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Facile and efficient synthesis of benzoxazole derivatives using novel catalytic activity of PEG-SO3H
⁎Corresponding author. Tel.: +91 8983387871. rupeshchikhale7@gmail.com (Rupesh V. Chikhale)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
A highly efficient, simple and rapid method for the preparation of various 2-aminobenzoxazoles and other benzoxazole derivatives using a catalytic amount of poly (ethylene glycol)-bound sulfonic acid (PEG-SO3H) is described. PEG-SO3H is found to be an economical and reusable catalyst with low catalytic loading. The percent yield was found to be satisfactory, experimental set up and purification of final products are facile and easy.
Keywords
Poly (ethylene glycol)-bound sulfonic acid (PEG-SO3H)
2-Aminobenzoxazole
Benzoxazole derivatives
1 Introduction
Benzazoles like benzoxazole, benzothiazole and benzimidazole derivatives are of immense importance in chemical (Yoshida et al., 2005), agrochemical dye-stuff (Tian and Ling, 2007), polymer (Vicini et al., 2008) and pharmaceutical industries (Murugesan et al., 2009). These compounds have a broad spectrum of biological and pharmacological activities such as antihypertensive (Vicini et al., 2003), antiepileptic (Jain et al., 2007), antimicrobial (Walczynski et al., 1999), phosphodiesterase inhibitor (Tsurumi et al., 1973), neuropeptide binding (Siddiqui et al., 2007), antiviral (Yildiz-Oren et al., 2004) and pesticidal activity (Mccracken and Stillwell, 1991). Benzoxazole and its derivatives like 2-aminobenzoxazole find extensive therapeutic importance in medicine for indications such as neural disorders (Wang et al., 2007), antineoplastic (O’Donnell et al., 2010), anti-inflammatory (Cheung et al., 2002), treatment of metabolic disorders (Clark et al., 2000), irritable bowel syndrome (IBS) (Muller et al., 1999), antiviral (Sato et al., 1997), thrombolytic (Surleraux et al., 2002) and sleep disorders (Laibekman et al., 2003). The classical route for the synthesis involves nucleophilic displacement of a 2-substituted benzoxazole, 2-substituents include Cl (Cox et al., 2010), SH (Seefelder and Leuchs, 1962) and SCH3 (Katz and Cohen, 1954) or OPh (Yamato et al., 1984) with an amine. Drawbacks of these routes include penultimate intermediates that involve multiple steps to prepare, utilization of harsh reagents and conditions, or generation of undesirable byproducts. Cyclodesulfurization of an intermediary thiourea may involve a toxic heavy-metal oxide (Kroeber et al., 1994) potentially explosive oxidant (Ogura et al., 1981) or transition metal (Chang et al., 1986) to facilitate cyclization. Previously reported methods to generate 2-aminobenzoxazoles directly from 2-aminophenols may require the preparation of a thioisocyanate (Wishart et al., 2003), N-cyanodithioimido carbonate (Tian et al., 2005), or chloroformadinium salt (Heinelt et al., 2004) prior to cyclization. 2-Aminobenzoxazoles have also been prepared directly from benzoxazoles using chloroamines (Wittenbrook, 1975) or formamides (El-Faham et al., 2006) as amine substitutes. 2-Aminobenzoxazoles can also be prepared from 2-chlorobenzoxazoles by reaction with hydrazine hydrate, ammonia, or amines (Sam and Plampin, 1964). Benzoxazol-2-amine is either obtained via reaction with concentrated ammonia (Doeller, 1939) or with ammonia in methanol. N-Alkyl- and N-arylbenzoxazol-2-amines are formed in a solvent-free reaction of 2-chlorobenzoxazoles and amines (Takahashi and Koshiro, 1959; Patil and Townsend, 1971). Alternatively, the reaction is carried out in aqueous solution (King and Acheson, 1949; Wamhoff and Materne, 1973) refluxing benzene or toluene (Ried and Schmidt, 1964), 1,1,2,2-tetrachloroethane (Zinner and Niendorf, 1956) or acetonitrile/triethylamine (Holan et al., 1967). Dimethylformamide is found not suitable since N,N-dimethylbenzoxazol-2-amine is formed after prolonged heating (Zare et al., 2010). A continued interest has led to the development of a wide variety of synthetic methods and new reagents for the synthesis of these compounds. Many of these methods have major drawbacks such as use of expensive chemicals, poor yield, hazardous reagents, solvents, tedious work-up procedures and failures in synthetic method.
