Oxazinones 1.3- oxazine-4-ones

In an approach to the AB rings of rubrolone 65, Boger examined the use of oxazinones as a replacement for triazines. Reaction of l,3-oxazin-6-one 66 with enamines 67 produced the corresponding pyridines 70. The reaction proceeds in a manner analogous to the triazines however, instead of losing nitrogen, these systems lose CO2 via the intermediate bicyclo[2.2.2]octanes 68. The resultant 69 then loses pyrrolidine as in the triazine example. 

A recent variation of these reactions uses 6/f-l, 3-oxazin-6-ones as the electron-deficient heterodiene in place of the triazine.113114 With cyclopropene at — 35 C oxazinone 45 furnishes the 4//-azepine 46 in excellent yield. Likewise, with 3-methylcyclopropene the 4-methyl derivative 46 (R = Me) is formed. Cycloaddition with 1-methylcyclopropene, however, generates a mixture of 7-tert-butyl, 2-methyl 3-methyl- and 5-methyl-4//-azepine-2,7-dicarboxylate in a 2 1 ratio and a 97 % overall yield. 

Methyl-8-(2-chlorophenyl)-3,4-dihydro-177,877-pyrido[2,l-f][l,4]oxazine-7,9-carboxylate was obtained by cyclization of l,4-dihydropyridine-3,5-dicarboxylate 338 in the presence of 3M HC1 <1997CAP2188071>. Mild catalytic hydrogenation of oxazinone 339 over 5% Pd/C catalyst afforded 3,4-diphenyl-9-hydroxyperhydropyrido[2,l-f][l,4]oxazin-l-one via sequential iV-carbobenzyloxy (fV-Cbz) deprotection and reductive amination <1998TL3659>. 

A novel heterocyclic system has been achieved from methyl 3-aminopyra-zine-2-carboxylate and several aroyl chlorides, leading to 3-aroylamino derivatives the latter are cyclized with dibromotriphenylphosphorane to 2-arylpyrazino[2,3-rf][3,l]oxazin-4-one (94S405). Furthermore, vinylimino-phosphoranes and diphenylketene react (Scheme 87) to give nonisolable vinylketenimines (233) which afford, with a second equivalent of ketene in a [4 + 2]-cycloaddition, 1,3-oxazinones (234) [89JCS(P1)2140]. 

The asymmetric alcoholytic ring opening of 4-substituted-2-phenyl-4,5-dihydro-l,3-oxazin-6-ones proved to be a efficient method for the preparation of enatiomerically pure /3-amino acid derivatives <2005AGE7466>. Treatment of 2,4-diphenyl-4,5-dihydro-l,3-oxazin-6-one 208 in the presence of the bifunctional chiral thiourea catalyst 211 resulted in formation of an enantiomerically enriched mixture of the unchanged oxazinone (iJ)-208 and allyl (4)-3-benzoyl-amino-3-phenylpropanoate 209. The resolved material (iJ)-208 and the product 209 could easily be separated by a selective hydrolytic procedure that converted oxazinone (iJ)-208 quantitatively into the insoluble iV-benzoyl /3-amino acid 210 (Scheme 37). 

An improved route to the enantiomerically pure 5,6-diphenyltetrahydro-l,4-oxazin-2-ones is shown in Scheme 44 <2005SL693>. The starting amino alcohols are commercially available but can also be obtained by resolution of the (-)-mandelic acid salts of the two enantiomers. The reaction time was significantly shorter than with older methods and the yields over the three steps were 75% for the A-/-butoxycarbonyl oxazinone and 86% for the A -benzylox-ycarbonyl oxazinone. 

Photochemical addition reactions are exhibited by oxazinones. Thus, irradiation of a mixture of the oxazin-4-one (54) and 1,1-dimethoxyethylene yields the [2 + 2] adduct (55) which fragments to the azetine (56) on heating (77TL431). 

We have observed that 6-methyl-2-phenyl-l,3-oxazin-4-one (74) photocycloadds regiospecifically to 1,1-dimethoxyethene68 and to furan. The regiochemistry is the same as observed with 3-ethoxyisoindolenone (50) and 2-aryl-2-oxazolinone (65). The oxazinone (74) like the aryloxazolinones is not reactive with other olefins. 

Several informative reviews have been published since the 1970s, and include a survey by Steglich et al. <86G36l> of the uses of l,3-oxazin-6-ones as versatile intermediates in heterocyclic syntheses and a more general summary of the chemistry and uses of oxazinones covering the period 1976-1985 by Zakhs et al. <87KGS1443>. More recent work is reviewed by Yamamoto and Morita <92YG887>. 

A, A -Dimethylamino)-l,3-oxazin-6-ones (101) react with hydroxide ion to give ureas, with methanol to generate ureas and carbamates, and with water to form jS-ketoamides and enaminamides (Scheme 24). In all but two of these reactions the progenitors of the observed products are vinyl isocyanates (102), which are in equilibrium with the oxazinones (see Section 6.05.5.3) <87JOC3426>. 

