4-iodo-5-substituted oxazoles

Vedejs and Luchetta exploited the ambident reactivity of 2-lithiooxazoles to prepare a series of 4-iodo-5-substituted-oxazoles 917 (Scheme 1.246). Initially, they found that 896 (R = H, Ri 7 H) reacted with LiHMDS and I2 to produce a mixture containing the desired 4-iodo-5-substituted oxazole 917 together with the 2-iodo-5-substituted oxazole 918 and the 2,4-diiodo-5-substituted oxazole 919. The ratio of 917 918 depended on the nature of the electrophile, the solvent, and the base. 

TABLE 1.64. 4-IODO-5-SUBSTITUTED AND 2-IODO-5-SUBSTITUTED OXAZOLES FROM 2-LITHIOOXAZOLES AND IODINE"... 

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 ... 

Imembrine, a tropolone natural product related to colchicine was also synthesized via an oxazole-acetylene Diels-Alder reaction followed by a [4 -H 3]-oxyallyl cycloaddition.Here, 8-iodo-5,6,7-trimethoxyisoquinoline 269 was converted to 5-substituted oxazole 270 in four steps and 42% overall yield (Fig. 3.81). Thermolysis of 270 in refluxing o-dichlorobenzene effected the desired intramolecular Diels-Alder cycloaddition with concomitant loss of the Boc-protecting group to afford the tetracyclic furan 271 in 90% yield. At this point, 271 was subjected to the [4 + 3] cycloaddition in the presence of l,3,3-trichloro-2-propanone and 2,2,2-trifluoroethanol. Subsequent dechlorination of the intermediate (not shown) with zinc provided the oxabicyclic 272 as a single regioisomer in 73% yield. The synthesis of imembrine was completed in three steps from 272. 

To functionalize the C5 position, Williams and Fu developed a 2-phenylsulfonyl substituted oxazole. The C5 position of this oxazole can be cleanly deprotonated with LDA and trapped with either NIS or NBS to form the 5-iodo- or 5-bromo-2-phenylsulfonyloxazole in good yield. The same report details that the 2-phenylsulfonyl group can subsequently be displaced with alkyl, alkenyl, or aryl lithium reagents to form 2,5-disubstituted oxazoles efficiently. A triflate at the C5 position can be prepared from the corresponding oxazolone however, the oxazolone decomposes at room temperature, and Kelly reported that attempted Stille coupling with C5 triflates failed due to decomposition of the triflate. ... 

The first iodine-catalyzed synthesis of 2-alkyl substituted oxazoles 130 by a decarboxylative domino reaction was reported. Aryl methyl ketones 128 were transformed in situ into a-iodo ketones and then, by the Kornblum oxidation, into 1,2-diketones. After the addition of the a-amino acid 129, an l2-mediated cyclization/decarboxylation gave oxazoles 130. The reaction proceeds better if the Ar has electron-donating substituents and if the R group is a branched alkyl chain or phenyl residue. The reaction used oxone to regenerate iodine (13JOC6065). 

Other methods of converting propargylamides to oxazoles are also known. Thus, N-trifluoroacetylpropargylamines have been regioselectively converted to (E)-iodo(vinyl)sulfones which, in turn, were converted to 2-trifluoromethyl-5-substituted oxazoles by the base treatment [44],... 

Attempts to carry out substitution reactions on oxazoles in acid media, such as nitration with nitric and sulfuric acids or chlorosulfonation, fail because the highly electron-deficient oxazolium cation is involved. Phenyloxazoles are nitrated at the para positions of the phenyl groups 2,5-diphenyloxazole affords 5-(4-nitrophenyl)-2-phenyloxazole, as expected. Nitrooxazoles are now available by the action of dinitrogen tetroxide on the corresponding iodo compounds (81JHC885). Benzoxazoles are nitrated at the benzene ring thus 2-methyl-benzoxazole gives a mixture of 5- and 6-nitro derivatives. 

Scheme 58). 2-Chloro-oxazole or -thiazole substrates 141 were used for substitution in the electrophilic 2-position. The 2-chloro-A -methylimidazole, however, showed low reactivity, and therefore the iodo analog was used in the coupling. A similar series of reactions was run for carbosubstitution in the 4-position in 1,2-azoles. ... 

Isocyanides are very usefiil tools in the synthesis of N-heterocycles such as indoles, imidazoles, tetrazoles, and oxazoles. To form 2,3-disubstituted indoles such as 3-substituted 2-iodo indoles 1518, o-isocyano cinnamates 1517 are important intermediates. They are prepared in high yield (87% for 1517) by dehydration of o-(N-formylarnino)cinnamate 1516 with phosgene [1153, 1166]. 

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