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China

c Department of Chemistry, Shanghai Normal University, Shanghai 200234, China

Received 14 May 2010

Abstract

A reaction of a-bromo aromatic ketones in water with microwave irradiation gave the corresponding a-hydroxy aromatic

ketones in good yields. The use of microwaves was found to significantly improve yields and shorten the reaction time. This reaction

afforded a very clean, convenient method for the synthesis of a-hydroxy aromatic ketones.

# 2010 Xiang Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: a-Hydroxy aromatic ketones; a-Bromo aromatic ketones; Microwave irradiation

Over the past 20 years, the application of microwave irradiation towards the acceleration of a wide range of organic

and inorganic reactions, has received considerable attention [1]. The main benefit of performing reactions under

microwave (MW) irradiation condition is the significant rate-enhancements, cleaner reaction profiles, inexpensive

reagents, simple product isolation procedures, and the higher yields that can frequently be observed.

In the synthesis of various natural products and pharmacologically active compounds, a-hydroxyketones are

potentially valuable synthetic intermediates for the preparation of a range of compounds of biological products [2].

General synthetic methods for their preparation include transformation of a-haloketones to a-hydroxyketones using

cesium formate [3], oxidative synthesis of ketones catalyzed by a palladium (II) complex [4] or with certain other

oxidizing agents [5], synthesis of a-hydroxyketones from terpene aldehydes by TMSCN and the Grignard reagent [6].

Most of the synthetic methodology could not provide satisfactory reaction conditions due to the expensive and

dangerous reagents needed. As a result, development of the direct and non-toxic methods is considered

enthusiastically for the synthesis of a-hydroxyketones.

Not surprisingly, synthesis of a-hydroxyketones could be carried out by using microwave irradiation instead of

conventional heating methods. We tried the nucleophilic substitution reaction of a-bromo aromatic ketones with water

under microwave irradiation condition without any catalysts or additives and obtained the corresponding a-hydroxy

aromatic ketones. This reaction afforded a direct, one-pot, clean and convenient synthetic method for a-hydroxy

aromatic ketones (Scheme 1).

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Chinese Chemical Letters 22 (2011) 53–56

* Corresponding author.

E-mail address: liuxiang@jiangnan.edu.cn (X. Liu).

1001-8417/$ – see front matter # 2010 Xiang Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2010.07.027

A sealed Teflon vessel was employed for microwave-assisted synthesis of a-hydroxy aromatic ketones. The effects

of some factors, including microwave irradiation time, pressure, and substrate concentration, on the yields of a-

hydroxy aromatic ketones was examined and the results were showed in Table 1.

The effect of microwave irradiation time (15, 20, 25, 30 and 35 min) on yields was investigated and the results were

showed in Table 1 (the third column). The results indicated that the yields of a-hydroxy aromatic ketones gradually

increased with the increase of the microwave irradiation time and reached the maximum value at a definite moment

(25 min for 1b, for example). But after that the yields began to go down, and the color of products evidently became

more yellow. The reason for this may be assumed that some adverse reactions happened because of the excessive

irradiation time.

The effect of pressure (0.25, 0.28, 0.30, 0.33 and 0.35 MPa) on yields was also investigated and the results were

summarized in Table 1 (the fourth column). The results demonstrated that the yields of a-hydroxy aromatic ketones

rose when the pressure increased. The 0.28–0.33 MPa pressure was suitable for microwave-assisted synthesis of a-

hydroxy aromatic ketones because the reaction temperature in this pressure range could provide enough internal heat-

transfer. When the pressure exceeded the 0.33 MPa, the lower yields were received because the reverse reaction would

arise with increase of the pressure (temperature).

X. Liu et al. / Chinese Chemical Letters 22 (2011) 53–5654[()TD$FIG]

Scheme 1.

Table 1

The effects of some factors, including irradiation time, pressure, substrate concentration, on yields.

Entry Substrate Irradiation time (min)a/Yield (%)d Pressure (MPa)b/Yield (%)d Substrate concentration (g/L)c/Yield (%)d

1 1a 15/58 0.25/46 8/68

2 1a 20/68 0.28/60 10/72

3 1a 25/75 0.30/75 12/75

4 1a 30/80 0.33/82 14/68

5 1a 35/70 0.35/70 16/66

6 1b 15/73 0.25/68 8/80

7 1b 20/82 0.28/78 10/85

8 1b 25/88 0.30/88 12/88

9 1b 30/85 0.33/80 14/78

10 1b 35/80 0.35/72 16/65

11 1c 15/62 0.25/50 8/70

12 1c 20/70 0.28/65 10/75

13 1c 25/77 0.30/77 12/77

14 1c 30/72 0.33/70 14/68

15 1c 35/65 0.35/62 16/55

16 1d 15/70 0.25/60 8/70

17 1d 20/80 0.28/75 10/80

18 1d 25/87 0.30/87 12/87

19 1d 30/78 0.33/82 14/72

20 1d 35/65 0.35/75 16/60

21 1e 15/82 0.25/68 8/78

22 1e 20/88 0.28/75 10/80

23 1e 25/82 0.30/82 12/82

24 1e 30/75 0.33/80 14/72

25 1e 35/68 0.35/73 16/60

a Irradiation time was variable, while pressure and substrate concentration were 0.30 Mpa and 12 g/L, respectively.b Pressure was variable, while irradiation time and substrate concentration were 25 min and 12 g/L, respectively.c Substrate concentration was variable, while irradiation time and pressure were 25 min and 0.30 MPa, respectively.d The yields were provided by the column separation.