There has been a rapid and extensive growth in the development of catalysts, novel reagents for the synthesis of these compounds for organic, inorganic and pharmaceutical use. Need for a new, efficient, reusable, economic and eco-friendly catalyst has led to the development of polymer bound catalysts. They are used in solution phase, solid phase synthesis, and microwave assisted synthesis because these methods offer benefits such as enhanced reaction rate, greater selectivity, ease at experimental work-up and comparatively high yields. These are of two types; soluble and insoluble polymer based, depending on the nature of polymer bound catalyst. The experimental work-up such as, washing, filtration, and isolation is easier with polymer bound catalyst of insoluble nature. An ideal one would act as a solvent and catalyst; however such examples are rare like ionic liquids, carbon dioxide, micellar systems etc. Poly (ethylene glycols) bound catalysts have been reported earlier by Wang et al. and Zare et al., for the synthesis of carboxyl pheneoxyacetic acid derivatives under solvent free conditions and acylals in the presence of solvents, respectively (Zare et al., 2010; Kidwai et al., 2010). Recently various new catalysts are reported for the synthesis of benzazoles such as CAN supported PEG (Rao et al., 2004), microwave assisted synthesis (Mohammadpoor-Baltork et al., 2008), and silica sulfuric acid catalyst (Mohammadpoor-Baltork et al., 2008), but for the synthesis of 2-aminobenzoxazoles these methods have some serious drawbacks relating to low substrate tolerance, low yield, weak selectivity and long reaction times.
Earlier in our lab the use of silica gel as a green catalyst for the synthesis of benzodiazepines (Chikhale and Khedekar, 2013) and substituted dihydropyrimidines was reported (Chikhale et al., 2009). Herein, we report the synthesis of 2-aminobenzoxazoles and various other derivatives of benzoxazole employing poly (ethylene glycol)-bound sulfonic acid (PEG-SO3H) that acts concurrently as reaction promoter and reaction solvent (Fig. 1).
Diagrammatic representation of synthesis of 2-aminobenzoxazoles and various other derivatives of benzoxazole employing poly (ethylene glycol)-bound sulfonic acid (PEG-SO3H).
2 Experimental
2.1 Materials and methods
The uncorrected melting and boiling points of compounds were determined by the open tube capillary method using Thermonik precision apparatus (model-C-PMP-2, Mumbai, India), in Celsius scale. The purity of the compounds was verified by precoated TLC plates (E-Merck Kieselgel 60 F254). IR spectra were recorded using KBr pellets on a Perkin–Elmer 337 Spectrophotometer from Perkin–Elmer International Incorporation, Rorkreuz, Switzerland (νmax in cm−1). 1H NMR spectra were recorded on a Bruker W.M. 400 Spectrometer (Bruker AG, Fallanden, Switzerland) at 360 MHz using tetramethylsilane (TMS) as internal standard. (Chemical shifts in δ ppm). Mass spectra (FAB-MS) were recorded on 70 V on a Jeol D-300 spectrophotometer (Jeol Ltd., Tokyo, Japan) and elemental analysis was carried out using a FLASH EA 1112 CHN analyzer (Thermo Finngen, Italy).
2.2 Preparation of poly ethylene glycol (PEG)-bound sulfonic acid catalyst
To a solution of poly (ethylene glycol)-6000 (1 mmol) in dichloromethane (15 mL) was added chlorosulfonic acid (10 mmol) at cold temperature (0–8 °C). The resulting solution was stirred mechanically at 20 °C for 16 h, and then concentrated under reduced pressure. Diethyl ether was added and the precipitated product was washed three times to give PEG-SO3H (Fig. 2). 1H NMR (400 MHz, CDCl3): d 12.85 (s, 1H, SO3H), 4.23 (s, 2H, CH2SO3H), 3.49–3.66 (m, PEG).
Diagrammatic representation of synthesis of poly (ethylene glycol)-bound sulfonic acid (PEG-SO3H).
In order to determine the amount of catalysts required for carrying out these reactions, another study was carried out involving different concentrations of catalysts for individual sets of reactions i.e., for substituted benzoxazole derivatives. The control study was carried out for representative reactions from each series. The first example involved the conversion of phenylurea into 2-aminobenzoxazole derivatives using different concentrations; the study was carried out as given in Table 1. The comparative study of the required concentration and time for completion of reaction was made (Fig. 3).
| Sr. No. | Amount of PEG-SO3H | Time (min) | Yield (%) | Solvent |
|---|---|---|---|---|
| Scheme 1 | ||||
| 1 | 0.1 g (∼0.83 mol%) | 450 | 70 | Chloroform |
| 2 | 0.15 g (∼1.25 mol%) | 420 | 78 | Chloroform |
| 3 | 0.2 g (∼1.65 mol%) | 300 | 85 | Chloroform |
| 4 | 0.25 g (∼2.1 mol%) | 300 | 85 | Chloroform |
| Scheme 2 | ||||
| 1 | 0.1 g (∼0.83 mol%) | 600 | 50 | Dioxane + Chloroform |
| 2 | 0.15 g (∼1.25 mol%) | 540 | 60 | Dioxane + Chloroform |
| 3 | 0.2 g (∼1.65 mol%) | 360 | 80 | Dioxane + Chloroform |
| 4 | 0.25 g (∼2.1 mol%) | 360 | 80 | Dioxane + Chloroform |
| Scheme 3 | ||||
| 1 | 0.1 g (∼0.83 mol%) | 558 | 65 | Chloroform |
| 2 | 0.15 g (∼1.25 mol%) | 480 | 70 | Chloroform |
| 3 | 0.2 g (∼1.65 mol%) | 420 | 80 | Chloroform |
| 4 | 0.25 g (∼2.1 mol%) | 378 | 80 | Chloroform |
- Study of % yield of the different class of products obtained against concentration of PEG-SO3H.
