Organic Chemistry InternationalVolume 2011 (2011), Article ID 751894, 5 pagesdoi:10.1155/2011/751894

Research Article

Microwave-Assisted Solution Phase Synthesis of Novel 2-{4-[2-(N-Methyl-2-pyridylamino)ethoxy]phenyl}-5-Substituted 1,3,4-Oxadiazole  Library

Santosh L. Gaonkar,1,2 Izuru Nagashima,¹ and Hiroki Shimizu¹

¹Molecular and Biological Technology Research Group, Bioproduction Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Hokkaido, Sapporo 062-8517, Japan²Department of Chemistry, Manipal Institute of Technology, Karnataka, Manipal 576014, India

Received 16 October 2011; Accepted 1 December 2011

Academic Editor: Kirpal Bisht

Copyright © 2011 Santosh L. Gaonkar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

A new series of 2-{4-[2-(N-methyl-2-pyridylamino)ethoxy]phenyl}-5-substituted 1,3,4-oxadiazoles were synthesized by the oxidative cyclization of hydrazones derived from 4-[2-(methylpyridin-2-ylamino)ethoxy]benzaldehyde and aryl hydrazines using chloramine-T as an efficient catalyst. All steps were assisted by microwave irradiation. Microwave enables all these reactions to be simple, rapid, high yielding, and avoid chromatograph purification and led environmentally benign total synthesis of focused oxadiazole library. All the synthesized compounds were isolated in good yield and characterized by ¹H NMR, ¹³C NMR, and elemental analyses. The title compounds represent a novel class of biologically active heterocycles.

1. Introduction

1,3,4-Oxadiazoles are versatile lead compounds for designing potent bioactive agents. This interesting class of heterocyclic compounds shows broad spectrum of biological activities. Substituted 1,3,4-oxadiazoles have revealed antimicrobial [1], anti-inflammatory [2], antimycobacterial [3], analgesic [4], anticonvulsant [5], antihypoglycemic [6], and insecticidal properties [7]. Compounds possessing oxadiazole moieties show anticancer [8, 9] and tyrosinase inhibitory activities [10]. Oxadiazoles are used as fluorescent whiteners and also act as muscle relaxants [11].

Meanwhile, microwave-assisted organic synthesis is a rapidly growing field in organic chemistry [12–14]. In the early days, domestic microwaves were used with poor reproducibility. Moreover, accidents were common due to the lack of control. The introduction of dedicated equipment by CEM, milestone, biotage, plazmatronika, Anton Paar and domestic companies Shikoku Instrumentation, EYELA and so on allowing for the online monitoring of temperature, power and pressure had a large impact on the further development of this research field [15]. In particular, the pharmaceutical industry requires the production of a higher number of novel chemical entities, which requires chemists to employ a number of resources to reduce the time for the production of compounds. In general, most organic reactions have been heated using traditional heat transfer equipment such as oil baths, sand baths, and heating jackets. These heating techniques are, however, rather slow, and a temperature gradient can develop within the sample. In addition, local overheating can lead to product, substrate, and reagent decomposition. Microwave radiation provides an alternate to conventional heating as it utilizes the ability of liquids or solids to transform electromagnetic energy into heat.

In our previous studies, we have synthesized 2-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}-5-substituted 1,3,4-oxadiazoles which showed promising antimicrobial [1] as well as anticancer activities [8, 9]. Recently, we have reported microwave-assisted synthesis of the antihyperglycemic drug rosiglitazone [16]. In continuation to our work on the synthesis of biologically active heterocycles [17, 18], herewith, we are reporting as an efficient microwave-assisted synthesis of novel 2-{4-[2-(N-methyl-2-pyridylamino)ethoxy]phenyl}-5-substituted 1,3,4-oxadiazole library by using CEM Discover microwave synthesizer (Scheme 1).

Scheme 1: Synthesis of 2-[4-[2-N-methyl-2-pyridylamino)ethoxy]phenyl]-5-substituted 1,3,4-oxadiazole library.

