Keywords

Natural catalyst, Aryl aldehydes, Benzothiazole, Benzoxazole

Introduction

The traditional reaction conditions increases the environmental pollution posed by utility of toxic, volatile organic solvents. Thus these organic processes generate lot of waste and have rigorous impact on living systems. Hence cleaner green reaction conditions with environmentally acceptable and renewable raw materials which offer environmental and economic advantages over traditional synthetic processes are necessary.

Uses of natural catalyst, environmentally benign solvent under mild reaction condition are the fundamental aspects of green chemistry. Natural catalysts represent a unique class of biocatalysts which are eco-friendly, inexpensive, nonhazardous; biodegradable has large number of application in the organic transformations [1-5].

Benzazoles such as benzathiazole, benzoxazole are privileged structural motifs having potential applications in the pharmacological and biological activities in medicinal chemistry [6-10]. Benzothiazoles are biologically active compounds which is used as valuable intermediates in various organic syntheses [11] and found in variety of natural products showing diverse medicinal applications [12-17]. Further, benzoxazoles exhibits photophysical and photochemical properties and shows chromophoric effect by enhancing the emission quantum yield through decrease in the non-radioactive decay rate constant on the fluorescence of conjugated compound [18]. Some of the typical reported methods for the synthesis of benzothiazoles and benzoxazoles include the reaction of 2-aminothiophenol or 2-aminophenol with variety of aryl aldehydes [19-30]. However, present methods exhibits certain drawbacks such as tedious catalyst preparation, expensive reagents, prolonged reaction times, use of toxic solvent, lower yields, and complicated workup procedures. Therefore, synthesis of benzazole derivatives using natural catalyst, eco-benign solvent under mild reaction condition is highly desirable. Herein, we chose water as a reaction media for condensation of 2-aminothiophenol or 2-aminophenol with variety of aryl aldehydes using natural catalyst, because water is considerably safe, eco-friendly, non-toxic, and inexpensive compared to other organic solvents.

Citrus limonium, Citrus aurantium, and Citrus indica are important species of the citrus family, locally known as Limbu or Nimbu in India. The juice obtained from lemon is sour in taste used to control the high blood pressure, arthritis and rheumatism, asthma and to prevent kidney stone it is also well known plant species for antioxidant activity as well as for anti-carcinogenic activity. Acidity caused due to presence of citric and ascorbic acids (vitamin C) to lemon juice are responsible to works as an acid catalyst in organic transformation.

In continuation our research work for the development of sustainable methodologies for the synthesis of bio-active heterocyclic scaffolds [31-32], herein we report the synthesis of benzothiazoles and benzoxazoles by employing lemon juice as a natural, bio-degradable catalyst under mild reaction condition.

Materials and Methods

All chemicals were purchased from local sources (Spectrochem and Thomas Bakers) and were of used without further purification. All reactions were carried out under air atmosphere in dried glassware. Melting points were measured by an open capillary method under open atmosphere. The products were in good agreements with those of known compounds by their spectral data. The FT-IR spectra were measured on Bruker ALPHA FT-IR spectrometer. The NMR spectra were recorded on a Bruker AC (400 MHz for ¹H NMR and 100 MHz for ¹³C NMR) spectrometer using CDCl₃ as the solvent and TMS as an internal standard. The δ -values are expressed in parts per million (ppm).

Preparation of lemon juice

Fresh lemon was purchased from the local market. The pieces were made using a knife and pressed in a fruit juicer to obtain the juice. Then the juice was filtered through filter paper to remove solid material and clear portion of juice was used as a catalyst. The pH of the extracted lemon juice was found to be 2.3.

General procedure for the synthesis of benzazoles

In typical procedure, 2-aminothiophenol or 2-aminophenol (1 mmol), aryl aldehyde (1 mmol), and lemon juice: water mixture (1:1 v/v) (4 mL) was added in the reaction vessel. The reaction mixture was stirred at 80°C temperature for a specified time (Table 1). After reaction completion as analyzed by TLC, the reaction mixture was quenched with cold water and stirred continuously until free flowing solid was obtained. The resulting solid was filtered, air dried and recrystallization from ethanol to get pure product. The identity of the compound [2-(4-chlorophenyl) benzothiazole] was ascertained on the basis of ¹H NMR and ¹³C NMR spectroscopy as shown in Figures 1 and 2. The physical and spectral data are in agreement with the literature data.

Entry	Amine	Aldehyde	Product (3)	Lemon juice		Pineapple juice		Orange juice
				Time (min)	Yieldb (%)	Time (min)	Yieldb (%)	Time (min)	Yieldb (%)
1	1a	H		45	91	50	90	50	88
2	1a	4-NO2		50	90	55	88	55	87
3	1a	3-NO2		51	88	56	87	58	86
4	1a	4-Cl		52	88	55	86	60	84
5	1a	4-Br		60	87	64	85	65	83
6	1a	4-CN		50	60	55	88	55	86
7	1a	4-CH3		65	88	70	87	75	86
8	1a	4-OCH3		70	87	74	80	80	83
9	1a	4-OH		72	88	75	84	85	82
10	1a	3,4,5-OCH3		90	84	95	85	99	80
11	1b	H		120	82	125	81	130	80
12	1b	4-NO2		75	90	90	86	90	84
13	1b	4-Cl		80	89	85	85	90	81
14	1b	4-OCH3		100	88	105	83	105	80

Table 1: Lemon juice catalyzed synthesis of benzothiazole and benzoxazole^a.

Figure 1: ¹H-NMR spectra of 2-(4-chlorophenyl) benzothiazole.

Figure 2: ¹³C NMR spectra of 2-(4-Chlorophenyl) benzothiazole.

