Substituted oxazoles

More recently, Williams has described the one pot synthesis of 2-substituted oxazoles 11 by the thermolysis of triazole amides 9 the reaction does not proceed photo-chemically.<92TL1033> Although the reaction does not involve addition to a nitrile, it is an interesting application of a diazo compound since the proposed zwitterionic intermediate 10 is a resonance form of a diazo imine, so formally the reaction may be thought of as a thermal decomposition of a diazo imine (Scheme 6). 

Because of the presence of the extra phenyl substituent in the present case, further enolization is prevented, and therefore ring closure to an oxazole cannot occur. Thus, prevented from further reaction, the adduct undergoes a slow breakdown to reproduce the original enolate, and the 2-oxazole anion, which is then able to react irreversibly with the benzaldehyde to produce the observed 2-substituted oxazole product. 

Simple triazoles are thermally stable to ca. 300°C. However, triazole carboxamides, when heated to 150°C in sulfolane, rearrange with the elimination of nitrogen to give 2-substituted oxazoles. The reaction is general and it is useful for the synthesis of oxazoles with diverse 2-substitutents in excellent yields even for bulky substituents (Scheme 1). This reaction does not occur photochemically... 

Ferrini and Marxer65 have recently shown that vinylene carbonate reacts with primary amides, in the presence of polyphosphoric acid, to yield 2-substituted oxazole derivatives. Yields are low (2-34%), and phenoxy- and phenyl-acetamide, p-methylbenzamide, and salicylamide do not give oxazole derivatives. Although the reaction has been interpreted according to Scheme 3, the nucleophilic attack of a nitrile molecule (from the amide dehydration), with a nitrilium salt as intermediate (Scheme 4), cannot be excluded.06... 

Lithiooxazoles exist in equilibrium with their open chain forms one solution for the synthesis of 2-substituted oxazoles involves 2-silylation (and then reaction with an electrophile). By correct choice of silylating agent, it is possible to trap the ring-closed or ring-opened forms (Scheme 58) <2002TL935>. 

Substituted oxazoles can typically be prepared by C-2 lithiation followed by quenching with an electrophile. However, this protocol suffers from an accompanying side reaction as the lithiated ring system is in equilibrium with its open-chain form and does not reliably afford the expected C-substituted products. 

Intramolecular Diels-Alder reactions between oxazoles and acetylenes have also been used as a key step in a number of natural product syntheses. For example, cycloadducts 69 and 70 were derived from intramolecular Diels-Alder reactions of their respective acylic 2-substituted oxazole precursors. These cycloadducts were key intermediates in the syntheses of natural products (—)-stemoamide and (- -)-colchicine, respectively (Scheme 11) <2000JA4295, 2000T10175>. 

A one-pot synthesis of furan 2-substituted-3-carboxylic and 2-substituted-3,4-dicarboxylic esters was reported. Thus, reaction of an acyl isocyanate with trimethylsilyldiazomethane, a safe replacement for hazardous diazomethane, gave 2-substituted oxazoles, which were treated with dimethyl acetylenedicarboxylate or ethyl propiolate to afford the corresponding di- and trisubstituted furans in good yields <04S1359>. 

Oxazoles. Acylation and pyrolysis of the hydroxy amides in decalin provides 2-substituted oxazoles by way of cyclodehydration and retro-Diels-Alder reaction. Imidazoles are similarly prepared from the vic-diamine. 

Short and Ziegler employed propargylamides as precursors to (E)-p-iodo (vinyl)sulfones, which were key intermediates in their synthesis of 5-[(phenylsul-fonyl)methyl]-2-substituted oxazoles (Scheme 1.73). Here, a propargylamide 274 was iodosulfonated photolytically to afford the key ( )-p-iodo(vinyl)sulfones 275. 

TABLE 1.21. 5-[(PHENYLSULFONYL)METHYL]-2-SUBSTITUTED OXAZOLES FROM PROPARGYL AMIDES VIA ( )-P-IODO(VINYL)SULFONES ... 

Jacobi s group cyclodehydrated iV-carbobenzyloxy-D-prolyl-L-alanine methyl ester 438 using POCVpyridine to prepare large quantities (50 g) of the 5-methoxy-4-methyl-2-substituted oxazole 439 (Scheme 1.121). Both 439 and ent-439 were key starting points for their enantiospecific syntheses of (+)-norsecurinine and (—)-norsecurinine. 

Freeman s group ° prepared a series of 5-amino-4-cyano-2-substituted oxazoles 517 from carboxylic acids and aminomalononitrile tosylate (AMNT) (Scheme 1.140). Presumably, AMNT is acylated by a carboxylic acid using DCC, which produces an intermediate A-acylamino nitrile 516 that is cyclized under the reaction conditions to yield 517. The yields of 517 are fair to excellent, and the reaction tolerates a wide variety of functional groups. This further extended the scope of their earlier work. ° Representative examples are shown in Table 1.35. 

Trimethylsilyl)oxazoles behave as soft carbanion equivalents and readily react with a wide variety of electrophiles to afford 2-substituted oxazoles. 

Armstrong and co-workers" described a general synthesis of fra i-4-aIkenyl-oxazoles as a model reaction for their synthetic approach to calyculins. The authors prepared a 4-(iodomethyl)-2-substituted-oxazole 1135, starting from the corresponding amide (Scheme 1.296). Arbuzov reaction of 1135 with triethylphosphite gave the phosphonate 1136. Heating 1135 with tri-n-butylphosphine using... 

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