Oxazole Comforth synthesis

The Comforth synthesis of oxazoles is useful for the preparation of 4-methoxycarbonyl derivatives, which are found in many natural products (92CC1240). In this method, a glycine imidate is reacted with a strong base and methyl formate to give an enolate that cyclizes upon treatment with acetic acid (Scheme 32). 

A microwave assisted Comforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>. 

Williams, D. R. McClymont, E. L. Carbanion methodology for alkylations and acylations in the synthesis of substituted oxazoles. The formation of Comforth rearrangement products. Tetrahedron Lett. 1993, 34, 7705—7708. 

Metallation of the acyclic imidate salt (47) followed by reaction of the intermediate dianion with aldehydes leads to the production of the oxazoles (48 Scheme 19). This procedure constitutes a useful modification of the Comforth oxazole synthesis. 

Practically no effort has so far been made to study the mechanism of this synthesis. Comforth, in his review,4 has suggested two possible routes for cyclization of the keto amides. Alberti and his co-workers37 have supported the mechanism of transformation of a-acylamino ketones to oxazoles by the enolization of two carbonyl groups [Eq. (2)], a mechanism proposed by Wiley.1... 

Comforth oxazole synthesis (Scheme 1). This method has been shown to be widely applicable, although it employs a complex, multi-step pathway.11... 

More than 50 years ago, Comforth described the synthesis of 4-oxazolecar-boxyUc acid esters via cyclization of the potassium salts of C-formylated imidates. This method continues to find further applications and has been used to prepare a variety of structurally diverse and complex oxazoles as shown in the following examples. 

Barrett and co-workers prepared a key intermediate oxazole 350 in their synthesis of calyculin A using Comforth methodology (Scheme 1.94). The benzyl ester of (/ )-2-methyl-4-pentenoic acid 347 was converted to (/ )-2-methyl-4-pentenenitrile 348 in two steps. Pinner reaction of 348, followed by amine exchange with glycine methyl ester, gave the imidate 349 in 73% yield. Base-catalyzed formylation of 349 with in situ cyclization produced the 2-alkyl-4-oxazolecarboxylic acid methyl ester 350 in good yield. This entire sequence... 

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