2 -Oxazolones, cycloaddition

The cycloaddition of nitrones with ketenes produced 5-isoxazolidinones as well as oxazolones, as shown in Scheme 162 (78H(9)457, 79JOC2961). In a similar fashion, nitrones also react with ketenimines to generate the 5-isoxazolidinone imines (75JHC175, 68JHC881). 

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 reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

An extensive review of the use of chiral Lewis acid catalysts in Diels-Alder cycloadditions has been presented. Brpnsted acid-assisted chiral Lewis acids have been shown to be highly efficient catalysts for the enantioselective Diels-Alder reactions of a- and /3-substituted-Q, /i-enals with numerous dienes. The chiral Lewis acid-catalysed Diels-Alder reaction between cyclopentadiene and alkenoyloxazolidi-nones can be catalysed by bis(oxazolone)magnesium catalysts. ... 

Cycloadditions have been carried out to 37/-indoles (222, 223) (125,126), N-arylmaleimides (224) (127,128), l,2), -azaphospholes (225) (129), 5(47/)-oxazo-lones (226) (130), and 4,5-dihydrooxazoles (230) (131). The primary cycloadducts from the reaction of oxazolones (e.g., 226 with diaryl nitrile imines), derived from tetrazoles in refluxing anisole, do not survive. They appear to lose carbon dioxide and undergo a dimerization-fragmentation sequence to give the triazole 228 and the diarylethene 229 as the isolated products (130). In cases where the two aryl substituents on the oxazole are not the same, then, due to tautomerism, isomeric mixtures of products are obtained. 

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). ... 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

The thermal [4 + 2] cycloaddition of 3-acetyl-2(3F/)-oxazolone 84 to the reactive dienes, o-quinodimethane 224 and isobenzofuran 226, generated from benzocyclobutane and 1-ethoxydihydroisobenzofuran, respectively, proceeds... 

The thermal cycloaddition of 3-acyl-2(3/7)-oxazolones 157 to dialkyl azodicar-boxylates 228 proceeds smoothly under mild conditions (at 80 °C) to give the regiocontrolled cycloadducts 229 exclusively, although two other possible addition modes exist neither diazetidines 230 (1,2-addition) nor isoxazolidines 231 (1,3-addition) are detected. In the case of chiral N-substituents diastereoselectivities of up to 72% de have been obtained. Treatment of the chiral cycloadducts 229 with acidic methanol gives tra i-5-hydrazino-4-methoxy-2-oxazolidmone derivatives 232 that are precursors for a variety of optically active a-amino acids 233 and 2-oxazolidinone auxiliaries 234 (Fig. 5.56 Table 5.10, Fig. 5.57)7 ... 

Acetyl-2(3//)-oxazolone 84 serves as a good 1,3-dipolarophile in the [3+2] cycloaddition to A-alkyl-a-phenylnitrones 239, giving a mixture of the four possible isomers 240-243, but with the predominant formation of the exo-syn adduct 240 (Fig. 5.59). Diastereoselective cycloadditions proceed when mixtures of optically active 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazolones and A-benzyl- and A-ferf-butyl-a-phenylnitrones are heated at 110 °C ... 

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). 

Phosphites and 2,2-bis(trifluoromethyl)-5(2//)-oxazolone 71 react with elimination of carbon dioxide to give 2-aza-4-phospha-l,l-bis(trifluoromethyl)-l,3-butadiene 72 that can be used as a synthon for the previously unknown hydrogen-substituted nitrile ylide 72a in [3 + 2]-cycloaddition reactions. Examples of cycloadditions of 72a with dipolarophiles to give heterocyclic compounds 12t-ll are shown in Scheme 7.18. 

A new and completely different methodology involving a cycloaddition reaction has been described. The reaction between diphenylketene, ferf-butylcyanoketene or dimethylketene with 2,4,6-trimethylbenzonitrile A-oxide gave the corresponding 5(4//)-oxazolones 107 in moderate yields (Scheme 7.30). 

Monosubstituted-5(4//)-oxazolones behave differently upon reaction with imines. Here, 4-methyl-2-phenyl-5(4/7)-oxazolone 196 (Ri = Ph, R2 = Me) reacts with imines derived from 2-furancarboxaldehyde or 2-thiophenecarboxaldehyde to give 3-amino-p-lactams 197. On the other hand, 196 reacts with chlorosul-fonyl isocyanate in a [2 + 2] cycloaddition to give dioxazabicycloheptanones 198 as shown in Scheme 7.60. ... 

One strategy to prepare saturated 5(4//)-oxazolones from unsaturated oxazo-lones takes advantage of the reactivity of the exocyclic double bond. In this context, numerous reactions have been explored including reductions, Michael reactions, cycloaddition reactions, and many others. These reactions will be discussed in the context of the reactivity of the exocyclic double bond of the unsaturated oxazolones and will be described in Section 7.4.3. 

The mechanism of the thermal conversion of 4-cyclopropenyl-4-substituted-5(4f/)-oxazolones to pyridines has been studied. A stepwise cycloaddition of the initially generated nitrile ylide has been proposed to account for the observed products. 

Mesoionic oxazolones (munchnones) 297 can be generated by cyclodehydration of N-substituted a-amino acids 295 or by alkylation of oxazolones 296 (Scheme 7.98). These compounds are reactive and versatile 1,3-dipoles that undergo cycloaddition reactions with dipolarophiles to generate a variety of heterocyclic systems. In particular, this is an extremely versatile methodology to prepare pyrroles that result from elimination of carbon dioxide from the initial cycloadduct. Numerous examples have appeared in the literature in recent years and several have been selected for discussion. The reader should consult Part A, Chapter 4 for an extensive discussion and additional examples. 

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). ... 

TABLE 7.27. SUBSTITUTED PYRROLES VIA CYCLOADDITION OF DIPOLAROPHILES WITH MUNCHNONES PREPARED FROM SATURATED 5(4/ )-OXAZOLONES... 

Cycloaddition reactions of A -(phenylmethylene)benzenesulfonamide with meso-ionic oxazolones 311 produces 2,5-disubstituted imidazoles 313 in a highly regio-selective process via cycloreversion of cycloadduct 312 and subsequent loss of benzenesulhnic acid. 

TABLE 7.29. PYRIMIDIN-6-ONES EROM CYCLOADDITION REACTIONS OF SATURATED 5(4i7)-OXAZOLONES WITH 1,3-DIAZADIENES ... 

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). 

Both reactions have been utilized to prepare heterocyclic compounds such as pyrazoles 681 (X = A -Ph) and isoxazoles 681 (X = O) as shown in Scheme 7.214. " Starting from an unsaturated 5(4//)-oxazolone 677, either a cycloaddition-ring-opening reaction sequence (677 678 680) or a ringopening-cycloaddition reaction sequence (677 679 680) affords the same product. 

Diels-Alder reactions of 4-heteromethylene-5(4/7)-oxazolones have been described. ( )-4-(Chloromethylene)-5(4//)-oxazolone 737 reacts with 2,3-dunethyl-butadiene in the presence of ethylaluminum dichloride to afford the cycloadduct 738. The cycloaddition reaction is characterized by high diastereoselectivity and occurs without appreciable isomerization of the dienophile. Further synthetic transformations of 738 yield 1-amino-3,4-dimethyl-6-hydroxy-cyclohex-3-enecar-boxylic acid 739 (Scheme 1.121) Examples of Diels-Alder reactions of acyclic dienes and unsaturated 5(4//)-oxazolones are shown in Table 7.50 (Fig. 7.61). 

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). ... 

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