Shivani Soni
,
Nusrat Sahiba
,
Sunita Teli
,
Pankaj Teli
,
Lokesh Kumar Agarwal
and
Shikha Agarwal
*
Synthetic Organic Chemistry Laboratory, Department of Chemistry, MLSU, Udaipur-313001, Rajasthan, India. E-mail: shikhaagarwal@mlsu.ac.in
First published on 11th August 2023
Benzoxazole is a resourceful and important member of the heteroarenes that connects synthetic organic chemistry to medicinal, pharmaceutical, and industrial areas. It is a bicyclic planar molecule and is the most favorable moiety for researchers because it has been extensively used as a starting material for different mechanistic approaches in drug discovery. The motif exhibits a high possibility of broad substrate scope and functionalization to offer several biological activities like anti-microbial, anti-fungal, anti-cancer, anti-oxidant, anti-inflammatory effects, and so on. There has been a large upsurge in the synthesis of benzoxazole via different pathways. The present article presents recent advances in synthetic strategies for benzoxazole derivatives since 2018. A variety of well-organized synthetic methodologies for benzoxazole using 2-aminophenol with aldehydes, ketones, acids, alcohols, isothiocyanates, ortho-esters, and alkynones under different reaction conditions and catalysts, viz. nanocatalysts, metal catalysts, and ionic liquid catalysts, with other miscellaneous techniques has been summarized.
Oxazole is an unsaturated five-membered heterocycle that contains O and N heteroatoms at positions 1 and 3, separated by a C-atom (Fig. 1a), and was first developed in 1947.7,8 Benzoxazole (Fig. 1b) is a fused bicyclic aromatic planar heterocycle containing benzene and a 1,3-oxazole ring structure.9,10 The benzene ring is planar and composed of six carbon atoms, while the 1,3-oxazole ring contains one atom each of oxygen (O) and nitrogen (N). The fusion of these rings creates a bridging structure, resulting in a fused bicyclic system with aromatic properties.7–10 The characteristics of benzoxazole11,12 are depicted in Table 1.
Molecular formula | C7H5NO |
---|---|
IUPAC name | 1,3-Benzoxazole |
Molecular weight | 119.121 g mol−1 |
Melting point | 27–30 °C |
Boiling point | 182 °C |
Density | 1.2 ± 0.1 g cm−3 |
Appearance | White to light yellow solid |
Odor | Similar to pyridine |
Solubility | Insoluble in water |
It is an overarching framework of numerous biologically active compounds that are involved in synthetic, agrochemical, pharmaceutical, and material chemistry.13,14 This skeleton is prominent in synthetic compounds and exhibits a broad range of biological activities, such as antimicrobial,15 antitubercular,16 antioxidant,17 antifungal,18 anti-inflammatory,19 anti-allergic,20 antihyperglycemic,21 antidepressant,22 cytotoxic agents,23,24 anticonvulsant,25 and analgesic agents.26 They are isosteres of the nucleic acid bases guanine and adenine that help them to easily interact with biological receptors in the human body.27 There is a diverse range of market-available drugs (Fig. 2) that have benzoxazole as the leading moiety:28 namely, calcimycin,29 tafamidis,30 boxazomycin B,31 salvianen,32 UK-1,33 flunoxaprofen,34 chlorzoxazone,35 and pseudopteroxazole.36 Its derivatives also act as whitening agents,37 elastase inhibitors,38 α-glucosidase inhibitors,39 and fluorescent probes for different metal ions.40 A diverse array of benzoxazole moieties has been discovered as isolated constituents of various natural product: closoxazole A and B, AJI9561, nataxazole, and nocarbenzoxazole G and F are examples of benzoxazole derivatives that have been found in natural sources13,14 (Fig. 3).
They are one of the most favorable moieties in terms of synthetic aspects as they have a vast substrate scope and chemoselectivity.41 They are generally prepared by the condensation of 2-aminophenol with acids and their derivatives,42 oxidative coupling,43 or other different methodologies.44
In the past few decades, a generous amount of research has been done on the synthesis and biological activity of benzoxazole derivatives. However, previous reviews have conveyed scattered information; therefore, there is a need for a systematic compilation of the most recent research. In this article, several methods of benzoxazole synthesis using 2-aminophenols with different compounds like aldehydes, acids and their derivatives, benzyl alcohol, alkynones, isothiocyanates, ketones, ortho-esters, amongst others are demonstrated. This review aims to accentuate several synthetic approaches from the last five years under different conditions to synthesize these scaffolds.