In this experiment, the effect of substrate concentration (8, 10, 12, 14 and 16 g/L) on yields was also examined and

the results were displayed in Table 1 (the fifth column). The results of Table 1 revealed that the yields reached the peak

value at 12 g/L substrate concentration. When the substrate concentration exceeded 12 g/L, the lower yields were

obtained because the substrates were not completely scattered in water and could not absorbed microwave energy

effectively. Since water could absorb the microwave energy and provide enough internal heat-transfer to accelerate the

reactions within a certain range [7], it is necessary that microwave energy was absorbed more effectively by solvents

such as water. In factor, the water acted as both reactant and reaction solvent in this experiment, which would

contribute to green chemistry.

In conclusion, we have developed a very clean, convenient method for the synthesis of a-hydroxy aromatic ketones

by using microwave-assisted synthesis. Although any catalysts or additives were not involved in reaction, the 75–88%

yields of a-hydroxy aromatic ketones were achieved under suitable conditions of microwave irradiation. Of particular

importance is the one-pot synthesis of a-hydroxyketones, which is more convenient than the method used heretofore.

The use of microwaves was found to not only improve yields but also shorten the reaction time, as opposed to

traditional heating methods.

1. Experimental

All the chemicals and solvents used are of analytical grade obtained from commercial suppliers. All melting points

were measured on a SPSIC WRS-1B melting apparatus and were uncorrected. IR spectra were recorded on a Boman

FTLA2000 IR spectrometer. 1H NMR spectra were recorded on a 400 MHz Varian Unityinova 400 NMR

spectrometer.

A mixture of 1b (0.60 g) and water (50 mL) was taken in a sealed Teflon vessel and was irradiated with

microwave for 25 min at 0.30 MPa in an HWL08-A experimental microwave oven which equipped with pressure

monitoring device. After the irradiation was completed, the mixture was extracted with ethyl acetate (2 � 45 mL).

The ester solution was washed with a saturated aq NaCl (2 � 45 mL). The ester solution was dried over Mg2SO4

and concentrated in a vacuum. The resulting oil was chromatographed on silica gel column (hexane–

EtOAc = 3:1). White column-shaped crystals of 2b (0.53 g, 88% yield) were obtained and characterized by IR and1H NMR [8].

Acknowledgments

This research was financially supported by the National Special Fund for State Key Laboratory of Bioreactor

Engineering (No. 2060204) and the National Natural Science Foundation of China (No. 20672037).

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[8] 2a: white column-shaped, mp 88.1–88.9 8C; IR (KBr, cm�1) n: 3427, 1684; 1H NMR (400 MHz, CDCl3): d 7.94–7.92 (d, 2H), 7.66–7.63(t, 1H),

7.54–7.50 (t, 2H), 4.90 (s, 2H), 3.55–3.53 (t, OH). 2b: white column-shaped, mp 98.1–98.5 8C; IR (KBr, cm�1) n: 3397, 1682; 1H NMR

(400 MHz, CDCl3): d 7.92 (s, 1H), 7.81–7.80 (d, 1H), 7.63–7.61 (d, 1H), 7.49–7.45 (t, 1H), 4.88–4.87 (d, 2H), 3.44 (s, OH). 2c: white needle-

X. Liu et al. / Chinese Chemical Letters 22 (2011) 53–56 55

shaped, mp 122.2–122.4 8C; IR (KBr, cm�1) n: 3425, 1681; 1H NMR (400 MHz, CDCl3): d 7.87–7.85 (d, 2H), 7.49–7.46 (d, 2H), 4.86–4.85 (d,

J = 4.0 Hz, 2H), 3.51–3.49 (t, J = 4.0 Hz, OH). 2d: white column-shaped, mp 88.1–88.5 8C; IR (KBr, cm�1) n: 3430, 1687; 1H NMR (400 MHz,

CDCl3): d 7.83–7.81 (d, 2H), 7.31–7.29 (d, 2H), 4.85–4.84 (d, J = 4.0 Hz, 2H), 3.53–3.51 (t, J = 4.0 Hz, 1H), 2.43 (s, 3H). 2e: white column-

shaped, mp 104.4–104.7 8C; IR (KBr, cm�1) n: 3419, 1681; 1H NMR (400 MHz, CDCl3): d 7.92–7.90 (d, 2H), 6.99–6.97 (d, 2H), 4.84 (s, 2H),

3.90 (s, 3H), 3.61 (s, 1H).

X. Liu et al. / Chinese Chemical Letters 22 (2011) 53–5656