Oxazoles Davidson oxazole synthesis

DAVIDSON Oxazole Synthesis Synthesis of Iriaryl oxazoles from a-hydroxyketones (benzoins)... 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

Application of the Davidson oxazole synthesis to products of the Passerini reaction has expanded the usefulness of this well-known route <91LAll07>. The a-acyloxy ketones or a-acyloxy -keto esters employed in the Davidson synthesis are not readily available. However, the use of arylglyoxals as the carbonyl component of the Passerini reaction, along with cyclohexyl isocyanide and carboxylic acids, gives a wide variety of iV-cyclohexyl-2-acyloxy-3-aryl-3-oxopropionamides (151). Reaction of these intermediates with ammonium formate in acetic acid affords A -cyclohexyl-2,4-diaryl-5-oxazolecarboxamides (152) in fair yields (Scheme 69). 

The Davidson oxazole synthesis is the reaction of an acylated a-hydroxy carbonyl with an ammonium cation, typically ammonium acetate to yield oxazoles. The Davidson synthesis is also linear, as all three substituents are contained in the precursor. The reaction is most efficient in preparing 2,4,5-trisubstituted oxazoles, where C5 is aryl substituted. Yields suffer when preparing a 2,4-disubstituted or a mono-substituted oxazole. The COX-2 inhibitor tilmacoxib was prepared by Haruta in this manner. ... 

The Davidson oxazole synthesis describes the preparation of substituted oxazoles 2 from the condensation of / -keto-esters 1 with ammonia or ammonium acetate. A general reaction scheme is depicted below. 

Jefferys has modified the Davidson oxazole synthesis by using phenacyl bromides and ammonium acetate to yield 2-methyl-4-(or 4,5-di-)-substituted oxazoles. He was also able to extend the syntheses outlined by Japp and Davidson to obtain 4,5-dialkyl and 4-aryl oxazoles. These oxazoles together with 2-methyloxazole were then quatemized and transformed into cyanine and merocyanine dyes. 

This synthesis of oxazoles was much studied by Davidson and co-workers, who investigated both the mechanism of formation of oxazoles and also a general method to prepare substituted oxazoles. It was eventually found that the reaction gave better results when synthesizing 2,4,5-tri-substituted oxazoles with an aromatic substituent at C-5 and mediocre yields for the formation of 2,4-disubstituted or mono-substituted oxazoles. 

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