Ultrasound promoted green synthesis of benzofuran substituted thiazolo[3,2-b][1,2,4]triazoles

1 Introduction

Benzofuran compounds are pervasive in nature mainly among the plant kingdom [1]. The naturally occurring compounds with a benzofuran moiety are generally endowed with various physiological and pharmacological properties such as being anticonvulsant [2], antiallergic [3], in vitro anti HIV [4], antitumor [5], antiinflammatory [6], antimicrobial [7] and are also used in cosmetics [8] and building blocks of optical brighteners [9]. Recently, 1,2,4triazole derivatives have also occupied a distinctive place in the field of medicinal and pharmaceutical chemistry [10], [11] as well as in industry [12]. These compounds exhibit significant properties like being antiviral [13], antifungal, antimicrobial [14], analgesic, diuretic [15], antineoplastic and antiproliferative [16], [17], [18], [19], [20], [21], [22], [23]. Previously, these compounds were synthesized involving the reaction of 2-(2-bromoacetyl benzofurans) with 5-mercapto-1,2,4triazole, but the results were not encouraging due to a longer reaction time, poor yield and also the use of hazardous chemicals [24]. Molecular bromine used for the preparation of bromo acetyl derivatives also causes serious health problems like skin disorder [25], disruption of thyroid function [26], slow neural [27] and cognitive development and DNA damage [28], [29]. It aggressively reacts with metal as it is a corrosive material and causes severe damage to our environment [30]. Keeping this in view, the synthesis of the titled compounds was taken up.

Chemists are always under pressure to develop environmentally benign procedures which avoid the use of hazardous chemicals, mainly organic solvents. In continuation of our work on development of greener and efficient routes for the synthesis of heterocyclic compounds [31], [32], we wish to report our efforts towards the synthesis of the title compounds using ultrasound and microwave irradiation, which involve, the reaction of 2-acetyl benzofuran with 3-aryl-5-mercapto-1,2,4triazole directly in the presence of molecular iodine, avoiding bromination of 2-acetyl benzofuran without using hazardous chemicals.

Simple experimental procedure, high yield, improved selectivity, shorter reaction time and avoiding use of hazardous chemicals are the main advantages of ultrasonic (US) [33] and microwave (MW) [34] based synthesis. The effect of ultrasound observed during the organic synthesis is due to the cavitation process which creates enlarged vapour cavities in irradiated liquid. Cavitation induces very high local temperature and pressure inside the cavities, leading to turbulent flow of liquid and enhanced mass transfer [35], [36], [37], [38].

2 Materials and methods

Melting points were determined in open capillary tubes and were uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR spectrophotometer (USA). NMR spectra were recorded on a Bruker Avance (Germany) (400 MHz) instrument using tetramethyl silane (TMS) as an internal standard. Sonication was performed using an Oscar make probe sonicator (Maharashtra, India) of 20 kHz and Labsoul make ultrasonic bath (Labsoul India, Ambala, India) of 40 kHz when combined ultrasound experiments were performed and the probe was immersed in the tube which was placed in ultrasonic bath. The reaction were carried out in a Samsung microwave oven (Samsung India, New Delhi) (operating between 100 W and 750 W, Model no. G273V). All the solvents were distilled and dried according to literature procedure. All the chemicals were purchased from Merck (Mumbai, India). Etions reagent was received from Sigma-Aldrich Chemicals (New Delhi, India).

