The Fischer oxazole synthesis is a chemical synthesis of an oxazole from a cyanohydrin and an aldehyde in the presence of anhydrous hydrochloric acid. This method was discovered by Emil Fischer in 1896. The cyanohydrin itself is derived from a separate aldehyde. The reactants of the oxazole synthesis itself, the cyanohydrin of an aldehyde and the other aldehyde itself, are usually present in equimolar amounts. Both reactants usually have an aromatic group, which appear at specific positions on the resulting heterocycle. A more specific example of Fischer oxazole synthesis involves reacting mandelic acid nitrile with benzaldehyde to give 2,5-diphenyl-oxazole. History Fischer developed the Fischer oxazole synthesis during his time at Berlin University. The Fischer oxazole synthesis was one of the first syntheses developed to produce 2,5-disubstituted oxazoles. Mechanism The Fischer oxazole synthesis is a type of dehydration reaction which can occur under mild conditions in a rearrangement of the groups that would not seem possible. The reaction occurs by dissolving the reactants in dry ether and passing through the solution dry, gaseous hydrogen chloride. The product, which is the 2,5-disubstituted oxazole, precipitates as the hydrochloride and can be converted to the free base by the addition of water or by boiling with alcohol. The cyanohydrins and aldehydes used for the synthesis are usually aromatic, however there have been instances where aliphatic compounds have been used. The first step of the mechanism is the addition of gaseous HCl to the cyanohydrin 1. The cyanohydrin abstracts the hydrogen from HCl while the chloride ion attacks the carbon in the cyano group. This first step results in the formation of an iminochloride intermediate 2, probably as the hydrochloride salt. This intermediate then reacts with the aldehyde; the hydroxyl group of 2 abstracts a hydrogen from the nitrogen, while the lone pair of the nitrogen attacks the electrophilic carbonyl carbon on the aldehyde. The following step results in an SN2 attack followed by the loss water to give a chloro-oxazoline intermediate 4. Next is the tautomerization of the a ring proton. The last step involves an elimination and the loss of an HCl molecule to form the product 6, which is the 2,5-diaryloxazole. Applications Diarylazoles are common structural motifs in both natural products and drug candidates, however they are difficult to synthesize. Diaryloxazoles are generally prepared through the Fischer oxazole synthesis or Robinson-Gabriel synthesis, where the oxazole ring is constructed via either synthesis. The