2.3 General procedure for the synthesis of benzoxazole derivatives
2.3.1 General procedure for the synthesis of substituted benzoxazole derivatives starting from substituted o-nitro phenols and substituted aldehydes (Scheme 1)
A solution of substituted o-nitro phenols (10 mmol) in a minimal quantity of chloroform was prepared and transferred into a three-neck round bottom flask. A spiral condenser, overhead stirrer and dropping funnel were attached to the reaction flask. PEG-SO3H (2.1 mmol) was added with stirring for 30 min subsequently substituted aldehydes (10 mmol) were added via a dropping funnel over a period of 30 min and further heated for 4–6 h at 50–60 °C. The reaction mixture was cooled to room temperature and the resulting solid mixture was washed with strong ammonia solution and filtered to remove catalyst. The solution was evaporated under vacuum (Scheme 1). The resulting products were recrystallized from rectified spirit to obtain substituted 2-aminobenzothiazoles (Table 2).
Synthesis of substituted benzoxazole derivatives starting from substituted o-nitro phenols and substituted aldehydes.
|
|||||
|---|---|---|---|---|---|
| Entry | R | R1 | Product | Yield (%) | mp (°C) |
| 1 | H |
|
|
94 | 136–138 |
| 2 | H |
|
|
92 | 210–212 |
| 3 | H |
|
|
95 | 165–167 |
| 4 |
|
|
|
90 | 150–152 |
| 5 |
|
|
|
90 | 132–135 |
| 6 |
|
|
|
94 | 121–124 |
| 7 | H |
|
|
93 | 163–165 |
| 8 |
|
|
|
98 | 137–139 |
| 9 |
|
|
|
95 | 142–144 |
| 10 | F |
|
|
90 | 129–131 |
2.3.1.1 2-Phenyl-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol and benzaldehyde employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.5. 1H NMR: δ 8.30–8.32 (m, 3H); 8.1 (dd, J = 1.2, 7.1 Hz, 1H); 7.8 (d, 8.3 Hz, 1H); 7.5 (m, 3H); 7.3 (d, 8.2 Hz, 1H). 13C NMR: δ 166.6, 165.5, 150.4, 146.0, 132.1, 129.0, 127.9, 127.0, 126.5, 126.3, 119.5, 112.2. HRMS (M+) Calculated: 195.2166, Found: 195.200.
2.3.1.2 2-(2,4-Dimethoxyphenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol and dimethoxy benzaldehyde employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.3. 1H NMR: δ 8.26 (s, 1H); 8.15 (d, J = 8.8 Hz, 1H); 8.07 (dd, J = 1.3, 7.1 Hz, 1H); 7.8 (d, J = 8.4 Hz, 1H); 6.66 (dd, J = 2.1, 6.5 Hz, 1H); 6.63 (d, J = 2.1 Hz, 1H); 4.05 (s, 3H); 4.0 (s, 1H); 3.9 (s, 3H). 13C NMR: δ 166.8, 164.3, 164.1, 160.3, 149.7, 146.3, 132.8, 126.3, 126.0, 119.3, 111.8, 108.4, 105.5, 99.1, 56.2, 55.6, 52.2. HRMS (M+) Calculated: 255.2686, Found: 255.2700.
2.3.1.3 2-(4-Methoxyphenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol and para-methoxy benzaldehyde employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.3; 1H NMR: δ 8.26–8.23 (3H, m); 8.10 (1H, dd, J = 8.4, 1.5 Hz); 7.76 (1H, d, J = 8 Hz); 7.07 (2H, m); 3.99 (3H, s); 3.93 (1H, s). 13C NMR: δ 166.7, 165.5, 162.8, 150.3, 146.3, 129.8, 126.5, 126.3, 119.0, 114.4, 112.0, 55.5, 52.3. HRMS (M+) Calculated: 225.2426 Found 225.2312.
