The oxazole is formed from the Ugi intermediate, which is ideal to undergo Robinson-Gabriel cyclodehydration with sulfuric acid
Many cyclodehydrating agents have been discovered to be of use in the Robinson–Gabriel synthesis.
developed a solid-phase synthesis of 1,3-oxazole-based peptides on solid phase from dipeptides by oxidation of the side-chain followed by Wipf and Miller's cyclodehydration of β-ketoamides described above.
Lilly Research Laboratories has disclosed the structure of a described dual PPARα/γ agonist that has possible beneficial impact on type 2 diabetes.
The initial steps follow the Fischer oxazole synthesis, although the acid-catalyzed cyclization occurs in two steps rather than one, which ensures the formation of the di-chloro intermediate, preventing formation of the regioisomer.
Diarylazoles are common structural motifs in both natural products and drug candidates, however they are difficult to synthesize.
Starting with aspartic acid β esters undergoing acylation to differentiate the first substituent, linked to carbon-2, followed by Dakin-West conversion to keto-amide to introduce the second substituent, and ending with the Robinson-Gabriel cyclodehydration at 90°C for 30 minutes with either phosphorus oxychloride in DMF or catalytic sulfuric acid in acetic anhydride.
The Robinson–Gabriel synthesis is an organic reaction in which a 2-acylamino-ketone reacts intramolecularly followed by a dehydration to give an oxazole.