Sayyahi et al.45 introduced a new magnetic solid acid nanocatalyst ([Fe3O4@SiO2@Am-PPC-SO3H] [HSO4]) for benzoxazole synthesis (3) using 2-aminophenol (1) and aldehyde (2) in water under reflux conditions for about 45 min and found 79–89% yield. The catalyst can be easily separated and used for 4 consecutive runs with significant catalytic activity. High yield, shorter reaction time, and ambient reaction conditions are additional benefits of the present protocol (Scheme 2; method 1).
Thin-layered nano h-BN/fl-G films were prepared and applied as an active catalyst to the synthesis of benzoxazole derivatives (3) by Rendón-Patiño and co-authors.46 The coupling of 2-aminophenol (1) and p-substituted benzaldehyde (2) in water/p-xylene at 70 °C showed a low yield of the desired product. The authors further devised an experiment for the reusability of the catalyst for 5 sequential cycles. Low yields and less substrate scope are the demerits of this method (Scheme 2; method 2).
In 2018, Bahrami et al.47 proposed a condensation reaction of 2-aminophenol (1) and aromatic aldehydes (2) in the presence of aqueous H2O2, ethanol, TTIP (titanium tetraisopropoxide), and the catalyst MTAMO (mesoporous titania–alumina mixed oxide) at 50 °C to give 2-substituted benzoxazole (3). The authors concluded that the reaction gave excellent yields (90–96%) in a short reaction time. The advantages of this procedure are that it is efficient and eco-friendly, and has an inexpensive catalyst with ease of operation (Scheme 2; method 3).
Agashe et al.48 synthesized a nanomaterial strontium carbonate from strontium nitrate, sodium hydroxide, and ethylene glycol in distilled water via a hydrothermal reaction. The synthesized SrCO3 was used as a catalyst for the synthesis of benzoxazole derivatives (3) from 2-aminophenol (1) and substituted benzaldehyde (2) via a grindstone method using a mortar and pestle at RT for 20 min to obtain a high yield in solvent-free conditions. The reusability of the catalyst, short reaction time, high yield, and eco-friendly approach are the characteristics of the present protocol (Scheme 2; method 4).
Moghaddam and co-workers49 reported a one-pot synthesis of 2-phenyl benzoxazole (3) catalyzed by a palladium-supported [SMNP@GLP] [Cl] nanocatalyst. The reaction between 2-aminophenol (1) and aldehydes (2) in the presence of O2, K2CO3, and DMF solvent at 80 °C with stirring for 18 h gave good to excellent yields. The authors synthesized 18 derivatives with 83–95% yield. This [SMNP@GLP] [Cl] nanocatalyst can be reused for 6 consecutive runs without losing its efficiency and gave a better yield than other methods. Effortless synthesis, high yield, good atom economy, and eco-friendliness are the specific benefits of this method but a long reaction time (18–48 h) is a major limitation of this method (Scheme 2; method 5).
Kumar and co-authors50 demonstrated a β-carboline scaffold consisting of benzoxazole synthesis (5) by the reaction between 1-formyl-9H-pyrido[3,4-b] indole (4) and 2-aminophenol (1) catalyzed by nano-ZnO using DMF as a solvent at 100 °C to give moderate yields. Operational simplicity and easy workup are special characteristic features of this approach. Low yields and high temperatures are major drawbacks of this method (Scheme 3).
The synthetic strategy for benzoxazole developed by Agashe et al. was found to be highly efficient among the described nanocatalyzed protocols.
Suryavanshi and co-authors51 utilized a metal oxide alumina catalyst for benzoxazole synthesis (3). 2-Aminophenol (1) and aldehyde (2) were stirred in acetonitrile solvent at room temperature for 5 h to attain a moderate yield (55–75%). The use of green solvents, recyclable catalysts, and a facile and eco-friendly synthesis are noteworthy advantages (Scheme 4; method 1).
