Synthesis and Reactions of Oxazole: Oxazole is a 1, 3-azole having an oxygen atom and a pyridine type nitrogen atom at the 3-position in a five-membered ring. The scientist Hantzsch was first to introduce it in 1887. Oxazole is a liquid with a boiling point of 69°C. Unlike imidazole and thiazole, oxazole is not naturally occurring. Oxazoles are weakly basic. The lone pair of electrons on the pyridine type nitrogen is not involved in maintaining aromaticity but it is available for protonation. Thus, the lone pair of electrons impart basicity to the molecule.
The partially reduced oxazoles are called oxazolines while fully saturated oxazole is called oxazolidine.
Chemical Synthesis of Oxazole
(i) Ethyl α-hydroxy keto succinate reacts with formamide to give diethyl-oxazole-4, 5- dicarboxylate. In the next step, it is subjected to hydrolysis and subsequent decarboxylation to oxazole.
(ii) Robinson-Gabriel Synthesis: In this method, an α-acylamino ketone undergoes cyclization and dehydration to give 2, 5 –diaryloxazoles.
Polyphosphoric acid, phosgene, or anhydrous hydrogen fluoride are used to induce cyclization while H2SO4, PCl3, POCl3, or SOCl2 may be used as a dehydrating agent in this reaction.
(iii) Reaction of α-halo ketones with primary amides:
(iv) From isocyanides with acid chlorides: Isocyanides when treated with t-butyllithium give α – metallated isocyanide. The latter when reacted with carboxylic acid derivatives (e.g., acid chloride, ester, or amide) gives oxazole.
(v) Reaction of α-Hydroxy amino ketones with aldehyde: The α-hydroxyamino ketone reacts with an aldehyde in the presence of sulfuric acid and acetic anhydride to give oxazole. The C2 – atom in oxazole comes from the aldehyde.
(vi) From α – Aminocarbonyl compounds:
(vii) Fischer Oxazole synthesis: This synthesis was discovered by Emil Fischer in 1896. In this method, a cyanohydrin reacts with an aldehyde in the presence of anhydrous HCl to give substituted oxazole.
Chemical Reactions of Oxazole
The oxazole ring contains:
(a) Pyridine-type nitrogen at 3-position: It explains protonation (basicity), N-alkylation, and nucleophilic attack at C2-atom.
(b) Furan type oxygen at 1-position: It explains diene-type behavior of oxazole to undergo Diels-Alder reactions with alkenes and alkynes dienophiles (cycloaddition reactions). The presence of electron-releasing substitutions on the oxazole ring facilitates the reactions with dienophiles.
(i) Protonation (Basicity): Oxazole is a weak base. It reacts with acids to form unstable salts (hydrochloride/picrate salts).
(ii) N-alkylation: Oxazoles from quaternary salts, N-alkyloxazolium salts with alkylating agents.
(iii) Electrophilic substitution reactions: The oxazole ring does not undergo electrophilic substitutions easily unless the ring is substituted with electron releasing substituent. The order of reactivity of positions in the oxazole ring is C4 > C5 > C2.
Nitration, sulfonation, and chlorosulfonation do not occur in unsubstituted oxazole rings due to highly electron-deficient oxazoline cation. When the electron releasing substituents are present in the ring, electrophile easily attacks.
Another example of electrophilic substitution is the Mercuration of oxazole with mercuric acetate in acetic acid.
Vilsmeier – Haack formylation is yet another example
(iv) Nucleophilic substitution reactions: Oxazole with unsubstituted 2-position gets easily deprotonated at C2-position by a strong base. Otherwise, oxazole rarely undergoes nucleophilic substitution reactions. Electron withdrawing substituent at C4 facilitates nucleophilic attack at most electron-deficient C2-position. For example, the halogen atom at C2 of the oxazole ring is easily replaced by a nucleophile.
In most cases, nucleophile attacks on the oxazole ring rather result in the cleavage of the oxazole ring than actual nucleophilic substitution reactions. For example, oxazoles get transformed into imidazoles via ring cleavage when treated with ammonia /formamide (nucleophile).
(v) Metallation: Lithium preferentially attacks the most electron-deficient C2-atom. The resulting 2-lithia-oxazoles are unstable and get cleaved to the open-chain isocyanides.
(vi) Oxidation: The oxazole ring is opened by the action of oxidizing agents such as cold potassium permanganate, chromic acid, and ozone. Oxazole is normally stable to the action of hydrogen peroxide. 2 – substituted oxazoles can be converted to N-oxides.
(vii) Reduction: Oxazoles are relatively easily reduced. Reduction of the oxazole ring to oxazolidines can be effectively done with sodium in ethanol. Other reducing agents cause reduction and cleavage of the ring to give open-chain products.
(viii) Cycloaddition reactions: Oxazoles easily undergo cycloaddition across 2, 5-positions. The presence of electron-donating substituents on the oxazole ring facilitates the reactions with dienophiles. The adducts so obtained serve as important precursors for substituted pyridine or furan derivatives. Cycloadditions have been reported with alkene, alkyne, and benzyne dienophiles.
(i) Alkene dienophile:
(ii) Alkyne dienophile:
(iii) Benzyne dienophile:
Applications in Drug Synthesis
Oxazole is one of the important components in penicillin (antibiotic) structure. The Oxazole family includes oxazoles, isoxazoles, oxazolines, oxadiazoles, oxazolidones, benzoxazoles, etc. Oxazoles display versatile biological activities including antibacterial, antifungal, antiviral, antitubercular, anticancer, anti-inflammatory, analgesic, antidiabetic, etc.
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