Intermediate oxazole

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

When aniline derivatives 9-87 bearing an alkyne moiety were used as the reaction input together with an aldehyde and 9-80, furo[2,3-c]quinolines 9-88 were obtained (Scheme 9.18) [58]. Here, an intermediate oxazole is also assumed to occur, enter-... 

An iterative oxazole assembly via a-chloroglycinates 152, obtained from primary amides by treatment with glyoxylate esters and SOCI2, has been reported. Compounds 152 reacted rapidly with dimethylaluminium acetylides to give oxazoles 153. This technique allows polyoxazole construction and has been exploited for the total synthesis of (-)-muscoride A 155, by application of the same sequence to the intermediate oxazole amide 154 <03AG(E)1411>. 

ElectophUic iodination using I2 has also been employed to effect net oxidation of oxazolines to 2-substituted 4-oxazolecarboxylic acid esters. Koskinen and co-workers" " ° prepared an intermediate oxazole fragment of calyculin using this method (Scheme 1.18). Here, the oxazoline 57 was first treated with LiHMDS and TMSCl to protect the carbamate as a sUyl amide followed by treatment with KHMDS and iodine to generate the oxazole 58. Interestingly, the authors also isolated diastereomeric spirocyclic ortho ester aminals 59 in 25 to 30% yield under these reaction conditions. 

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... 

This chapter is an attempt to present the important results of studies of the synthesis, reactivity, and physicochemical properties of this series of compounds. The subject was surveyed by Bulka (3) in 1963 and by Klayman and Gunther (4) in 1973. Unlike the oxazoles and thiazoles. there are few convenient preparative routes to the selenazoles. Furthermore, the selenium intermediates are difficult to synthesize and are often extremely toxic selenoamides tend to decompose rapidly depositing metallic selenium. This inconvenience can be alleviated by choice of suitable reaction conditions. Finally, the use of selenium compounds in preparative reactions is often complicated by the fragility of the cycle and the deposition of metallic selenium. 

Enamines and enolate anions react with benzofuroxan to give quinoxaline di-A -oxides (Scheme 38) (69AHC(10)1). Sydnones (274) with phenyl isocyanate give 1,2,4-triazoles (275) (76AHC(19)l), and from (276) the intermediate adduct (277) can be isolated (73JA8452). This is one of the few instances in which such primary cycloadducts have been isolated in the oxazole series of mesoionic compounds. 

Photolysis in general produced oxazoles and a variety of other products including aminochalcones, nitriles, aldehydes and chalcone oximes. A number of photolytic intermediates have been postulated, represented by (151), (152), (153) and (154) (77CL1195, 75T1373, 73HCA2588, 73TL2283). 

Ingham proposed the following sequence to explain the formation of oxazole products following his study of the reaction of benzaldehyde with mandelonitrile and hydrogen chloride. In the event, addition of hydrogen chloride to the cyanide is the first step providing the intermediate iminochloride 5 (Ari = Ph), which upon reaction with benzaldehyde affords oxazole 2 (Ari, Ar2 = Ph) via intermediate 6 (Ari, Ar2 = Ph). 

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. ... 

In 1909, Robinson demonstrated the utility of acylamidoketones as intermediates to aryl-and benzyl-substituted 1,3-oxazoles through cyclization with sulfuric acid. Extension of sulfuric acid cyclization conditions to alkyl-substituted oxazoles can give low yields, for example 10-15% for 2,5-dimethyl-l,3-oxazole. Wiegand and Rathbum found that polyphosphoric acid can provide alkyl-substituted oxazoles 4 in yields equal to or greater than those obtained with sulfuric acid. Significantly better yields are seen in the preparation of aryl- and heteroaryl-substituted oxazoles. For example, reaction of ketoamides 5 with 98% phosphoric acid in acetic anhydride gives oxazoles 6 in 90-95% yield. ... 

More recent examples have employed a milder reagent system, triphenyl-phosphine and dibromotetrachloroethane to generate a bromo-oxazoline, which is subsequently dehydrohalogenated. Wipf and Lim utilized their method to transform intermediate 11 into the 2,4-disubstituted system of (+)-Hennoxazole k Subsequently, Morwick and coworkers reported a generalized approach to 2,4-disubstituted oxazoles from amino acids using a similar reagent combination, triphenylphosphine and hexachloroethane. ... 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

The development of the key intermediate, 5-(2-methoxy-4-nitrophenyl)oxazole (25), in the preparation of the hepatitis C drug candidate, VX-497, utilizes a van Leusen reaction of aldehyde 24 with TosMIC. ... 

Modification of the oxazole, as in 13 allowed for the formation of vitamin Ba analogs, such as 15 via intermediate pyridine 14. 

In the photochemical isomerization of isoxazoles, we have evidence for the presence of the azirine as the intermediate of this reaction. The azirine is stable and it is the actual first photoproduct of the reaction, as in the reaction of r-butylfuran derivatives. The fact that it is able to interconvert both photochemically and thermally into the oxazole could be an accident. In the case of 3,5-diphenylisoxazole, the cleavage of the O—N bond should be nearly concerted with N—C4 bond formation (8IBCJ1293) nevertheless, the formation of the biradical intermediate cannot be excluded. The results of calculations are in agreement with the formation of the azirine [9911(50)1115]. The excited singlet state can convert into a Dewar isomer or into the triplet state. The conversion into the triplet state is favored, allowing the formation of the biradical intermediate. The same results [99H(50)1115] were obtained using as substrate 3-phenyl-5-methylisoxazole (68ACR353) and... 

Some data were obtained from the photochemical isomerization of amino-isoxazoles. 5-Aminoisoxazoles gave the corresponding azirine (Scheme 21) [70JCS(C)1825] when a4-carboethoxy-substituted derivative was used, no azirine was isolated and the oxazole was the only product obtained (Scheme 21) (72CB748). The azirine intermediate was not observed upon irradiating 3-amino derivatives [91H(32)1765]. 

The irradiation of 3-carbomethoxyisoxazole (47) gave the corresponding oxazole (48) in very low yields (5-8%) without the isolation of the corresponding azirine (Scheme 22) [71JCS(C)1196]. Also in this case calculations show that the energy of the triplet state allows the formation of the biradical intermediate and then of the azirine. However, the low yields of the conversion can be explained considering that the transformation of the biradical intermediate into the azirine is an endothermic reaction (Fig. 10) [99H(50)1115]. 

The irradiation of 3-phenyl-4-acetyl-5-methylisoxazole (49) gave the isomeric oxazole (50) (Scheme 22) (75JA6484 76HCA2074). The reaction can involve the formation of the biradical intermediate starting from the triplet state, in agreement... 

Oxazol-5(4//)-ones as intermediates in the formation of macrolides, cyclodep-sipeptides, and cyclopeptides 99JHC1539. 

Treatment of a 3-aminotriazolopyridine with acid gave the imidazopyridine 242 (81T1787), also obtained from the 3-nitro derivative by catalytic reduction (83AHC79). Quaternary salts derived from compound 2, when treated with tri-ethylamine and subsequently heated give 2-pyridylcyanamides 243 or 2-(oxazol-l-yl)pyridines 244 depending on the alkyl group (86H(24)2563) the ylides are presumably intermediates (see also Section IV.I). 

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). 

Despite the above, there is also considerable evidence to suggest that oxazole formation proceeds via an intermediate nitrile ylide, particularly in the catalysed reactions (see below). Nitrile ylides have been detected in laser flash photolysis studies of diazo compounds in the presence of nitriles, and stable nitrile ylides can be isolated in some cases.<94CRV1091>... 

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