2.3.1.4 Methyl 2-octyl-1,3-benzoxazole-6-carboxylate
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol methyl benzoate and octanal employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.18 (d, J = 1.2 Hz, 1H); 8.05 (dd, J = 1.4 Hz, 7.0 Hz, 1H); 7.69 (d, J = 8.3 Hz, 1H); 4.0 (s, 3H); 2.95 (t, J = 7.6 Hz, 2H); 1.88 (q, J = 7.4 Hz, 2H), 1.28–1.46 (m, 10H); 0.87 (t, J = 6.7 Hz, 3H). 13C NMR: δ 170.2, 166.7, 150.4, 145.3, 126.5, 125.9, 119.0, 111.9, 52.3, 31.7, 29.1, 29.0, 28.7, 26.6, 22.6, 14.0. HRMS (M+) Calculated: 289.3694, Found: 289.3724.
2.3.1.5 Methyl 2-propyl-1,3-benzoxazole-6-carboxylate
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol methyl benzoate and propanal employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.16 (d, J = 1.3 Hz, 1H), 8.05–8.02 (dd, J = 1.51, 6.7 Hz, 1H), 7.69–7.67 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 2.96–2.92 (t, J = 7.4 Hz, 2H), 1.96–1.91 (m, 2H), 1.08–1.04 (t, J = 7.42 Hz, 3H). 13C NMR: δ 170.0, 166.7, 150.4, 145.3, 126.5, 125.8, 119.0, 111.9, 52.2, 30.6, 20.0, 13.7. HRMS (M+) Calculated: 289.3694, Found: 289.3724.
2.3.1.6 Methyl 2-pentyl-1,3-benzoxazole-6-carboxylate
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol methyl benzoate and pentanal employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.16 (d, J = 0.9 Hz, 1H), 8.04–8.02 (dd, J = 1.5, 6.87 Hz, 1H), 7.69–7.67 (d, J = 8.3 Hz, 1H), 3.94 (s, 3H), 2.97–2.93 (t, J = 7.6 Hz, 2H), 1.94–1.86 (m, 2H), 1.47–1.35 (m, 4H), 0.93–0.89 (t, J = 7 Hz, 3H). 13C NMR: δ 170.2, 166.7, 150.4, 145.3, 125.9, 119.0, 111.9, 52.3, 31.2, 29.6, 28.7, 26.2, 22.2, 13.8. HRMS (M+) Calculated: 247.2896, Found: 247.2900.
2.3.1.7 2-Cyclohexyl-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol and cyclohexanal employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.3. 1H NMR: δ 8.17 (d, J = 1 Hz, 1H); 8.04 (dd, J = 1 Hz, 7.1 Hz, 1H); 7.7 (d, J = 8.3 Hz, 1H); 3.96 (s, 1H); 2.97 (m, 1H); 2.18 (m, 2H); 1.88 (m, 2H); 1.72 (m, 3H); 1.27 (m, 3H). 13C NMR: δ 173.2, 166.7, 150.2, 145.3, 126.5, 125.8, 119.1, 111.9, 52.2, 38.0, 30.3, 25.6, 25.5. HRMS (M+) Calculated: 201.2643, Found: 201.2710.
2.3.1.8 2-(Propan-2-yl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol methyl benzoate and isopropanal employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.5; 1H NMR: δ 8.17 (s, 1H), 8.05–8.03 (d, J = 8.33 Hz, 1H), 7.71–7.69 (d, J = 8.31 Hz, 1H), 3.95 (s, 3H), 3.31–3.24 (m, 1H), 1.49–1.47 (d, J = 7.6 Hz, 6H). 13C NMR: δ 174.0, 166.6, 50.3, 145.2, 126.5, 125.8, 119.1, 111.9, 52.2, 28.9, 20.1. HRMS (M+) Calculated: 219.2365, Found: 219.2371.
2.3.1.9 Methyl 2-(butan-2-yl)-1,3-benzoxazole-6-carboxylate
It was synthesized using the procedure given in Section 2.3.1 from o-nitro phenol methyl benzoate and isobutanal employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.17 (1H, s); 8.03 (1H, d, J = 8 Hz); 7.69 (1H, d, J = 8 Hz); 3.94 (3H, s); 3.08 (1H, sextuplet, J = 6 Hz); 1.99–1.74 (2H, m); 1.44 (3H, d, J = 7 Hz); 0.96 (3H, t, J = 7 Hz). 13C NMR: δ 173.5, 166.7, 150.3, 145.2, 126.5, 125.8, 119.1, 112.0, 52.3, 35.8, 27.9, 17.7, 11.5. HRMS (M+) Calculated: 233.2631, Found: 233.2733.
2.3.1.10 2-(6-Fluoro-1,3-benzoxazol-2-yl)phenol
It was synthesized using the procedure given in Section 2.3.1 from meta fluro-3-nitro phenol and 2-hydroxy benzaldehyde employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.5; 1H NMR: δ 8.23–8.26 (m, 2H); 7.70–7.74 (m, 1H); 7.55–7.58 (m, 3H); 7.33–7.35 (dd, J = 2.4 Hz, 5.6 Hz, 1H); 7.13–7.16 (m, 1H). 13C NMR: δ 131.5, 128.9, 127.4, 126.8, 120.3, 120.2, 112.6, 112.4, 98.8, 98.5. HRMS (M+) Calculated: 211.2160, Found: 211.2231.