In 2020, George and Sreekumar52 prepared palladium complexes of dendronized amine polymer (EG–Gn–Pd, n = 0, 1, and 2) catalysts for the synthesis of benzoxazoles (3). The reaction between 2-aminophenol (1) and benzaldehyde (2) with an EG–G2–Pd catalyst (10 mg) in ethanol at 50 °C for 3 h gave 88% product yield. The catalyst can be reused for 5 cycles with low degradation of catalytic activity, and a low amount of catalyst loading, air as an oxidant, and water as the only by-product are the unique merits of this protocol (Scheme 4; method 2).
In 2021, Wu et al.53 demonstrated an FeCl3-catalyzed aerobic oxidation reaction for the synthesis of 1-benzoxazolyl-o-carboranes (3) from 2-aminophenol (1) and 1-formyl-o-carborane (2) with toluene as a solvent at 110 °C for 24 h to give 50–96% yield depending on substitution. However, AgNO3 as a co-oxidant provided an excellent yield of 91–99%. High yield, good atom economy, a facile synthetic approach, and operational simplicity are the main features of this approach (Scheme 4; method 3).
Jilani and co-workers54 synthesized 2-substituted benzoxazole acetic acid derivatives (3) via an oxidative coupling reaction between methyl-3-amino-4-hydroxyphenylacetate (1) and aldehydes (2), catalyzed by lead tetraacetate in ethanol and the further addition of 90% NaOH solution in ethanol and water at RT for 3 h. Their cytotoxic activity against cancer cell lines, namely MCF-7 (human breast cancer cells) and HCT-116 (human colorectal carcinoma cells), was also evaluated. Cytotoxic activity was elevated in the presence of an acetic acid group at the fifth position on the benzoxazole moiety (Scheme 4; method 4).
In 2019, Layek et al.55 prepared nickel(II) complexes of benzoyl hydrazones and used them as catalysts for the synthesis of 2-aryl benzoxazoles (3). The Ni(II) complex-assisted intramolecular cyclization of 2-aminophenol (1) and aromatic aldehydes (2) in the presence of DMF and K2CO3 at 80 °C for 3–4 h, provided 87–94% yields. A low amount of catalyst loading and high yield are the plus points of this method (Scheme 4; method 5).
In 2022, Patil et al.56 demonstrated the potassium-ferrocyanide-catalyzed synthesis of benzoxazole derivatives (3) with the grinding method using a mortar and pestle under solvent-free conditions from 2-aminophenol (1) and aromatic aldehydes (2) at RT and found 87–96% yield in less than 2 min. The short reaction time, excellent yield, easy workup, nontoxic catalyst, and solvent-free and modest reaction conditions make this a greener approach (Scheme 4; method 6).
Sirgamalla and colleagues57 used a Cu2O catalyst in the reaction of 2-aminophenol (1) and substituted aryl aldehydes (2) in DMSO (dimethyl sulfoxide) at RT for 2–5 h to obtain a high yield of 2-substituted benzoxazoles (3). The authors synthesized 37 derivatives with 70 to 95% yield. The compounds displayed antifungal activity and this activity is similar to the standard drug voriconazole against Aspergillus niger. This approach has some benefits, like high yield, ambient reaction conditions, and good atom economy (Scheme 4; method 7).
Patil et al.58 reported the TiO2–ZrO2-catalyzed synthesis of 2-aryl benzoxazole derivatives (3) from the reaction between 2-aminophenol (1) and aromatic aldehyde (2) in acetonitrile at 60 °C for 15–25 min and obtained 83–93% yield. This procedure has several significant advantages: viz. the use of green catalysts, shorter reaction time, high yield, and environmental friendliness (Scheme 4; method 8).
Ravikumar and co-authors59 synthesized tetrazole fused benzoxazole derivatives (7) and analyzed their cytotoxicity in cancer cell lines. The reaction between 2-aminophenol (1) and 4-amino benzaldehyde (6) in ethanol using Pb(OAc)4 in acetic acid under reflux conditions, followed by reactions with HCl, NaNO2, and NaN3, then further reaction with aromatic nitriles in isopropanol and ZnBr2 was used to obtain tetrazole fused benzoxazoles and their anticancer activity was analyzed against cancer cell lines such as MCF-7, KB, Hop62, and A-549 (Scheme 5).
Patil et al.'s synthetic strategy for benzoxazole was found to be highly efficient among the described metal-catalyzed protocols.
