Synthesis of 2,5-disubstituted oxazoles

Natural product o-methylhalfordinol 117 is a basic principle of the oxa-zole alkaloids of Halfordia scleroxyla and Aegle marmelos. Annuloline 119, a blue fluorescent pigment, has been isolated from the roots of rye stalk Lolium multifiorum. The total synthesis of 2,5-disubstituted oxazole alkaloids o-methylhalfordinol and annuloline is based on the aza-Wittig reaction (Scheme 48). Thus 4-methoxyphenacylazide 115, triphenylphos-... 

Thus, an oxygen nucleophile reacted intramolecularly with the alkynyl triple bond, and another example of this is provided by the synthesis of 2,5-disubstituted oxazoles from 7V-propargylcarboxamides under mild conditions using 5 mol% AUCI3 in acetonitrile 22... 

In this reaction, initially, acetophenone 36 was converted to a-iodo acetophenone 39 by iodine, which was further transformed into phenyl glyoxal 40 by DMSO (dimethyl sulfoxide). The formed aldehyde then reacted with 2-aminothiophenol 37 to provide intermediate 41, which was further converted to 42 through an intramolecular 1,2-addition. Then, 42 underwent iodine-catalyzed oxidative dehydrogenation to afford the desired product 2-acyl benzothiazole 38 (Scheme 9.9). Very recently, the same authors reported the synthesis of 2,5-disubstituted oxazoles using a similar domino process [17]. 

Fischer oxazole synthesis, reported in 1896 by Emil Fischer, is one of the earliest methods reported for the synthesis of 2,5-disubstituted oxazoles. It entails the reaction of cyanohydrin with aldehyde under dry acidic conditions to form the corresponding oxazole. ... 

The synthesis of 2,5-disubstituted oxazoles from methyl ketones and benzylamines in a metal and peroxide-free environment is achieved using l2-promoted domino oxidative cyclization involving C-H bond cleavage and the formation of C-N and C-0 bonds. Slow oxidation of A-acetyl homocysteine thiolactone by iodate to A-acetyl homocysteine thiolacone sulfoxide occurs in a reaction S1 having 1 3 stoichiometry (oxidant reductant). The stoichiometric ratio in excess of 103 (reaction S2) is 2 5 because excess 103 oxidizes the r ion, generated in reaction SI, to I2. The stoichiometry ratio for the I2 oxidation (reaction S3) is 1 1. Complex kinetics are observed because reactions SI, S2 and S3 occur simultaneously with comparable rates. 

The readily available ethyl 2-chlorooxazole-4-carboxylate proved to be a versatile scaffold for the synthesis of 2,4-disubstituted oxazoles and 2,4,5-trisubstituted oxazoles. 

Eguchi and co-workers ° developed a general synthesis of 2,5-disubstituted and 2,4,5-trisubstituted oxazoles from an intramolecular Aza-Wittig reaction of (Z)-p-(acyloxy)vinyl azides (Scheme 1.74). An a-bromoketone 277 was converted to an a-azidoketone 278, which was O-acylated at 78°C to give, exclusively, a (Z)-p-(acyloxy)vinyl azide 279. This was attributed to intramolecular chelation of lithium by the enol oxygen and the a-nitrogen atom of the azide. 

A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used l-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1-(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>. 

Oxazole IV-oxides cannot be made by oxygenation of oxazoles. The only method of synthesis remains the condensation of monooximes of 1,2-dicarbonyl compounds with aldehydes in the presence of hydrogen chloride (equation 132) (15CB897). The aldehyde may be aromatic or aliphatic (including formaldehyde) and the oxime may be derived from an aromatic diketone or it may be an a-keto aldoxime, leading to a 2,5-disubstituted oxazole IV-oxide. It may also contain an additional carbonyl group as in equation (133). 

Perhaps the simplest method of oxazole synthesis would involve bromina-tion of a ketone in the presence of an amide as shown in Eq. (6), that is, generating the required a-bromo ketone in situ. Marquez88 thus prepared several 4-phenyl 2,5-disubstituted oxazoles by adding calculated amounts of bromine to a heated mixture of ketone and amide. With unsymmetrical... 

Balaban and co-workers " prepared 2,5-disubstituted oxazoles via side-chain bromination with NBS, followed by dehydrobromination with pyridine. Kashima and Arao described a synthesis of oxazoles using NBS/AIBN to effect oxidation of an oxazoline. In this case, the product was a 5-bromooxazole, e.g., 63 (Scheme 1.19). This study was limited to only three examples of 2-aryloxazoles. 

Kawase described a direct and general synthesis of 2,4-disubstituted 5-(trifluoromethyl)oxazoles 500 from reaction of an A -acyl-A-benzyl amino acid 499 with trifluoroacetic anhydride in pyridine (Scheme 1.136). In general, the best... 

Radspieler and Liebscher prepared several 4-chloro-2,5-disubstituted oxazoles 1520 from aromatic acyl cyanides 1519. These oxazoles are the first examples in which the 2-substitutent was not derived from an aromatic aldehyde. They extended this methodology to prepare suitably functionalized dichloro indole bis-oxazole C-D-E fragments. Their approach is noteworthy as the first synthesis of such fragments that does not involve chlorination of an intact oxazole ring. 