2.3.2 General procedure for synthesis of substituted benzoxazole derivatives starting from substituted 2-amino phenols and substituted benzoic acids (Scheme 2)
A solution of substituted 2-amino phenols (10 mmol) was prepared in a mixture of Dioxane:Chloroform (1:1) arranged in a three neck flask, to it a solution of substituted benzoic acid (10 mmol) in chloroform was added drop wise over a period of 1 h with constant stirring. To this mixture PEG-SO3H (2.1 mmol) was added and the reaction was carried out for 5–6 h at 60–65 °C, progress of reaction was monitored by TLC. After completion of reaction as determined by TLC, the reaction mixture was cooled to room temperature and the resulting solid was washed with strong ammonia solution and filtered to remove catalyst, then dried under vacuum (Scheme 2). The resulting products were recrystallized from rectified spirits to obtain substituted 2-aminobenzoxazoles (Table 3).
Synthesis of substituted benzoxazole derivatives starting from substituted 2-amino phenols and substituted benzoic acids.
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|---|---|---|---|---|---|
| Entry | R | R1 | Product | Yield (%) | mp (°C) |
| 11 | H |
|
|
95 | 136–138 |
| 12 | H |
|
|
97 | 148–150 |
| 13 | H |
|
|
98 | 144–145 |
| 14 | H |
|
|
92 | 157–158 |
| 15 | H |
|
|
98 | 203–206 |
| 16 | H |
|
|
97 | 165–167 |
| 17 | H |
|
|
97 | 53–55 |
| 18 | 4-Me |
|
|
95 | 93–95 |
| 19 | 4-Cl |
|
|
90 | 107–108 |
| 20 | 4-F |
|
|
98 | 109–110 |
2.3.2.1 2-Phenyl-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.5; 1H NMR: δ 8.32 (dd, 2H, J = 5.6 Hz, J = 2.1 Hz), 7.79–7.86 (m, 1H), 7.53–7.67 (m, 4H), 7.36–7.44 (m, 2H). 13C NMR: δ 163.1, 150.8, 142.2, 131.4, 128.9, 127.6, 127.2, 125.1, 124.6, 120.0, 110.6. HRMS (M+) Calculated: 195.0684, Observed: 195.0683.
2.3.2.2 2-(4-Chlorophenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and para chloro benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.22 (d, 2H, J = 7.8 Hz), 7.77–7.84 (m, 1H), 7.57–7.65 (m, 1H), 7.52 (d, 2H, J = 7.8 Hz), 7.36–7.44 (m, 2H). 13C NMR: δ 162.1, 150.8, 142.0, 137.8, 129.3, 128.9, 125.7, 125.4, 124.8, 120.1, 110.6. HRMS (M+) Calculated: 229.6617, Found: 229.7001.
2.3.2.3 2-(3,4-Dichlorophenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and 3,4-dichloro benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.5; 1H NMR: δ 8.37 (d, 1H, J = 1.8 Hz), 8.09 (dd, 1H, J = 8.2 Hz, J = 1.8 Hz), 7.77–7.83 (m, 1H), 7.58–7.65 (m, 2H), 7.38–7.45(m, 2H). 13C NMR: δ 160.9, 150.8, 141.9, 135.9, 133.5, 131.1, 129.3, 127.1, 126.5, 125.7, 125.0, 120.3, 110.7. HRMS (M+) Calculated: 264.1067, Found: 264.120.
2.3.2.4 2-(4-Bromophenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and 4-bromo benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.5; 1H NMR: δ 8.16 (m, 2H), 7.78–7.84 (m, 1H), 7.68–7.75 (m, 2H), 7.59–7.66 (m, 1H), 7.37–7.45 (m, 2H). 13C NMR: δ 162.1, 150.8, 142.0, 132.3, 129.0, 126.3, 126.1, 125.4, 124.8, 120.1, 110.7. HRMS (M+) Calculated: 274.1127, Found: 274.1221.
2.3.2.5 4-(1,3-Benzoxazol-2-yl)benzonitrile
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and 4-cyano benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.37 (d, 2H, J = 8.5 Hz), 7.80–7.87 (m, 3H), 7.60–7.68 (m, 1H), 7.39–7.49 (m, 2H). 13C NMR: δ 160.6, 150.9, 141.9, 132.7, 131.1, 128.0, 126.2, 125.1, 120.6, 118.2, 114.7, 110.9. HRMS (M+) Calculated: 220.2261, Found: 220.2301.