In 2019, Nguyen and co-authors60 reported the synthesis of benzoxazole derivatives (3) using a Brønsted acidic ionic liquid gel catalyst in solvent-free conditions for the condensation and aromatization of 2-aminophenol (1) and aldehydes (2) at 130 °C for 5 h. The authors synthesized 14 derivatives with 85–98% yield. The catalyst was reusable for up to 5 consecutive runs without significant loss in its efficiency. Recoverable green catalysts, high yield, and facile workup are the attractive features of this method. High temperatures and long reactions limit the merits of this method (Scheme 6; method 1).
The synthesis of benzoxazole derivatives (3) by a condensation reaction between 2-aminophenol (1) and aldehydes (2) using a magnetic nanomaterial Fe3O4-supported Lewis acidic ionic liquid (LAIL@MNP) was investigated by Nguyen and co-workers.61 In this study, the reactants were sonicated under solvent-free conditions at 70 °C for 30 min to deliver moderate to high yields. Reusability of the catalyst, easy workup, solvent-free conditions, shorter reaction time, and a green pathway are advantages of this process (Scheme 6; method 2).
Zhou and co-authors62 prepared an ionic liquid [BMIm]2[WO4] catalyst via ion exchange using an ion exchange resin, H2WO2, and an ethanol solution of [BMIm]OH for 3 h and utilized this catalyst to synthesize various derivatives of benzoxazole (3). The reaction between 2-aminophenol (1) and aromatic aldehydes (2) using 1,4-dioxane as a solvent in the presence of air as an oxidant at 100 °C gave a decent yield. Several major benefits of this method are the use of air as an oxidant, base-free conditions, and catalyst recyclability for up to 5 consecutive runs (Scheme 6; method 3).
Nguyen et al.63 reported the phosphonium acidic ionic liquid [triphenyl(butyl-3-sulfonyl) phosphonium toluene sulfonate catalyzed synthesis of 2-aryl benzoxazole (3) from 2-aminophenol (1) and aryl aldehydes (2) at 100 °C under solvent-free conditions. The authors prepared 35 derivatives with 65–96% yield. Simple workup, recyclability of the catalyst, and solvent-free synthesis made this a green and efficient protocol (Scheme 6; method 4).
In 2020, Nguyen and co-authors64 introduced eosin Y as an effective photocatalyst to prepare benzoxazole derivatives (3). The reaction between 2-aminophenol (1) and aldehyde (2) in methyl cyanide or DMSO solvent using K2CO3 as a base and TBHP (tert-butyl-hydroperoxide) oxidant was exposed to radiation under argon with a blue LED (3 W) for 24 h. The authors prepared 18 derivatives with 58–92% yield. The advantages associated with this method are avoidance of the use of pre-synthesized catalysts and the traditional heating process (Scheme 7; method 1).
Mathapati et al.65 used fluorophosphoric acid as a highly effective acid catalyst for the synthesis of benzoxazole derivatives (3) by the reaction of 2-aminophenol (1) and aromatic/aliphatic aldehyde (2) in ethanol under stirring at room temperature for 2.4 h. The advantages of this protocol are the use of inexpensive and stable catalysts with shorter reaction time and ambient conditions (Scheme 7; method 2).
A condensation reaction between 2-aminophenol (1) and aldehydes (2) to produce 2-aryl benzoxazole derivatives (3) in good yield using a pent-ethylene diammonium pentachloro bismuth [NH3(CH2)5NH3BiCl5(III)] catalyst at RT under solvent-free conditions was reported by Benzekri et al.66 in 2018. Recyclability of the catalyst for up to 6 cycles, and solvent-free conditions make this a green and sustainable approach. However, less substrate scope is the demerit of this protocol (Scheme 7; method 3).
Kottayil et al.67 developed a method for the synthesis of benzoxazole derivatives (3) catalyzed by a homogenous ISO-PECH (isosorbide-initiated poly epichlorohydrin-cored) polyamine organocatalyst. The condensation reaction of 2-aminophenol (1) and aromatic aldehydes (2) in methanol at RT for 2–5 min gave a 92–99% yield. Economical and reusable catalysts, high yield, short reaction time, and easy workup are the special merits of this method (Scheme 7; method 4).
The facile and elementary synthesis of benzoxazole derivatives (3) using an RHCAC (rice husk derived chemically activated carbon) catalyst via the reaction of 2-aminophenol (1) and aldehydes (2) in ethanol and water (1:2) was reported by Asatkar et al.68 who obtained excellent yields. Biodegradable and reusable catalysts, high yield, and easy workup are the main features of this protocol (Scheme 7; method 5).
