Cyanohydrins, Fischer oxazole synthesis

Fischer oxazole synthesis. Condensation of equimolar amounts of aldehyde cyanohydrins and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid. 

F. From Cyanohydrins and Aldehydes (Fischer Oxazole Synthesis). 120... 

Fischer oxazole synthesis, reported in 1896 by Emil Fischer, is one of the earliest methods reported for the synthesis of 2,5-disubstituted oxazoles. It entails the reaction of cyanohydrin with aldehyde under dry acidic conditions to form the corresponding oxazole. ... 

Fischer s name is associated with a great number of important organic transformations, such as the Fischer indole synthesis, Fischer esterification, Kiliani-Fischer synthesis, and the Fischer oxazole synthesis. The Fischer oxazole synthesis was one of his first contributions in his early years in the Berlin University (currently Humboldt University). In 1896 he published a new synthesis of 2,5-diaryloxazoles using an acid-catalyzed condensation of cyanohydrins with aldehydes. 

In 1977 Davis, Temai et al. introduced an interesting variation to the synthesis. In their efforts to form substituted 2,5-diaryl oxazoles, a simple modification of the Fischer oxazole synthesis rendered a good yielding process. Acyl cyanide replaces cyanohydrins, which reacts with aldehyde to form 2,5-diaryl-4-chloro- (or bromo-) oxazoles. An example for such variation is the synthesis of the chloro-oxazoles 14. Benzoyl cyanide (12) reacts with aldehyde 13a at 0 C in the presence of HCl, and the mixture is stirred overnight to give 14a in a 75% yield. Similarly, benzoyl cyanide reacts with aldehyde 13b to give 14b in a 65% yield. 4-Bromo-oxazoles can also be formed using such variation. An example is the synthesis of 16 by the reaction of p-nitrobenzoyl cyanide (15) with benzaldehyde in the presence of HBr the 4-bromo adduct is formed in a 68% yield. 

Oxazoles are a common structural motif foxmd in numerous molecules that display antiviral, antifungal, antibacterial, and antiproliferative activities [150,151]. Classical methods for oxazole synthesis include Robinson-Gabriel synthesis by dehydration of 2-acylaminokefones, Fischer oxazole synthesis from cyanohydrins and aldehydes, Bre-dereck reaction with a-haloketones and formamide. Van Leusen reaction with aldehydes and TosMIC, Hantzsch reaction, and aza-Wittig reaction [152]. 

---