5 -Oxazolones 1.3- dipolar cycloadditions

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

The 1,3-dipolar cycloaddition of a-keto carbenoids to the polar double bond of heterocumulenes provides a direct access to five-membered heterocycles. The reaction of a-diazo ketones 132 with phenyl isocyanate in the presence of a Rh2(OAc)4 catalyst affords the 1,3-cycloadduct, 3-phenyl-2(3//)-oxazolones 133 (Fig. 5.32). ... 

On heating, 4-(isopropoxy)-2-phenyl-2-(trifluoromethyl)-5(2/i/)-oxazolone 65 underwent decarboxylation to the alkoxy-substituted nitrile ylide 66 that was trapped in a 1,3-dipolar cycloaddition by trifluoroacetophenone to generate 68." Other dipolarophiles reacted similarly. In the absence of a dipolarophile, cyclization of 66 yielded the isoindole 67 (Scheme 7.16 Table 7.11, Fig. 7.12). 

Munchnones 298 obtained in situ by N-alkylation of 5(4/f)-oxazolones undergo 1,3-dipolar cycloaddition with dimethyl acetylenedicarboxylate to give Al-alkylpyr-roles 299. 1,3-Dipolar cycloaddition of munchnones with triphenylvinylphos-phonium bromides affords tri- and tetrasubstituted pyrroles 300. In this case, the interaction of the phosphonium group with the carbonyl group leads to high levels of regioselectivity (Scheme 7.99 Table 7.27, Fig. 7.29). ... 

Finally, reaction of 2,4-diphenyl-5(4//)-oxazolone 322 with 4-phenyl-A -tosyl-1-azabuta-1,3-diene was found to be highly dependent on the experimental conditions. At room temperature the sole product was 323 that arises from alkylation of 322 by addition at the imine carbon. However, heating 322 and 4-phenyl-A-tosyl-1-azabuta-1,3-diene gave rise to several products including a 2-pyridone 324, 2,3,6-triphenylpyridine 325, and the pentasubstituted pyrroles 326 and 327. The authors postulated two different reaction mechanisms. Here, both a 1,3-dipolar cycloaddition of the oxazolone and a nucleophilic addition of the oxazolone are possible and that may account for the formation of 324—327. The marked differences in reactivity of 4-phenyl-A-tosyl-l-azabuta-l,3-diene relative to A-alkyl- or A-aryl-1-aza-1,3-dienes was attributed to the powerful electron-withdrawing nature of the tosyl group (Scheme 7.107). ... 

The exocyclic double bond of 4-arylidene-5(47/)oxazolones 383 reacts with diazomethane in a 1,3-dipolar cycloaddition reaction to give the corresponding... 

Diphenyldiazomethane has also been used in 1,3-dipolar cycloadditions with 4-arylmethylene-5(47/)-oxazolones 670 to prepare gem-diphenyl-spirocyclopropane oxazolones 671." A number of 671 analogues were evaluated as antibacterial agents. " In addition, 671 derivatives were precursors for new 1-aminocyclopropanecarboxylic acid derivatives 672, for example, l-(benzoylamino)triphenylcy-clopropanecarboxylic acid 672 (R = Ar = Ph) (Scheme 7.211). 

TABLE 7.47. OXAZOLONE SPIROCYCLOPROPANES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4/7)-OXAZOLONES WITH DIAZOMETHANE... 

The reaction of nitrile oxides with 4-arylmethylene-5(4//)-oxazolones 675 to give the corresponding spiroisoxazoline oxazolones 676 is also well known.The regiochemistry of this cycloaddition reaction was initially incorrectly assigned but a careful study of the reaction showed that the regiochemistry of the 1,3-dipolar cycloaddition of nitrile oxides is the same as that observed with nitrile imines (Scheme 7.213). Examples of spiroisoxazoline oxazolones are shown in Table 7.49 (Fig. 7.60). 

Dipolar cycloaddition of 4-arylmethyleneisoxazol-5-ones 794 and 2-methyl-4-phenyl-5(4//)-oxazolone 795 leads to pyrrole-3-carboxyhc acids that have been isolated as hydroxamates 796. The authors carried out this cycloaddition-nitrile oxide addition as a one-pot reaction (Scheme 7.243). ... 

A synthesis of the marine antibiotic from Pseudomonas bromoutilis has been achieved by 1,3-dipolar cycloaddition of the oxazolone (388) with diethyl acetylenedicarboxylate (73CI(L)275). Hydrolysis and decarboxylation gave the pyrrole (390), identical with a sample prepared previously by other workers, and converted by them to pentabromopseudilin (391 Scheme 85) (66JA4509). 

Oxazole derivatives have been thoroughly studied and display a wealth of synthetic opportunities. The mesoionic miinchnones undergo 1,3-dipolar cycloadditions across the C(2)—C(4) positions. The 5(4H)-oxazolones have excited interest for a long time because they undergo fission of the C(5)—O bond to afford a-amino acids. Appropriately substituted dihydrooxazoles and oxazolidines are effective carriers of asymmetry, and they have only begun to be exploited in this role although numerous possibilities have been demonstrated. 

The exo double bond of 4-alkylidene and 4-arylidene-5(4//)-oxazolones undergoes cycloaddition reactions with 1,3-dipolar reagents. For example, nitrile oxides add to 2-phenyl-4-ethoxymethylene-5(4//)-oxazolone (88) to give spirocyclic products that may be hydrolyzed to 4-aminoisooxazoles... 

Oxazolones are simply cyclic anhydrides of A-acyl-a-amino acids, and are constructed in the way that this implies. If the nitrogen also carries an aUcyl group, cyclisation " can only lead to an overall neutral product by adopting a zwitterionic stracture, for which no neutral canonical form can be written - a mesoionic structure. Mesoionic oxazolones (named miinchnones by Huisgen after their discovery at the University of Munchen, Germany) undergo ready dipolar cycloadditions,with loss of carbon dioxide from the initial adduct the examples" show the conversion of a miinchnone into a mesoionic thiazolone and into an imidazole. 

Only 2,3-dihydropyrrolo[2,l-(>]thiazoles have been described. Reaction of 7V-acetylthiazolidine-2-carboxylic acid (303) in the presence of acetic anhydride provides mesoionic oxazolone intermediates (304) which undergo 1,3-dipolar cycloaddition with DMAD, to give unstable intermediate (305) which rapidly eliminates carbon dioxide to give 2,3-dihydro-5-methylpyrrolo[2,l-( ]thiazole-6,7-dicarboxylate (306) (Scheme 55) <88JMC1427>. 

The 1,3-dipolar cycloaddition of acetylenes and alkenes with oxazolones is widely used for the construction of the pyrrole ring. The presence of a CFs-group in the 1,3-dipolar component opens a pathway to 2-CF3-pyrroles, while the application of trifluoromethylated dipolarophiles provides 3-CF3-pyiroles. For example, the dimethyl pyrroledicarboxylate 120 was synthesized in 78 % yield by the reaction of the CFs-containing oxazolone 118, prepared from proline 117 and trifluoroacetic anhydride (TFAA), with dimethyl acetylene dicarboxylate (DMAD) [53]. 

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