Nguyen et al. (2020)69 suggested the use of elemental sulfur as an oxidant for the synthesis of benzoxazole (3). The oxidative coupling of 2-aminophenol (1) and aldehyde (2) occurred in the presence of hydrated sodium sulfide (Na2S·5H2O) and DMSO additive at 70 °C for 16 h to give 40–78% yield. Using elemental sulfur rather than oxygen as an oxidant is feasible in organic synthesis, as elemental oxygen suffers a great risk of explosion of flammable organic substrates, and in the gaseous state, its stoichiometric control is not readily possible. On the other hand, sulfur is highly desirable and possesses unique properties like being inexpensive and user-friendly, and it can be used under ambient reaction conditions. With this method, benzoxazole can be simply synthesized while avoiding high-pressure equipment for a larger scale (10–50 mmol) (Scheme 7; method 6).
Kashid et al.70 exemplified the use of PPA (polyphosphoric acid) as a catalyst as well as a solvent for the synthesis of benzoxazole derivatives (3) and analyzed their antioxidant and antimicrobial activity. The reaction between 2-aminophenol (1) and aromatic aldehydes (2) in 40% aq. NaOH solution to adjust the pH to 5–6, at 145–150 °C for 3–6 h gave good to excellent yield. Cost-effectiveness, eco-friendliness, and high yield are the benefits of this protocol while the use of high temperature is a drawback of this procedure (Scheme 8).
An efficient and facile heterogeneous base-catalyzed (KF–Al2O3) synthesis of 2-substituted benzoxazole (9) was reported by Bahadorikhalili and Sardarian.72 The reaction between 2-aminophenol (1) and acid derivatives (8) in acetonitrile and anhydrous MgSO4 at room temperature for 45–90 min gave 83–95% yields. No significant decrease was found in catalytic efficiency for 10 consecutive runs. High yield, wide substrate scope, no by-product generation, and operational simplicity are the remarkable merits of the protocol (Scheme 9; method 2).
Zhengyu et al.73 investigated a novel and efficient one-pot synthesis of 3-difluoromethyl benzoxazole-2-thiones (11) using an NaOt-Bu (sodium tert-butoxide) base and elemental sulfur and evaluated their insecticidal activities against Plutella xylostella. This methodology took place via cyclization and N-difluoromethylation of 2-aminophenol (1) and sodium chloro-difluoro-acetate (10) in DMF and a 4Å-type molecular sieve as an additive at 70 °C. Operational simplicity, high yield, broad substrate scope, and easily available reactants are the special features of this method (Scheme 10).
Park et al.74 demonstrated a proficient synthesis of nocarbenzoxazoles and their derivatives (14) in high yield by cyclodehydration, demethylation, and reduction reactions and analyzed their anti-inflammatory activity in LPS-induced raw cells (264.7) via a nitric oxide inhibitory effect. The reaction was performed with ethyl ester substituted benzoic acid (12), substituted benzoyl chloride (13), and POCl3 in 1,4-dioxane at 90 °C for 15 h, further reaction with BBr3/CHCl3/AlCl3 in CH2Cl2 at −78 °C to RT, and a further reduction reaction using LiAlH4 in THF at 0 °C to RT for 30 min, to give 91–97% product yield (Scheme 11; method 1).
Karumanchi and colleagues75 reported the synthesis of tafamidis (14), a benzoxazole derivative via a two-step synthesis. In the first step, o-benzoylation of 3-hydroxy-4-nitrobenzoic acid (12) was undertaken using 3,5-dichlorobenzoyl chloride (13) and K2CO3 in aq. isopropanol at 0–10 °C for 2 h then at 20–30 °C for 2 h. In the second step, reductive cyclization took place by Zn in MsOH at 100–110 °C for 2 h and a moderate yield of the desired product was obtained. Ease of operation and mild reaction conditions are the merits of this protocol (Scheme 11; method 2).
Safaei and co-authors77 prepared a new binuclear oxo-bridged iron(III) complex catalyst and used it for the synthesis of benzoxazole derivatives (9) by the reaction between benzyl alcohols (15) and 2-aminophenol (1) in ethanol–water (1:1) solvent and TBHP as an oxidant in water at 80 °C for 12 h in good yield. Moderate reaction conditions, and low catalyst loading, are additional features of the method (Scheme 12; method 2).
