Oxazole is an aromatic compound containing an oxygen and nitrogen separated by one carbon. It is prepared through several syntheses including the Robinson-Gabriel synthesis using 2-acylaminoketones, Fischer oxazole synthesis from cyanohydrins and aldehydes, and the Bredereck reaction with α-haloketones and formamide. Oxazoles are weakly basic and are used in fungicides, pesticides, and various drugs due to their ability to undergo substitutions and reactions like Diels-Alder. They are also involved in the biosynthesis of non-ribosomal peptides from serine or threonine.

1. Oxazole
C3H3NO
Prepared by- Dr. V. P. Nagulwar

2. Introduction
 It is azoles with an oxygen and a nitrogen separated by one carbon.
 Aromatic compounds but less so than the thiazoles.
 Weak base; its conjugate acid has a pKa of 0.8, compared to 7 for imidazole.
 Flammable and corrosive
 Boiling point is 69.5 °C
 A large number of substituted oxazole containing natural products have been isolated,
mostly from marine invertebrates and microorganisms.

3. Synthesis
 Robinson–Gabriel synthesis by dehydration of 2-acylaminoketones
 Fischer oxazole synthesis from cyanohydrins and aldehydes
 Bredereck reaction with α-haloketones and formamide
 Van Leusen reaction with aldehydes and TosMIC

4. Robinson–Gabriel synthesis
It is an organic reaction in which a 2-acylamino-ketone reacts intramolecularly followed by a
dehydration to give an oxazole. A cyclodehydrating agent is needed to catalyze the reaction-
concentrated sulfuric acid, phosphorus pentachloride, phosphorus pentoxide, phosphoryl
chloride, thionyl chloride, phosphoric acid-acetic anhydride, polyphosphoric acid and anhydrous
hydrogen fluoride.
Mechanism

5. Fischer oxazole synthesis
A chemical synthesis of an oxazole from a cyanohydrin and an aldehyde in the presence
of anhydrous hydrochloric acid. The cyanohydrin itself is derived from a separate
aldehyde.
Specific example of Fischer oxazole synthesis involves reacting mandelic acid
nitrile with benzaldehyde to give 2,5-diphenyl-oxazole

6. Bredereck reaction with α-haloketones and formamide

7. Mechanism

8. Van Leusen reaction
Reaction of a ketone with TosMIC leading to the formation of a nitrile. When aldehydes
are employed, reaction is particularly useful to form oxazoles and imidazoles.

9. Other pathways
Cyclo-isomerization of certain propargyl amides

10. From nitro-substituted benzoyl chloride and an isonitrile

11. Biosynthesis
Cyclization and oxidation of serine or threonine non-ribosomal peptides
Where X = H, CH3 for serine and threonine respectively, B = base
(1) Enzymatic cyclization (2) Elimination (3) [O] = enzymatic oxidation

12. Reactions
 Deprotonation of oxazoles at C2 is often accompanied by ring-opening to the
isonitrile.
 Electrophilic aromatic substitution takes place at C5 requiring activating
groups.
 Nucleophilic aromatic substitution takes place with leaving groups at C2.

13. N-Alkylation
N-Acylation

14.  Diels–Alder reactions with oxazole dienes can be followed by loss of oxygen to
form pyridines.
 Cornforth rearrangement of 4-acyloxazoles is a thermal rearrangement
reaction with the organic acyl residue and the C5 substituent changing
positions.
 Oxidation reactions- oxidation of 4,5-diphenyloxazole with 3 equivalents of
CAN to the corresponding imide and benzoic acid:

15. Uses
 Adrenergic Antagonists
 Fungicides
 Anthelmintic Agents
 Antihypertensive Agents
 Antiulcer Agents
• Pesticides
• Agrochemical Fungicides
• Insecticides

16. Some drugs with oxazole ring

17. References & Recommended Readings
1. Organic Chemistry, I. L. Finar
2. Text book of Organic Chemistry, A. Bahl and B.Bahl
3. Heterocyclic Chemistry, T. L. Gilchrist
4. Heterocyclic Chemistry, J. S. Clark
http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html
5. The Pharma Innovation Journal 2017, 6(1): 109-117