Selected spectral data

2-(phenyl) benzothiazole (Table 1, entry 1)

Off-white solid, MP: 111-113°C (34); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.10-8.13 (m, 3H), 7.92-7.94 (d, 1H, J=8 Hz), 7.50-7.54 (m, 4H), 7.39-7.43 (m, 1H) ); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 121.6, 123.2, 125.2, 126.2, 127.5, 129, 130.9, 133.6, 135, 154.1, 168; IR (KBr) (cm^-1): 3056, 1622,1448, 755, 623.

2-(4-nitorphenyl) benzothiazole (Table 1, entry 2)

Yellow Solid, MP: 229-331°C (34); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.09-8.14 (m, 2H), 7.93-7.95 (d, 2H, J=7.6 Hz), 7.66-7.93 (m, 1H), 7.18-7.28 (m, 2H), 7.03-7.15 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 121.6, 123.8, 124.3, 125.8, 126.2, 127.1, 128, 129.7, 132.8, 141.2, 147.7, 149.5, 157; IR (KBr) (cm^-1): 3044, 1627, 1557, 1360, 822, 756.

2-(4-chlorophenyl) benzothiazole (Table 1, entry 4)

White Solid, MP: 107-109°C (34); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.04-8.10 (m, 3H), 7.92-7.93 (d, 1H, J=8 Hz) 7.48-7.54 (m, 3H), 7.40-7.44 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 121.6, 123.3, 125.4, 126.5, 128.7, 129.2, 132.1, 135, 137, 154, 166.6; IR (KBr) (cm^-1): 3056, 1630,1445, 850, 733.

2-(4-nitrophenyl) benzoxazole (Table 1, entry 12)

Yellow Solid, MP: 263-265°C (34); ¹H NMR (400 MHz, CDCl₃): δ (ppm) 8.23-8.28 (m, 2H), 7.45-7.52 (m, 2H), 7.33-7.42 (d, 2H, J=8.4 Hz), 7.22-7.31 (d, 2H, J=7.4 Hz), 7.33-7. 84 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ (ppm) 122.6, 124.8, 124.5, 126.8, 128.4, 130.7, 132.4, 142.2, 148.7, 158.4; IR (KBr) (cm^-1): 3048, 1621, 1556, 1533, 1352.

Results and Discussion

Initially, in order to optimize various reaction conditions for the synthesis of benzothiazole we conducted the model reaction between 2-aminothiophenol (1 mmol), 4-nitrobenzaldehyde (1 mmol) and lemon juice:water (4 mL, 1:1, v/v) Scheme 1.

Scheme 1: Synthesis of benzazoles using lemon juice as a natural catalyst.

Initially, to study the effect of catalyst loading the model reaction was carried out at ambient temperature by increasing amount of lemon juice from 1 to 3 mL, but moderate product was obtained with prolonged reaction time (Table 2, entries 1-5). Continuing our effort by paying attention on yield, surprisingly the considerable influence on the yield (81%) obtained when the model reaction was carried out at 80°C in presence of 2 ml lemon juice (Table 2, entry 6). Further in order to check the effect of the solvent on the yield of the product, the above reaction was performed in different solvents like methanol, ethanol, and water at temperature 80°C. In all cases 81-90% yield of desired product was obtained (Table 2, entry 7-9). We also optimized the catalyst-solvent proportion on conducting the model reaction by changing lemon juice: water ratio (Table 2, entry 9-11). The result showed that 2:2 (lemon juice: water) proportions suitable for smooth conversion of reactant to corresponding product with respect to time and yield.

Table 2: Effect of catalytic amount of catalyst and temperature on time and yield of the model reaction^a.

With these optimized condition in hand, we extended this protocol for the synthesis of benzothiazoles and benzoxazole derivatives by using various natural catalyst such as pineapple juice, and orange juice. It was observed that, both pineapple and orange juice efficiently undergo this transformation giving satisfactory yield of anticipated product. The pH analysis of all above natural catalyst is summarized in Table 3. As juices are acidic in nature it was used as acid catalyst for this protocol. Among all, the pH of lemon juice was found to be lowest as 2.3. Therefore, the yield of benzothiazoles and benzoxazole derivatives by using lemon juice was quite high as compared to pineapple juice and orange juice (Table 1).

Next, we turned our efforts towards the scope and generality of protocol for the synthesis of benzothiazole and benzoxazole derivatives by reacting 2-aminothiophenol or 2-aminophenol with diverse array of aryl aldehydes and the results are depicted in Table 1. It was observed that, aromatic aldehydes bearing electron donating as well electron withdrawing groups reacted efficiently with 2-aminothiophenol and 2-aminophenol giving corresponding product in good to excellent yields. It was noticed that the aldehydes with electron donating groups required longer reaction time than the aldehydes with electron withdrawing groups.

We then compared results obtained by above protocol with the reported catalysts for synthesis of benzothiazoles and benzoxazole derivatives (Table 4). It was observed that the present protocol is best fitted with the previous results in terms of reaction time and product yields.

The possible mechanism for the synthesis of benzazole is depicted in Scheme 2. It is believed that carbonyl group is activated by acidity of natural catalyst for nucleophilic attack that led to the formation of intermediate (I). The intermediate I undergo intra-molecular cyclization, followed by air oxidation, leading to the formation of the desired product (II).

Scheme 2: Plausible mechanism for synthesis of benzazoles derivatives using natural catalyst.

Conclusion

In conclusion, we have developed simple and green protocol for synthesis of benzothiazoles and benzoxazole derivatives comprising the reaction of various aryl aldehydes with aminobenzenes in good to excellent yield using natural catalyst. This method offers several advantages such as mild reaction condition high yield, short reaction time, and simple experimental and workup procedure.

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