Han and co-workers78 developed a titania-supported iridium catalyst by an impregnation method and used it to prepare 2-substituted benzoxazoles (9) via acceptor-less dehydrogenative synthesis using 2-aminophenol (1) and primary alcohols (15) in mesitylene under an argon atmosphere at 80–170 °C for 18 h to give decent yields. This protocol has special properties like an easily recoverable and reusable catalyst with high efficiency, broad substrate scope, high yield, and low waste generation. Longer reaction time and high temperature limit the efficiency of the method (Scheme 12; method 3).
Bailu and colleagues80 disclosed a novel and facile one-pot synthesis of benzoxazole derivatives (9) promoted by TFA (trifluoroacetic acid) by the cleavage of the C–C double bond of N-(2-hydroxylphenyl) enaminones derived from the reaction of 2-aminophenol (1) and alkynones or diketones (16) in 1,2-dichloroethane (DCE) at 100 °C for 12 h to give 63–96% yield. This pathway provided broad substrate scope, less toxicity, economy, high product yield, and fewer by-products. The use of toxic solvents and a long reaction time are the disadvantages of the protocol (Scheme 13; method 2).
In 2020, Wu and colleagues82 disclosed the effective synthesis of glycosyl benzoxazole analogs (20) and evaluated their cholinesterase inhibition activity (AChE and BuChE). In this process, desulfurization and cyclization reactions took place using glycosyl isothiocyanate (19) and 2-aminophenol (1) for 8–10 h, with the later addition of p-toluene sulfonyl chloride in THF and pyridine to give the desired product. The presence of 4-methyl and 5-chloro substituents on the benzoxazole ring showed the highest inhibitory activity for AChE and BuChE, respectively. This procedure involved various benefits like ambient conditions, the use of green solvents, and economical and simple operation (Scheme 15).
Recently, Nguyen et al.84 proposed a unique and efficient sulfur-promoted synthesis of 2-benzoylbenzoxazoles (23) by the reaction of 2-aminophenol (1) and acetophenones (22) using NMM (N-methyl morpholine) in DMSO solvent at 110 °C for 16 h. The authors synthesized 35 derivatives in 35–85% yield. Easily available and cost-efficient reagents, operational simplicity, and a variety of substrate scopes are the significant features of this protocol (Scheme 17).
In 2019, Haghighat and co-workers86 synthesized an efficient and eco-benign periodic mesoporous organo-silica with bridged N-sulfonic acid groups (SA-PMO) catalyst and assessed its catalytic activity for the solvent-free synthesis of benzoxazoles (9) from 2-aminophenol (1) and ortho-esters (24) at 80 °C for 5–8 min. Simple workup, short reaction time, enriched yields, reuse of the catalyst for up to 5 runs with less change in yield, and solvent-free condition made this a green pathway (Scheme 18; method 2).
Scheme 19 Various pathways for the synthesis of benzoxazole using 2-aminophenol and different substrates. |
Rapolu et al.88 illustrated a facile simple one-pot reaction for the synthesis of benzoxazole derivatives (28) under microwave irradiation at 80 °C from 2-aminophenol (1) and EDC·HCl (27) in isopropanol. This pathway provided some merits like a one-step reaction, simple operation, shorter reaction time, and the use of MW irradiation (Scheme 19; method 2).
The 2,4,6-trihydroxy benzoic acid-catalyzed synthesis of 2-phenyl benzoxazole (3) from the oxidative coupling of 2-aminophenol (1) and benzylamine (29) under an O2 atmosphere was explained by Kumazawa and colleagues.89 The authors employed this reaction in four different solvents, ethyl acetate, acetonitrile, toluene, and p-xylene, at 70 °C–140 °C. Among the solvents, p-xylene proved the best solvent at a temperature of 140 °C (Scheme 19; method 3).
Gan et al.90 investigated a practical, convenient, and well-organized pathway for benzoxazole synthesis (31) by the cyclization of 2-aminophenol (1) and aryl acetylenes (30) in dimethyl formamide (DMF) using sulfur as an oxidant at 110 °C. A broad range of aryl acetylenes with electron withdrawing and donating groups was examined and gave low to moderate (40–71%) yield. A clean reaction profile, operational simplicity, and easily available starting materials are the plus points of this approach (Scheme 20; method 1).
