Synthesis, Reactions and Medicinal Uses of Oxazole

Oxazole

Synthesis

Robinson – Gabriel synthesis - The 2, 5 -diaryloxazole is formed by cyclizing and dehydrating a α-acylamino ketone.



Reaction of α - halo ketones with primary amides -



From isocyanides with acid chlorides - Anhydrous hydrogen fluoride, polyphosphoric acid, or phosgene are usually used to induce cyclization, while dehydrating agents, such as H2SO4, PCl3, POCl3, or SOCl2, are frequently used to induce dehydration.



Reaction with α - hydroxy amino ketones with aldehydes - By reacting with an aldehyde in the presence of sulfuric acid and acetic anhydride, the α-hydroxyamino ketone is converted to oxazole. C2 - atoms in oxazole are derived from aldehydes.



From α - aminocarbonyl compounds -

Reactions

Pyridine type nitrogen at 3 – position - Protonation (basicity), N-alkylation, and atoms attacked by nucleophiles can all be explained by it.

Furan type oxygen at 1 – position - Diels-Alder reactions (cycloaddition reactions) of oxazole with alkenes and alkynes are explained by its diene-type behavior. By substituting the oxazole ring with electron-releasing substituents, the reactions can be facilitated with dienophiles.

Protonation (Basicity) - Bases are weak in Oxazole. Salts are formed from its reaction with acids (hydrochloride or picrate).

N – alkylation - Quaternary oxazole salts, salts of N-alkyloxazolium with alkylating agents.



Electrophilic substitution reaction - Unless an electron releasing substituent is used to replace the oxazole ring, electrophilic substitutions of the ring are difficult. C4 > C5 > C2 are the positions of the oxazole ring that are most reactive.

Because oxazoline cations are highly electron-deficient, nitrous, sulfonated, and chlorosulfonated reactions do not occur in unsaturated oxazole rings. The electrophile easily attacks the ring when electron-releasing substituents are present.



Formylation Vilsmeier-Hack is another example



Nucleophilic substitution reaction - Deprotonation at C2 position is easy for an oxyazole with an unsubstituted 2-position. Generally, nucleophilic substitution reactions do not occur with oxazole. Nucleophilic attack on the most electron-deficient C2-position is facilitated by substituents withdrawing electrons at C4. A nucleophile can easily replace the halogen atom at C2 of the oxazole ring, for example.



In most cases, nucleophilic attacks on the oxazole ring cause the oxazole ring to split rather than undergo nucleophilic substitutions. In the presence of ammonia/formamide (a nucleophile), oxazoles become imidazoles via ring cleavage.



Metallation - The most electron-deficient C2-atom in the carbon chain is attacked by lithium first. Due to their instability, these 2-lithia-oxazoles break down into open-chain isocyanides.



Oxidation - By using cold potassium permanganate, chrome acid, and ozone, oxidizing agents can open the oxazole ring. Hydrogen peroxide generally does not affect oxazole. N-oxides can be formed from substituted oxazole.



Reduction - The oxidation of oxazole is relatively easy. The oxidation of oxyazoles is relatively easy. Open-chain products result from reduction and cleavage of the ring caused by other reducing agents.



Cycloaddition reaction - In the presence of 2, 5-positions, cycloaddition of oxazoles is easy. The oxazole ring contains electron-donating substituents that facilitate reactions with dienophiles. Thus, pyridine or furan derivatives can be prepared from these adducts. Benzyne, alkene, and alkyne dienophiles have been reported to undergo cycloadditions.

Alkene dienophile



Alkyne dienophile



Benzyne dienophile

Medicinal Uses

Oxazole's wide range of biological activity has been found to make it effective at combating bacteria, fungal infections, viral infections, tuberculosis, cancer, and inflammation.

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