AN UPDATE ON THE SYNTHESIS OF BENZOXAZOLES

Benzoxazoles being structurally similar to bases adenine and guanine interact with biomolecules present in living systems. These compounds possess antimicrobial, central nervous system activities, antihyperglycemic potentiating activity, analgesic, and anti-inflammatory activity. It can also be used as starting material for other bioactive molecules. Modifications in structure and the biological profiles of new generations of benzoxazoles were found to be more potent with enhanced biological activity. Considering all these, we have prepared this review and discussed the synthesis and biological activities of benzoxazoles.

A new series of 5 (or 6) methyl-2-substituted benzoxazoles (14) were described by Oren et al. [4]. Some of these compounds showed significant activity against Pseudomonas aeruginosa having MIC 2.5 mg/ml, providing higher potencies than the reference drugs.
The in vitro antibacterial and antifungal activities of six benzimidazole and benzoxazole derivatives (15) were tested on clinical isolates where two of the benzoxazoles were found to be active [5]. Some 2-(N-Aryl-carboxamidomethylthio)benzoxazoles (16) and corresponding sulfones (17) were prepared, and their antimicrobial activity was assayed against some bacteria and fungi and was found to exhibit 20-70% inhibition at a concentration of 0.1 mg/ml [6].
Bahadur and Pandey [8] reported the synthesis and antiviral activity of p-(2-benzoxazolyl) phenoxy acetic acid hydrazides (19) and corresponding arylidene hydrazides (20). These compounds were found to exhibit a significant antiviral activity in vitro but not in vivo.
Similarly, compound (28) on allylation with allyl iodide in dimethyl form amide results in the corresponding quaternary salt (30). Benzoxazoles react with two moles of diphenyl keten in a [2+2+2] cyclo addition involving the C=N double bond, affording an oxazine-fused benzoxazole. Benzoxazoles are resistant to alkaline hydrolysis but are readily cleaved by acids, probably because of nucleophilic attack.
Benzoxazole hydrolysis is relatively easy, 2-methyl benzoxazole giving o-acetamido phenol in hot water, although the reaction is more rapid in dilute acid.
Quaternary salts are hydrolyzed more readily as shown by the hydrolysis of N-methyl benzoxazole (32).
2-Methylbenzoxazole (31) reacts with benzaldehyde in the presence of zinc chloride to give the 2-benzylidene derivative (41) indicating the reactivity of the methyl group linked to azomethine system. (42) is reactive enough to couple with diazonium salts and reacts at the 2-methylene group with aldehydes, nitroso compounds, and amyl nitrite.

Synthesis
Benzoxazoles (44) have been obtained by heating o-aminophenol and carboxylic acids in the presence of PPA [13].
Thermal cyclization with acid catalysts is commonly employed to synthesize benzoxazoles (1).
Thermal dehydration [14] of o-(acylamino) phenols is most widely used for the preparation of these compounds (47).
Beckmann rearrangement of oximes of o-hydroxybenzophenones leads to the formation of benzoxazoles (48).
Benzoxazoles (49) can also be prepared by the action of potassium amide in liquid ammonia.
The synthesis of benzoxazoles (1) by the cyclocondensation reaction of o-aminophenol with S-methyl isothioamide hydroiodides on silica gel under microwave irradiation and also in a solvent under reflux [15].
The compounds (62) prepared by direct condensation of suitable aminophenol with substituted phenyl acetic acid [32].
The oldest method in the synthesis of benzoxazoles [35] (66) is heating or distilling 2-formamidophenols at elevated temperatures.
Solid phase synthesis of benzoxazoles was reported by Wang and Hauske [37]. 2-Aminophenol attached to a solid support can be converted to the corresponding benzoxazole (67) by the treatment with triphenylphosphine and diethyl azodicarboxylate in THF at room temperature, in high yield and purity.
A one-pot synthesis of benzoxazoles by chromium-manganese redox coupled reactions reported by Hari et al. [40]. The reaction in which a chromium-manganese redox couple is employed both to catalytically reduce an o-hydroxy nitroarene and to oxidatively cyclize a subsequently formed imine (70).
The intermediates of 5 and 6-nitrobenzoxazoles were prepared by the following routes: a. PPA-catalyzed ring closure of o-aminophenols with the appropriate carboxylic acids followed by nitration of benzoxazoles b. Acylation of nitroaminophenols with carboxylic acid chlorides and subsequent thermally induced cyclodehydration of the amides c. Oxidation cyclization of Schiff bases using lead (IV) acetate and d. Reaction of imino ethers derived from 2-cyanopyrazine or cyano-nitropyridine with o-aminophenols and nitration of corresponding benzoxazoles.
Facile synthesis of 2-substituted benzoxazoles via ketenes reported by Olagbemiro et al. [44]. The generation of diphenyl-, phenyl-, phenoxy-, and chloroketenes by the treatment of corresponding acid chlorides with triethylamine in the presence of 2-aminophenol resulted in good yields of 2-substituted benzoxazoles (75).

Jyothi and Merugu
Omar et al. [45] reported the synthesis of several 2-ethoxycarbonyl-benzoxazoles (76). They are synthesized in high yield by cyclodesulfurization of the corresponding thioureas and thiosemicarbazide derivatives with dicyclohexylcarbodiimide.
With ROH (R = Bu, aralkyl) to give the corresponding benzoxazoles. Benzoxazoles being structurally similar to bases adenine and guanine possess significant biological activities [47][48][49] and structural modifications can result in molecules with enhanced biological activity.

CONCLUSIONS
Considering the biological and pharmacological importance of these molecules, the synthetic strategies of various benzoxazoles were discussed and reviewed in this article.