With this method, Saeed and co-authors91 demonstrated an effective and facile synthesis of benzoxazole methyl ester (33). The reaction between 2-aminophenol (1) and thiourea (32) at 200 °C for 2 h produced benzoxazole-2-thiol which was further reacted with methyl chloroacetate in methanol for 6 h at reflux. The authors further studied Hirshfeld surface analysis via crystal packing interactions in which H–H interaction was found to make the biggest contribution (33.2%) to the entire crystal packing (Scheme 20; method 2).
In this procedure, efficacious elemental sulfur promoting the synthesis of benzoxazole derivatives (35) was introduced by Zhengyu and colleagues.92 The reaction of 2-aminophenol (1) and 2-bromo-3,3,3-trifluoropropene (34), NaHCO3 base, and 2,2′-azobis-(2,4-dimethylvaleronitrile) or bis(pinacolato)diboron (ADVN/B2Pin2) additive was conducted under a nitrogen atmosphere in DMF solvent at 100 °C for 15 h to obtain the desired product. A variety of derivatives was investigated in 38–85% yield by changing the substituents with different EWG and EDG at the aryl ring of the amino phenol. A simple workup process, a broad scope of functionalization, high yield, and cost-effectiveness are the highlights of this methodology with a long reaction time as its demerit (Scheme 20; method 3).
Rapolu et al.93 developed an eco-friendly and microwave-irradiated one-pot synthesis of the analog of 2-substituted benzoxazole (37) from 2-aminophenol (1) and carbodiimides (36) in ZnCl2 catalyst and isopropanol solvent at 80 °C for 30 min and found excellent yields (90–94%). This pathway is employed as an atom economic method with scaled-down toxicity, amount of solvent, and reaction time (Scheme 20; method 4).
TTIP | Titanium tetraisopropoxide |
MTAMO | Mesoporous titania–alumina mixed oxide |
H2O2 | Hydrogen peroxide |
K2CO3 | Potassium carbonate |
DMF | Dimethylformamide |
SrCO3 | Strontium carbonate |
ZnO | Zinc oxide |
FeCl3 | Ferric chloride |
AgNO3 | Silver nitrate |
NaOH | Sodium hydroxide |
MCF-7 | Michigan Cancer Foundation-7 |
HCT-116 | Homo sapiens colon carcinoma 116 |
Cu2O | Copper oxide |
DMSO | Dimethyl sulfoxide |
Pb(OAc)4 | Lead tetraacetate |
HCl | Hydrogen chloride |
NaNO2 | Sodium nitrite |
NaN3 | Sodium azide |
ZnBr2 | Zinc bromide |
KB | HeLa (Henrietta Lacks) KB |
Hop62 | Hopkins 62 |
A-549 | Human adenocarcinomic alveolar basal epithelial cell line |
Fe3O4 | Iron(II,III) oxide |
TBHP | tert-Butyl hydroperoxide |
LED | Light emitting device |
PPA | Polyphosphoric acid |
pH | Potential of hydrogen |
RHCAC | Rice-husk derived chemically activated carbon |
Na2S | Sodium sulfide |
MgSO4 | Magnesium sulfate |
NaOt-Bu | Sodium tert-butoxide |
POCl3 | Phosphoryl chloride |
BBr3 | Boron tribromide |
CHCl3 | Chloroform |
AlCl3 | Aluminium chloride |
CH2Cl2 | Dichloromethane |
LiAlH4 | Lithium aluminium hydride |
THF | Tetrahydrofuran |
MsOH | Methane sulfonic acid |
TFA | Trifluoroacetic acid |
DCE | 1,2-Dichloroethane |
AChE | Acetylcholinesterase |
BuChE | Butyrylcholinesterase |
CH3CN | Acetonitrile |
NCTS | N-Cyano-N-phenyl-p-toluene sulfonamide |
EDC·HCl | 3-Ethylcarbodimide hydrochloride |
MW | Microwave |
NaHCO3 | Sodium bicarbonate |
ADVN | 2,2-Azobis-(2,4-dimethylvaleronitrile) |
B2Pin2 | Bis(pinacolato)diboron |
EWG | Electron withdrawing group |
EDG | Electron donating group |
ZnCl2 | Zinc chloride |
NMM | N-Methyl morpholine |
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