2. Results and Discussions

All the reactions were carried out in CEM Discover microwave apparatus. Acid hydrazides 3 (a–t) were synthesized from corresponding acids by microwave irradiation for 20–50 min in the yield range 60–88%. Alcohol 6 was synthesized in 92% yield in 10 min at 140°C, which was converted to aldehyde 7 in 20 min at 100°C to yield 90%. Aldehyde 7 was converted to hydrazones 8 (a–t) in 20–30 min to yield 70–85%. Hydrazones 8 (a–t) were oxidatively cyclised under microwave irradiation in 20–50 min to gave title compounds 9 (a–t). Chloramine-T [19, 20] was used as an efficient reagent for the oxidative cyclization of aroyl hydrazones 8 (a–t) to give 1,3,4-oxadiazoles 9 (a–t) in good yield and purity, without column purification in any stage (Table 1). However, by conventional method, the reaction takes 6–10 h heating and results in impure product due to side reactions, which needs column purification or further crystallization, and yields are generally low. Though there are several reagents for cycloaddition, chloramine-T is found to be effective reagent since it is mild, easy to handle, commercially available, nontoxic, and water tolerant. All the synthesized 1,3,4-oxadiazoles were characterized by ¹H NMR ¹³C NMR and elemental analyses. ¹HNMR of all the synthesized oxadiazoles showed singlet in the region 3.0–3.4 due to –NCH₃ group, and two triplets in the region 3.9–4.2 and 4.1–4.4 are due to two methylene groups. The aromatic protons and other protons are observed in the expected region. ¹³CNMR of all the synthesized oxadiazoles showed peaks in the expected region.

Table 1

Entry
Oxadiazole
Structure
Yield (%)
Melting point (°C)

1
9a

78
161-162

2
9b

76
122–124

3
9c

74
139-140

4
9d

79
142–144

5
9e

72
151–153

6
9f

70
118–120

7
9g

80
158-159

8
9h

81
152-153

9
9i

80
124-125

10
9j

78
158–160

11
9k

69
oily

12
9l

81
159–161

13
9m

73
182–184

14
9n

78
156–158

15
9o

70
oily

16
9p

74
143–145

17
9q

81
129–132

18
9r

79
100-101

19
9s

80
109–111

20
9t

77
155–158

3. Conclusion

In conclusion, we have developed an efficient microwave-assisted method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles. Chloramine-T was used as an efficient catalyst for cycloaddition under microwave irradiation. The method is quicker, high yielding, environment friendly, and cleaner chemistries. The isolated products are very pure and do not need any column purification. The method is very useful for combinatorial synthesis new libraries in drug discovery. The full paper and biological evaluation will be published elsewhere in future.

3.1. General Procedure for the Synthesis of Aroyl Hydrazines 3 (a–t)

A solution of respective aromatic acid 1 (a–t) (0.5 g), ethanol (2 mL), and catalytic amount of conc. H₂SO₄ were inserted into CEM Discover microwave vessel, sealed and irradiated microwave at 100°C for 10–20 min. After the completion of the reaction by TLC (chloroform-ethyl acetate: 1 : 1), ethanol was removed and the product was extracted with dichloromethane, washed with dil. NaHCO₃ water and dried. Solvent was evaporated and the residue was dissolved in ethanol (2 mL), and 98% hydrazine hydrate (0.5 mL) was added. The mixture was irradiated at 120°C for 20–30 min. After the completion of the reaction by TLC (toluene/ethyl acetate/DEA, 7.5 : 2.5 : 1), the reaction mixture was cooled, and the solid formed was filtered and washed with chilled ethanol (1 mL) to get corresponding aroyl hydrazine 3 (a–t).

3.2. 2-(Methyl-pyridin-2-ylamino)ethanol 6

A mixture of 2-chloropyridine 4 (1.00 g, 8.81 mmol) and 2-(N-methylamino)ethanol 5 (1.33 g, 17.7 mmol) were introduced into a CEM discover vessel equipped with a magnetic stirrer. The vessel was sealed, and the reaction mixture was irradiated microwave (300 W) for 10 min at 140°C twice successively. The completion of the reaction was monitored by TLC (Toluene-ethyl acetate, 1 : 1). The reaction mass was cooled at room temperature, diluted with 2 mL water, and extracted into 10 mL ethyl acetate twice. The combined ethyl acetate layer was washed with water, saturated brine, dried over anhy. Na₂SO₄ and concentrated in vacuo to give 6 (1.23 g, 92%) as a pale yellow oil.

¹H NMR (CDCl₃): 3.05 (3H, s, NCH₃), 3.70 (2H, t, = 5.2 Hz, CH₂CH₂), 3.84 (2H, t, = 5.2 Hz, CH₂CH₂), 5.29 (1H, bs, OH, exchanges with D₂O), 6.52–6.58 (2H, m, ArH), 7.44–7.49 (1H, m, ArH), 8.39 (1H, d, = 4.2 Hz, ArH); ¹³C NMR (CDCl₃): 37.6, 49.7, 66.4, 111.5, 114.8, 137.4, 147.8, 158.2; IR (KBr pellet, cm⁻¹): 3069, 2961,1764, 1667, 1485; Anal. Calcd for C₈H₁₂N₂O: C, 63.13, H, 7.95, N, 18.41%. Found: C, 63.20, H, 7.85, N, 18.33%.

