Oxazoles 4-carboxylates

The hetero ring in 4-(l -hydroxyalkylidene)-5-oxazolones is cleaved by alcoholic HCl to form alkyl a-acylaminoacylacetates, which cyclize to oxazole-4-carboxylates [Eq. (25)]. This rearrangement occurs directly in alkali, and a carbon-14 tracer study has substantiated a mechanism involving ring opening followed by the alternative ring closure. ... 

The cyclizations of conjugated nitrile ylides forming substituted oxazoles and thiazoles were computed up to the MP4/6-31H-G level [OOJOC47]. Relative to 23, oxazole-4-carboxylic acid24 is stabilized by about -38.1 kcal/mol (Scheme 18). 

From Nocardia strains several closely related compounds (nocobactins, formo-bactin, amamistatins) were isolated that contain three typically Fe " binding sites, two hydroxamate units, and ahydroxyphenyloxazole stmcture (cf. Sect. 3.2 below). The C-terminus is A-hydroxy-cyc/o-Lys bound to a long chain 3-hydroxy fatty acid, whose hydroxy group is esterified by A -acyl-A -hydroxy-Lys, the a-amino group of which is bound to 2-o-hydroxyphenyl-5-methyl-oxazole-4-carboxylic acid (Table 4). For the amamistatins the configuration of the cyclic lysine was determined as L, the open one as d, and that of C-3 of the fatty acid as (S). The involvement in the iron metabolism was not investigated. 

The method described for the preparation of 4-methoxycarbonyl-2-methyl-1,3-oxazole is that of Cornforth, and is widely applicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates. The appropriate imidate hydrochloride required for step A is obtained from the reaction of a nitrile with an alcohol in the presence of hydrochloric add (eq. 1 ). A different synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing rhodium-catalyzed heterocycloaddition of a diazomalonate to a nitrile has been described in Organic Syntheses by Helquist, but appears to be less general than the present route. 

During an investigation of the synthesis of oxazole-4-carboxylates, Shapiro reported that chlorination of amino[(phenylthio)methyl]malonate derivatives 91 with A -chlorosuccinimide (NCS), followed by treatment with Hunig s base, afforded the oxazolines 93. The oxazolines 93 were then converted to the respective oxazole-4-carboxylates 94-97 through decarbomethoxylation and elimination of thiophenoxide in the presence of methyl iodide. Methyl iodide traps the ejected thiophenoxide that would otherwise demethylate the oxazole-4-carboxylate (Scheme 8.31). " ... 

The biosynthesis 237,5381 involves enzymatic dehydration of serine and threonine residues in a manner similar to the formation of thiazoles and dihydrothiazoles vide supra) with or without subsequent oxidation to yield the 2-(l-aminoalkyl)oxazole-4-carboxylic acid and 2-(l-aminoalkyl)dihydrooxazole-4-carboxylic acid shown in Scheme 38. These cyclic peptides display interesting physiological properties such as cytotoxicity/541, 569,5831 antitumor activities, or antineoplastic effects/523,5291 but as for the sulfur-containing compounds the mechanism of action is not yet understood despite extensive SAR studies. 515,521,540,5431... 

The oxazole-containing cyclic peptides are synthesized predominately by the direct use of suitably protected 2-(l-aminoalkyl)oxazole-4-carboxylic acids since oxidation of the ox-azolidine precursors to the oxazole ring with Mn0215581 or Ni0215861 (or even with H20215641 or... 

DBU (3mL, 20 mmol) was added to methyl 2-[(benzyloxycarbonylamino)oxazolidine-4-carboxylate (2.8 g, 9.6 mmol) in CQ4/MeCN/Py (2 3 3). After 3 h at rt, the solvent was extracted with 0.5 M HC1 and the aqueous phase reextracted with EtOAc (2 x). The EtOAc phase was washed with brine, dried (MgS04), and the solvent removed. Chromatography (silica gel, EtOAc/hexane 1 1) afforded methyl 2-[(benzyloxycarbonylamino)methyl]oxazole-4-carboxylate yield 0.94 g (33%). The oxazole ester (0.29 g, lmmol) was dissolved in dioxane (15 mL) and NaOH (0.12 g, in 5mL H,0) was added. The mixture was stirred at rt for 1 hr. The soln was neutralized with 10% aq KHS04 to pH 6, and the dioxane was removed. The soln was acidified to pH 3 and taken to dryness. The residue was crystallized (EtOAc/ hexane) yield 0.24 g (90%). 

Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester " (2.50 g, 11.4 mmol)... 

The flask was fllled with (45,55)-4-methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2.50 g) and 70 mL of dry diethyl ether. The solution was cooled to —78 °C using a dry ice-acetone bath. 

The oxazole (232) heated with formamide gave the imidazole (233) oxazolium cations undergo similar conversions. Primary amines convert oxazole-4-carboxylic acids (234) at 150°C into imidazoles (235) with accompanying decarboxylation (53CB88) (see CHEC 4.07 and 4.18). 

Ethyl 2-[(S)-l-(Benzyloxycarbonylamino)-3-methylbutyll-5-(l-methylindol-3-yl)oxazole-4-carboxylate... 

However, the only product obtained on nitration of 5-methyl-3-phenylis-oxazole-4-carboxylic acid is the 3-nitrophenyl product (91U PI). 

Esters of oxazole-4-carboxylic acids are easily hydrolyzed by hydrochloric acid to give salts of a-amino ketones (equation 5) the action of 2,4-dinitrophenjlhydrazine on the ester (133) in the presence of hydrochloric acid leads to the 2,4-dinitrophenylhydrazone (134). 

The 2-aryloxazoles have also been synthesized under microwave activation by the direct Stille and Suzuki cross-coupling reactions of 1,3-oxazoline (OXT) [17]. Nolt et al. [18] utilized the microwave-assisted Cornforth rearrangements for the preparation of substituted 5-amino-oxazole-4-carboxylate (v). 

Ethyl 2-phenyl-5>(1-azlrldlnyl)oxazole-4-carboxylate (3). A solution of 2-phenyl-5-ethoxyoxazole-4-carboxyiic acid chionde (1 257 g, 5 mmol) in PhH (20 mL) was stirred with azindine (0 215 g, 5 mmol) and tnelhytamme (0 5 g, 5 mmol) in PhH (40 mi.) (or 3 h at 20-°C. After washing with water, the solvent was removed and the residue crystallized (rom petroleum ether to give 1.032 g of 1 (80%)... 

I). A different synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing rhodium-cataiyzed heterocycioaddition of a diazomaionate to a nitriie heis been described in Organic Syntheses by Heiquist, but appears to be less general than the present route. 

The reaction of phthalic anhydrides 266 with methyl isocyanoacetate (267) in tetrahydrofuran in the presence of DBU gave a mixture of oxazole-4-carboxylates 268 and 269 (79CPB1373 79JAP(K)70285). Subsequently, products 268 and 269 were transformed into l-oxoisoquinoline-3-carboxylates in two steps. 

Alkyl isocyanatoacetates 390 were reacted with acid anhydrides in tetra-hydrofuran in the presence of 1 mol equiv. of DBU to give oxazole-4-carboxylates 391 in 60-85% yields (73JOC3571 74JAP(K) 135968). 

A series of 2-aryloxazoloquinolones 32 having high affinity for the GABA receptor were prepared via a Pd-catalyzed intramolecular diaryl coupling of ethyl 5-bromo-2-phenyl-oxazole-4-carboxylate with 2-aminophenylboronic acid followed by cyclization [37]. This one-pot intramolecular Suzuki reaction was followed by cyclization to afford a tricyclic compound 32. 

A synthesis shown below of ethyl oxazole-4-carboxylate illustrates a sophisticated use of this strategy, in which an imino ether and the potassium enolate of an aldehyde are involved " iminoethers on reaction with aminoacetal give amidines, which close in acid to give 2-substituted imidazoles. " " The process can be conducted without isolation of the intermediate. 

The starting nitrile may be alkyl, aryl, or even hydrogen cyanide, which leads to the synthesis of oxazole itself180 by hydrolysis and decarboxylation of the oxazole-4-carboxylate (89, R = H). Various exten-... 

Fusion of the sodium or potassium salt of 4-(a-hydroxyalkylidene)-2-oxazoline-5-ones (90) leads, by rearrangement, to oxazole-4-carboxylic acids (91) which can easily be decarboxylated to the corresponding oxazoles.2 4 This rearrangement occurs also in alkali, and a 14C tracer... 

It has long been known that the conversion of oxazoles into imidazoles may be accomplished by treatment at high temperatures with ammonia or amines.132 160 379 Oxazole-4-carboxylic acids are converted similarly into the corresponding decarboxylated imidazoles (228).302... 

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