2.3.2.6 2-(4-Methoxyphenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and 4-methoxy benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.4; 1H NMR: δ 8.13 (d, 2H, J = 8.2 Hz), 7.75–7.80 (m, 1H), 7.56–7.61 (m, 1H), 7.31–7.40 (m, 2H), 7.06 (d, 2H, J = 8.2 Hz), 3.91 (s, 3H). 13C NMR: δ 163.2, 162.3, 150.7, 142.3, 129.4, 124.6, 124.4, 119.7, 119.6, 114.4, 110.4, 55.5. HRMS (M+) Calculated: 225.2426, Found: 225.2312.
2.3.2.7 2-(2-Methoxyphenyl)-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 2-amino phenol and 2-methoxy benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.3; 1H NMR: δ 8.18 (dd, 1H, J = 7.7 Hz, J = 1.8 Hz), 7.83–7.90 (m, 1H), 7.60–7.66 (m, 1H), 7.52–7.58 (m, 1H), 7.35–7.42 (m, 2H), 7.11–7.17 (m, 2H), 4.06 (s, 3H). 13C NMR: δ 161.6, 158.5, 150.4, 142.2, 132.8, 131.3, 124.9, 124.3, 120.7, 120.3, 116.2, 112.1, 110.5, 56.2. HRMS (M+) Calculated: 225.2426, Found: 225.2322.
2.3.2.8 6-Methyl-2-phenyl-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 4-methyl-2-amino phenol and benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.3; 1H NMR: δ 8.24–8.31 (m, 2H), 7.68 (d, 1H, J = 8.2 Hz), 7.51–7.58 (m, 3H), 7.40 (t, 1H, J = 0.6 Hz,), 7.19 (dd, 1H, J = 8.0 Hz, J = 1.5 Hz, J = 0.6 Hz), 2.53 (s, 3H). 13C NMR: δ 162.6, 151.1, 140.0, 135.6, 131.3, 128.9, 127.5, 127.4, 125.8, 119.4, 110.8, 21.8. HRMS (M+) Calculated: 209.2432, Found: 209.2400.
2.3.2.9 6-Chloro-2-phenyl-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 4-chloro-2-amino phenol and benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2:Hexane), Rf = 0.3; 1H NMR: δ 8.16–8.23 (m, 2H), 7.64 (d, 1H, J = 8.5 Hz), 7.55 (d, 1H, J = 1.9 Hz), 7.45–7.57 (m, 3H), 7.30 (dd, 1H, J = 8.5 Hz, J = 1.9 Hz. 13C NMR: δ 163.7, 151.0, 140.9, 131.8, 130.7, 129.0, 127.7, 126.8, 125.3, 120.5, 111.2. HRMS (M+) Calculated: 229.6617, Found: 229.8901.
2.3.2.10 6-Fluoro-2-phenyl-1,3-benzoxazole
It was synthesized using the procedure given in Section 2.3.2 from 4-fluro-2-amino phenol and benzoic acid employing PEG-SO3H. TLC (1:1 CH2Cl2: Hexane), Rf = 0.3; 1H NMR: δ 8.20–8.28 (m, 2H), 7.72 (dd, 1H, J = 8.8 Hz, J = 4.9 Hz), 7.50–7.59 (m, 3H), 7.33 (dd, 1H, J = 8.0 Hz, J = 2.3 Hz), 7.13(td, 1H, J = 8.8 Hz, J = 2.3 Hz). 13C NMR: 138.4, 131.6, 128.9, 127.5, 126.9, 120.3. HRMS (M+) Calculated: 213.2071, Found: 213.2082.
2.3.3 General procedure for synthesis of substituted 2-amino benzoxazole derivatives starting from substituted anilines (Scheme 3)
Synthesis of substituted benzoxazol-2-amine or substituted 2-aminobenzoxazoles was carried out in two steps. First step involves the synthesis of substituted phenylurea from parent anilines followed by PEG-SO3H promoted cyclization. Substituted aniline (10 mmol) was added to a round bottom flask containing water. To it was added conc. HCl (10 ml), the mixture was warmed for about 10 min followed by addition of potassium cyanate (10 mmol) and was stirred for 1 h. The solid was allowed to precipitate (at low temperature 0–5 °C), the precipitate so obtained was filtered and dried. A solution of substituted phenylurea (10 mmol) was prepared in chloroform, to it PEG-SO3H (2.1 mmol) was added. The reaction mixture was stirred for about 6–7 h at 80–90 °C, progress and completion of reaction were monitored by the TLC method. After completion of the reaction it was allowed to cool to room temperature. The catalyst was filtered out. Filtrate was made basic by addition of ammonia solution leading to precipitation of the product which was collected and further recrystallized from rectified spirits (Scheme 3, Table 4).