3.3. 4-[2-(Methyl-pyridin-2-ylamino)ethoxy]benzaldehyde 7

A mixture of 9 (1.00 g, 6.66 mmol), 4-fluorobenzaldehyde (827 mg, 6.61 mmol), KOH powder (1.10 g, 19.6 mmol), and tetrabutylammonium hydrogen sulphate (TBAHS) (220 mg, 0.650 mmol) in water (1 mL) and toluene (3 mL) was introduced into a CEM Discover microwave vessel equipped with a magnetic stirrer. The vessel was sealed, and the mixture was irradiated by microwave for 20 min at 85–100°C. The completion of the reaction was monitored by TLC (Toluene-Ethylacetate, 1 : 1). The reaction mass was cooled and diluted with 5 mL water and extracted into 25 mL toluene twice. The combined toluene layer was washed with water, dried over anhy. Na₂SO₄, and concentrated under vacuo to give aldehyde 7 (1.53 g, 90%) as a pale yellow oil.

¹H NMR (CDCl₃): 3.05 (3H, s, 3H, NCH₃), 4.01 (2H, t, = 5.6 Hz, CH₂CH₂), 4.27 (2H, t, = 5.6 Hz, CH₂CH₂), 6.52–6.58 (2H, m, ArH), 6.99 (2H, d, = 8.6 Hz, ArH), 7.45 (1H, m, ArH), 7.80 (2H, d, = 8.6 Hz, ArH), 8.15 (1H, d, = 4.0 Hz, ArH), 9.83 (1H, s, CHO,); ¹³C NMR (CDCl₃): 37.3, 48.6, 66.0, 105.1, 111.3, 114.1, 129.2, 131.3, 136.5, 147.0, 157.3, 163.0, 190.1; Anal. Calcd for C₈H₁₂N₂O: C, 63.13, H, 7.95, N, 18.41%. Found: C, 63.20, H, 7.85, N, 18.33%.

3.4. General Procedure for the Synthesis of Aroyl Hydrazones 8 (a–t)

An equimolar mixture of aroyl hydrazine 3 (a–t) and 4-[2-(methyl-pyridin-2-ylamino)ethoxy]benzaldehyde 7 in isopropyl alcohol (4 mL) were inserted into CEM microwave vessel and irradiated for 20–50 min at 100°C. The progress of the reaction was monitored by TLC (Chloroform-ethyl acetate, 1 : 1). After the completion of the reaction, the mass was cooled and the solid formed was filtered to give aroyl hydrazones 8 (a–t) to yield 70–90%, which were directly used for next stage.

3.5. General Procedure for the Synthesis of 2-{4-[2-(N-Methyl-2-pyridylamino)ethoxy]phenyl}-5-Substituted 1,3,4-Oxadiazoles Typical Procedure 9g

A mixture of aroyl hydrazone 8g (0.102 g, 0.25 mmol) and Chloramine-T. 3H₂O (0.82 g, 0.29 mmol) in ethanol (1 mL) were introduced into CEM vessel and irradiated at 80–100°C for 20 min. The progress of the reaction was monitored by TLC. After the completion of the reaction, ethanol was removed, and residue was extracted with chloroform, washed with water, and dried. Chloroform was removed, and the residue was crystallized from ethanol to give 9g as white solid (0.081 g, 80%), mp. 158-159°C. ¹H NMR (CDCl₃, 400 MHz): 3.16 (s, 3H, NCH₃), 4.03 (2H, t, = 5.5 Hz, CH₂CH₂), 4.28 (2H, t, = 5.5 Hz, CH₂CH₂), 6.52–6.59 (2H, m, ArH), 7.03 (2H, d, = 8.6 Hz, ArH), 7.45–7.51 (3H, m, ArH), 8.02–8.07 (4H, m, ArH), 8.17 (1H, d, = 4.8 Hz, ArH). ¹³C NMR (CDCl₃, 100 MHz): 37.9, 49.4, 66.6, 105.7, 111.9, 115.0 (2C), 116.2, 122.58, 128.0 (2C), 128.7 (2C), 129.4 (2C), 137.3, 137.7, 147.9, 158.2, 161.8, 163.3, 164.7.

Acknowledgments

The authors thank the JSPS (Japan Society for the Promotion of Science) for Postdoctoral Fellowships for Foreign Researchers (Standard) to SLG. This research was supported by JSPS KAKENHI (20.08620), Grant-in-Aid for JSPS Fellows.

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