3 Results and discussion

The synthesis of 5-(benzofuran-2-yl)-acylthio-3-(4-chlorophenyl)-1,2,4triazole was achieved by the reaction of 2-acetyl benzofuran [39] and 5-mercapto-3-(4-chlorophenyl)-1,2,4triazole [40] and iodine in equimolar mixture of C₂H₅OH-H₂O (1:1) under dual frequency ultrasonication. The mixture was irradiated with dual frequency ultrasound using a bath cleaner (40 kHz) and a probe (20 kHz) for 45 min. The progress of the reaction was checked by TLC. The formation of the above mentioned compound was evidenced by comparison of the melting point 229–231°C with literature melting point (230–231°C) [24], appearance of a singlet at δ 4.75 due to CH₂ proton, a doublet at δ 7.42 due to two aromatic C_3″-H and C_5″-H and multiplet at δ 7.53–7.80 for six protons C_3′-H, C_4′-H, C_5′-H, C_6′-H, C_7′-H and N₄-H, and a doublet at δ 7.95 due to two aromatic protons (C₂^″-H and C_6″-H ) in its ¹H NMR, and in IR it showed absorption at 3485 cm⁻¹, 1670 cm⁻¹, 1612 cm⁻¹, 1560 cm⁻¹, 735 cm⁻¹ which were assigned to -NH, -C=O, -C=C, -C=N, -C-S stretching, respectively. Based upon this data, it was revealed that the compound obtained was 5-(benzofuran-2-yl)-acylthio-3-(4-chlorophenyl)-1,2,4triazole. Using the above conditions, various 3-aryl-5-benzofuran-2-yl-acylthio-1,2,4triozoles were prepared (IIIa–IIIh, Scheme 1, Table 1) in very high yield (82–87%).

Scheme 1:

Synthesis of 5-(benzofuran-2-yl) acylthio-3-(4-chlorophenyl)1,2,4triazoles (IIIa–IIIh).

Cavitation is the origin of sonochemistry. When ultrasound passes through a liquid it produces bubbles; these bubbles can undergo a violent collapse which generates very high temperature and pressure, which leads to fragmentation of molecule and produces short lived and highly reactive species locally. These short lived reactive chemical species are returned to bulk liquid at room temperature, thus reacting with other species. High yield may be due to multi frequency sonication which increases the reaction rate and yield of product. Multi frequency irradiation can disturb and break the surface continuity of a solution in a stronger way as compared to single frequency ultrasound, which results in enhancement of mass transfer and cavitation in solution.

Further, 5-(benzofuran-2-yl)-acylthio-3-(4-chlorophenyl)-1,2,4triazole was then cyclized using Eaton’s reagent under microwave irradiation and the reaction was found to be completed in 90 s. After working up the compound thus obtained has an m. pt of 214–215°C (literature m. pt. 215–216°C) [24] and in its IR, it showed absorption at 1602 cm⁻¹, 1506 cm⁻¹, 1470 cm⁻¹and 1170 cm⁻¹, 724 cm⁻¹ which were assigned to -NH, -C=O, -C=N, -C-S stretching. In its ¹H NMR, it exhibited a multiplet at δ 7.10–7.35 due to four protons (C_4′-H, C_5′-H, C_6′-H, C_7′-H), a doublet at δ 7.40 due to two aromatic protons (C_3″-H and C_5″-H), two singlets for one proton each at δ 7.44 and δ 7.80 due to C_3′-H, C_6′-H protons and a doublet at δ 8.15 due to two aromatic protons (C_2″-H and C_6″-H). Based upon the data obtained, it was revealed that the compound formed was 5-(benzofuran-2-yl)-2-(4-chlorophenyl)thiazolo[3,2-b][1,2,4]triazole (Scheme 2, Table 2).

Scheme 2:

Synthesis of 5-(benzofuran-2-yl)-2-(4-chlorophenyl)thiazolo[3,2-b][ 1,2,4]triazoles (IVa–IVh).

4 Conclusions

In summary, we developed a one pot, mild and highly efficient procedure for the synthesis of benzofuran substituted thiazolo[3,2-b][1,2,4]triazoles avoiding the use of toxic solvent. The synergistic effect of the combination of 40 kHz US bath and 20 kHz US probe reduces the reaction time and improves the yield. Our sonochemical method has several advantages over the existing method including improved yield, cleaner reaction, simple work up and short reaction time, which makes it an efficient and environmentally benign strategy for the synthesis of benzofuran substituted thiazolo[3,2-b][1,2,4]triazoles.