Synthesis of substituted 2-amino benzoxazole derivatives starting from substituted anilines.
|
||||
|---|---|---|---|---|
| Entry | R | Product | Yield (%) | mp (°C) |
| 21 | H |
|
97 | 128–132 |
| 22 | CH3 |
|
95 | 112–114 |
| 23 | NO2 |
|
92 | 150–152 |
| 24 | Cl |
|
97 | 180–185 |
| 25 | Br |
|
93 | 172–174 |
2.3.3.1 1,3-Benzoxazol-2-amine
Synthesis of 1,3-benzoxazol-2-amine was carried out in two steps. Aniline (10 mmol) was added to a round bottom flask containing water. To it was added conc. HCl (10 ml), the mixture was warmed for about 10 min followed by addition of potassium cyanate (10 mmol) and was stirred for 1 h. The solid was allowed to precipitate (at low temperature 0–5 °C), the precipitate was filtered and dried.
A solution of phenyl urea (10 mmol) was prepared in chloroform, to it PEG-SO3H (2.1 mmol) was added. The reaction mixture was stirred for about 6–7 h at 80–90 °C, progress and completion of reaction were monitored by the TLC method. After completion of the reaction it was allowed to cool to room temperature. The catalyst was filtered out. Filtrate was made basic by addition of ammonia solution leading to precipitation of the product which was collected and further recrystallized from rectified spirits. Yield: 97%, mp: 128–132 °C, TLC (1:1; CH2Cl2:Hexane), Rf = 0.5.
2.3.3.2 6-Methyl-1,3-benzoxazol-2-amine
Synthesis of 6-methyl-1,3-benzoxazol-2-amine was carried out in two steps, 4-methyl aniline (10 mmol) was added to a round bottom flask containing water. To it was added conc. HCl (10 ml), the mixture was warmed for about 10 min followed by addition of potassium cyanate (10 mmol) and was stirred for 1 h. The solid was allowed to precipitate (at low temperature 0–5 °C), the precipitate was filtered and dried.
A solution of tolylurea (10 mmol) was prepared in chloroform, to it PEG-SO3H (2.1 mmol) was added. The reaction mixture was stirred for about 6–7 h at 80–90 °C, progress and completion of reaction were monitored by the TLC method. After completion of the reaction it was allowed to cool to room temperature. The catalyst was filtered out. Filtrate was made basic by addition of ammonia solution leading to precipitation of the product which was collected and further recrystallized from rectified spirits. Yield: 95%, mp: 112–114 °C, TLC (1:1; CH2Cl2:Hexane), Rf = 0.5.
2.3.3.3 6-Nitro-1,3-benzoxazol-2-amine
Synthesis of 6-nitro-1,3-benzoxazol-2-amine was carried out in two steps, para-nitro aniline (10 mmol) was added to a round bottom flask containing water. To it was added conc. HCl (10 ml), the mixture was warmed for about 10 min followed by addition of potassium cyanate (10 mmol) and was stirred for 1 h. The solid was allowed to precipitate (at low temperature 0–5 °C), the precipitate was filtered and dried.
A solution of para-nitrophenyl urea (10 mmol) was prepared in chloroform, to it PEG-SO3H (2.1 mmol) was added. The reaction mixture was stirred for about 6–7 h at 80–90 °C, progress and completion of reaction were monitored by the TLC method. After completion of the reaction it was allowed to cool to room temperature. The catalyst was filtered out. Filtrate was made basic by addition of ammonia solution leading to precipitation of the product which was collected and further recrystallized from rectified spirits. Yield: 92%, mp: 150–152 °C, TLC (1:1; CH2Cl2:Hexane), Rf = 0.4.
2.3.3.4 6-Chloro-1,3-benzoxazol-2-amine
Synthesis of 6-chloro-1,3-benzoxazol-2-amine was carried out in two steps, para-chloro aniline (10 mmol) was added to a round bottom flask containing water. To it was added conc. HCl (10 ml), the mixture was warmed for about 10 min followed by addition of potassium cyanate (10 mmol) and was stirred for 1 h. The solid was allowed to precipitate (at low temperature 0–5 °C) the precipitate was filtered and dried.
A solution of para-chlorophenyl urea (10 mmol) was prepared in chloroform, to it PEG-SO3H (2.1 mmol) was added. The reaction mixture was stirred for about 6–7 h at 80–90 °C, progress and completion of reaction were monitored by the TLC method. After completion of the reaction it was allowed to cool to room temperature. The catalyst was filtered out. Filtrate was made basic by addition of ammonia solution leading to precipitation of the product which was collected and further recrystallized from rectified spirits. Yield: 97%, mp: 180–185 °C, TLC (1:1; CH2Cl2:Hexane), Rf = 0.4.