The same strategy has been reported for the synthesis of the marine alkaloid ahnazole C, isolated from the red seaweed Heraldiophylum sp., which showed antibacterial activity against Gram-negative pathogens. The formation of the central 2,5-disubstituted oxazole... 

Gold-catalyzed 5-exo-type cyclization is also useful for oxazole synthesis. It was reported that AuCls is efficient in the electrophilic activation of carbon-carbon triple bonds of A-propargylamides 144 to afford 2,5-disubstituted oxazoles 150 under mild conditions (Scheme 19.36) [59]. The reaction proceeds through stereospecific oxyau-ration to generate vinylgold(III) intermediates 149 [60], which would be converted to the oxazoles 150 by protodeauration and subsequent isomerization. Vinylgold... 

Rearrangement of alkoxycarbonyl imidazole acryl azides in diphenyl ether at high temperatures afforded imidazo[l,5-c]pyrimidinone or imidazo[4,5-c]pyridinone derivatives <02TL5879>. Efficient synthesis of imidazopyridodiazepines from peri annulation in imidazo[l,2-a]pyridine has been described <02TL9119>. A convenient synthesis of 3,6-disubstituted-2-aminoimidazo[l, 2-a]pyridines has been published <02TL9051>. Novel 2,3-dihydroimidazo[2,l-h][l,3]oxazoles were prepared from intramolecular nucleophilic i/wo-substitution of 2-alkylsulfonylimidazoles <02S2691>. 4,4 -Bi-l//-imidazol-2-ones were efficiently synthesized from 5-amino-ot-imino-1 //-imidazole-4-acetonitriles and isocyanates <02JOC5546>. 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

In recent years, several natural products containing 2,4-disubstituted oxazoles have been isolated and their synthetic routes were investigated. Several key intermediates required for the synthesis of target compounds were achieved via the Stille, Suzuki, Heck, and Sonogashira reactions. In addition, several 2,5-diaryloxzoles were prepared from 2-halo-... 

Oxidation of oxazolines using Mn02 was also employed in the synthesis of a beminamycin A fragment by Shin and co-workers ° and in the preparation of the naturally occiuring 2,4-disubstituted oxazole, phenoxan 28, by Yamamura s group" (Scheme 1.5). For beminamycin, the oxazoline 25 was synthesized in 61% yield by Mitsunobu dehydration of the serine-derived amide 24. 

TABLE 1.14. MICROWAVE ASSISTED SYNTHESIS OF 2-PHENYL-4-SUBSTITUTED OXAZOLES AND 4,5-DISUBSTITUTED 2-PHENYLOXAZOLES FROM ARYL KETONES, BENZONITRILE, AND MERCURY(II)TOSYLATE ... 

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. 

Synthesis. The preparation of these heterocycles was accomplished using traditional methodology. 2,4-Disubstituted and 2,4,5-trisubstituted compounds were prepared via the Hantzsch (21) synthesis. The Gabriel (22) and Robinson-Gabriel (23) syntheses were used to prepare the 2,5-disubstituted thiazoles and oxazoles, respectively. The intermediate keto-amides could be converted into thiazoles by heating with P4S] q pyridine or with Lawesson s reagent (24). 

By using a sequence of regiocontrolled halogenation and palladium-catalyzed coupling reactions, the synthesis of variously substituted oxazoles from 2-chlorooxazole-4-carboxylate was accomplished. The methodology was applied to the synthesis of a series of 2,4-disubstituted, 2,5-disubstituted, and 2,4,5-trisubstituted oxazoles (Equation 37) [37]. 

In 2007, Tron and Zhu reported the multicomponent synthesis of 5-iminoox-azolines (42) starting from a,a-disubstituted secondary isocyano amides (41), amines, and carbonyl components (see Fig. 15) [155]. The reaction presumably follows a similar mechanism as in the 2,4,5-trisubstituted oxazole MCR (described in Fig. 11) however, because of the absence of a-protons at the isocyano amide 41, the nonaromatized product is obtained. As in the 2,4,5-trisubstituted oxazole MCR, toluene was found to be the optimal solvent in combination with a weak Brpnsted acid. The reaction was studied for a range of aldehydes and secondary amines. In addition, a variety of functionalities such as acetate, free hydroxyl group, carbamate, and esters are tolerated. Clean conversions were observed for this MCR as indicated by NMR analysis of the crude products (isolated yield 50-68%). The... 

Alkyl-substituted oxazoles have been found to react with maleic acid or its anhydride in a diene synthesis to yield substituted pyridine readily converted to pyridoxine (39). In this route, ethyl d, 1-alaninate hydrochloride is treated with formic-acetic anhydride to yield ethyl N-formyl d,1-alaninate (78%). This compound is refluxed in chloroform with phosphorous pentoxide (40), quenched with aqueous potassium hydroxide, and the organic layer distilled to give 4-methyl-5-ethoxyoxazole (I) (60%). The resulting oxazole (I) is condensed readily with a number of appropriate dienophiles to form 2-methyl-3-hydroxy-4,5-disubstituted-pyridines containing substituents (III, a, b, c) which could be converted to pyridoxine as follows ... 

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. ... 

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