Comforth oxazole

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. 

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

Configuration, inversion of -Cope rearrangement Comforth oxazole rearrangements deamination-rearrangement homoallyl -migration... 

Copyrolysis 31,791 Corey oxidation 28,201 Comforth oxazole rearrangement 31, 318 Corrins... 

Williams and McClymont have observed that acylation reactions of the dianion of 2-(5-oxazolyl)-l,3-dithiane (15) lead to formation of 4,5-disubstituted oxazole products through a Comforth rearrangement pathway under base-induced, low-temperature conditions. For example, deprotonation of 15 with LiHMDS (3.0 equivalents) at -78°C, followed by addition of benzoyl chloride or p-chlorobenzoyl chloride and warming to 0°C, provided 16 in 74% and 47% yield, respectively. 

In 1949, Comforth showed that preparation of 2,5-disubstituted oxazoles was not limited to diaryloxazoles through condensation of aldehydes (benzaldehyde, n-hept-aldehyde) with a-hydroxy-amides (lactamide). The intermediate oxazolidone 13 were converted into oxazoles 14 on warming with phosphoryl chloride. ... 

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>. 

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). 

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. 

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 et al have devised a flexible method of synthesizing oxazoles ( 9) from the condensation of an imino ether (88) and ethyl glycinate hydrochloride, followed by reaction with an alkyl formate and potassium alkoxide, and cyclization of the product in hot acetic acid. The reported yields in various stages are fairly good. 

Oxazoles from Imidates/Thioimidates—Comforth Reaction... 

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... 

Fisher s oxazole formation occurs by the condensation of cyanohydrins with aldehydes in the presence of HCl in dry ethereal solution. The cyanohydrins and aldehydes used are usually aromatic in nature, although there are aliphatic examples that have been reported. There has been little study of the reaction mechanism such as that shown by Ingham and Comforth in the early nineteenth century the reaction details have also been published by others. " The first step of the mechanism is the addition of HCl to the cyanohydrin to from an iminochloride intermediate 2. This intermediate then reacts with the aldehyde, which is followed by water loss to give a chloro-oxazoline intermediate 4. Isomerization of two protons occurs, followed by the loss of an HCl molecule to form the 2,5-diaryloxazole end product. 

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