2.3.3.5 6-Bromo-1,3-benzoxazol-2-amine
Synthesis of 6-bromo-1,3-benzoxazol-2-amine was carried out in two steps, para-bromo aniline (10 mmol) was added to a round bottom flask containing water. To it was added conc. HCl (10 ml), the mixture was warmed for about 10 min followed by addition of potassium cyanate (10 mmol) and was stirred for 1 h. The solid was allowed to precipitate (at low temperature 0–5 °C), the precipitate was filtered and dried.
A solution of para-bromophenyl urea (10 mmol) was prepared in chloroform, to it PEG-SO3H (2.1 mmol) was added. The reaction mixture was stirred for about 6–7 h at 80–90 °C, progress and completion of reaction were monitored by the TLC method. After completion of the reaction it was allowed to cool to room temperature. The catalyst was filtered out. Filtrate was made basic by addition of ammonia solution leading to precipitation of the product which was collected and further recrystallized from rectified spirits. Yield: 93%, mp: 172–174 °C, TLC (1:1; CH2Cl2:Hexane), Rf = 0.3.
3 Results and discussion
The present article describes a highly economical, facile and clean method for the synthesis of chemically and pharmaceutically important benzoxazole derivatives by employing poly (ethylene glycol) supported sulfonic acid (PEG-SO3H) as a reusable catalyst. PEG acts as support for sulfonic acid as the catalyst as well as solvent medium. A study presented by Zare et. al., was taken into consideration to determine and optimize an optimal catalyst system for the synthesis of 2-aminobenzoxazole. Different molar concentrations of catalyst, duration of reaction, and use of solvent systems were used as presented in Table 1. It was observed that synthesis of 2-aminobenzoxazole was obtained in the highest yield of 97% at about 80–90 °C in the presence of a solvent system consisting of chloroform, instead of 78% when the reaction was carried out in the presence of PEG alone. The concentration of PEG-SO3H needed was studied keeping solvent and temperature constant; it was found that use of ∼2.1 mmol of catalyst gave optimum results. As the catalyst was recovered after each reaction, the ability to recycle the catalyst was investigated. After 3–4 cycles of use the% yield was hampered also the consistence of PEG-SO3H has changed. However, it was found that up to 3 cycles the catalytic activity provided good yields of the reaction product. This encouraged the use of PEG-SO3H in the synthesis of 2-amino derivatives of benzoxazole. A variety of substituents and methods were tested and two of these methods were optimized for their synthetic applicability. First, the synthesis uses 2-nitro phenols with aldehydes and second the synthesis involves 2-nitro phenols and carboxylic acids.
The first method involves the synthesis of benzoxazoles from substituted 2-nitro phenols and allyl or aryl aldehydes (Scheme 1). This method was optimized by use of chloroform as solvent medium along with PEG-SO3H, 4–6 h at 50–60 °C for the synthesis of 2-aminobenzoxazole derivatives. The products were obtained in a range of 90–96% which is satisfactory, also for production on a large scale (Table 2). The products like allyl derivatives found application in the coating industry and production of olefins. In figure number four (Fig. 4) it is tried to explain predicted possible mechanism for the synthesis of substituted benzoxazole derivatives starting from substituted o-nitro phenols and substituted aldehydes. The second method involved the synthesis of benzoxazoles from 2-amino phenols and carboxylic acids (Scheme 2). This method was optimized by use of a solvent system consisting of Dioxane:Chloroform (1:1) at 60–65 °C for about 5–6 h. The % yield was found to be satisfactory in the range of 90–97% (Table 3).
Predicted possible mechanism for synthesis of substituted benzoxazole derivatives starting from substituted o-nitro phenols and substituted aldehydes.
In reference to Scheme 3, all compounds (Table 4) are known and widely used for scaffold synthesis. These compounds were synthesized in excellent yields as compared to other methods; however our method involves two steps. In the first step phenyl urea of respective anilines was synthesized followed by their cyclization employing PEG-SO3H as a mild catalyst. Their physico-chemical properties are similar to those of the standard compounds which are commercially available.
All the synthesized compounds were analyzed by 1H NMR, 13C NMR and HR-MS for establishing their structures, compound 2.3.1.1. (Table 2, entry 1–10), compound 2.3.2.1. (Table 3, entry 11–20) and compound 2.3.3.1. (Table 4, entry 21–25) are compounds prepared by different methods hence their physico-chemical properties were studied and they were found to be identical to authentic samples prepared by different methods. This provided us with a new synthetic route to a variety of compounds and with the option of different substituents.
In summary, we have developed a more eco-friendly method to synthesize benzoxazole derivatives in excellent yields with high purity using a reusable PEG-SO3H catalyst very economically.
Acknowledgments
RVC is thankful to Council of Scientific and industrial Research (CSIR) New Delhi, India for providing financial support in form of SRF: 09/128/0080/2011/EMR-I. PBK acknowledges financial support by University Grants Commission (UGC) New Delhi, India in form of Major Research Project 41-744/2012 (SR).
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