As in many other areas of 1,3-oxazine chemistry, ketenes and isocyanates generated in situ are often used to prepare oxazin-6-ones. For example, 2,4-disubstituted l,3-oxazin-6-ones (135) are readily available through the thermolysis of 5-[(A-acylamino)alkylidene]-l,3-dioxane-4,6-diones (134). The latter are generated from the reactions of the appropriate ethyl acylimidate (133) and Meldrum s acid (Scheme 36) <86CPB1980>. Similarly, the bismethylthiomethylene derivative (136) reacts with benzamides in the presence of potassium hydroxide to afford the methyl-thioacylaminomethylene derivatives (137 R = MeS), which can be reacted further with ammonia to give the amino compounds (137 R = NHj). In turn, these products can be thermolyzed to afford the oxazinones (138 R = MeS) or (138 R = NH2), respectively (Scheme 37) <91SC1213>. 

Cytosine (139) reacts with hexafluoropropanone at 90°C in DMF to give the pyrimido-1,3-oxazine (140) (Equation (5)) <88IZV1433>, and fused and partly reduced 1,3-oxazine-2-ones, exemplified by compounds of the type (142), are obtained through the reactions of arylmethylenemalonaldehydes and chlorosulfonyl isocyanate. It seems possible that the reactions occur in stages, giving firstly monocyclic oxazinones (141), which then react with more reagent to afford the bicycles (142 R = SO2CI). These products are hydrolyzed to (142 R = H) when water is added (Scheme 38) <9274551>. 

Hydroxy-l,3-oxazin-6-ones (143) are formed by the reactions of benzamides with malonyl chloride in 1,2-dichloroethane. These products can easily be hydrolyzed to the imides (144). Depending upon the substituent in the aromatic ring of the benzamide, the 1,3-oxazinones may also be accompanied by hydroxypyrano-l,3-oxazinediones (145), especially if the reactions are conducted in THF as the solvent (Scheme 39) <87KGS382>. 

Chloro-5-cyano-2-(WA -dimethylamino)-l,3-oxazin-6-one (264) is available through the reaction of the salts (263) of alkyl 2,2-dicyanoacetates and dichloromethyleninimium chloride. The chlorine atom of the oxazinone can be displaced by alkanols to give the alkoxy derivatives (265 R = O-alkyl). Similar treatment with primary and secondary amines yields the corresponding diamino-1,3-oxazinones (e.g. 265 R = Et2N, NHPh or NHBu) (Scheme 75) <905959). 

A -(Aroylamino)norbornene carboxylates (317) are cyclized by treatment with thionyl chloride and triethylamine. The tricyclic 1,3-oxazinones (318) thus formed undergo retro-Diels-Alder reactions when heated at 150°C to give 2-aryl-l,3-oxazin-6-ones (319) and cyclopentadiene (Scheme 91) <84S345>. 

Diphenylcyclopropenone and its thione are well known as highly electrophilic carbonyl compounds, which react with pyridine /V-acylimines to give l,3-oxazin-6-ones 39,46 166 and -6-thiones,46 respectively. The reaction of pyridine JV-imine with the cyclopropenone in methanol gives methyl 3-aminoacrylate 40.167 It is likely that these reactions involve ketene intermediates which are intercepted either by internal nucleophiles or by the solvent. Benzo[c]cinnoline JV-acylimines also give the oxazinones 39, whereas the Al-benzimidoylimines give stable 1 1 adducts as a result of a difference in the preferred site of attack by the electrophilic cyclopropenone (Eq. 22).168... 

Detailed conformational analyses were carried out for the 3,4-dihydro-l/7,6/7-[l,4]oxazino[3,4- ]quinazolin-6-ones (219). The oxazine ring of (219) assumes two equally populated, rapidly interconverting half-chair conformations. Substitution at position 1 resulted in the predominance of one of the conformers <93JHC1413>. The orientations of the hydrogens and the half-chair and chair-like conformations of the oxazinone moieties were demonstrated for the [l,4]oxazino[3,4- ]quinazoline (216) <80JHC1169> and the pyridazino[6,l-c][l,4]oxazinone (220) <87JCS(P1)2517>. 

Oxazinones are accessible in several structural variants. For instance, 2-substituted l,3-oxazin-4-ones 19 result from the cycloaddition of ketenes to isocyanates. A second molecule of ketene acylates the OH function of the product 19 yielding the corresponding O-acetyl derivative ... 

An expedient montmorillonite KIO day-catalyzed cydoisomerization of sali-cylaldehyde 4-(yS-D-ribo- or j8-D-2 -deoxyribofuranosyl)semicarbazones yields benz-oxazinone nucleosides, 4-hydrazino-3,4-diliydro-3-(j8-D-ribo- or j8-D-2 -deoxyri-bofuranosyl)-21-f-benz[e]-l,3-oxazin-2-ones, which readily undergo reductive dehydrazination on alumina-supported copper(II) sulfate to furnish 3,4-dihydro-3-(jS-D-ribo- or yS-D-2 -deoxyribofuranosyl)-2H-benz[e]-l,3-oxazin-2-ones under the action of microwave irradiation (Scheme 8.37) [105]. The reaction is solvent-free. 

Continuation of the study of ring transformations of l,3-oxazin-4-ones has led to the discovery of new routes to 5-acetyl-pyrimidinones (313) (Scheme 75 path a), 1,2,4-oxadiazoles (314) (path b), and isoxazoles (315) (path In buffered hydroxylamine hydrochloride solution, nucleophilic ring-opening of the oxazinone (path a) leads ultimately to oxadiazole (314). In contrast, hydroxylamine hydrochloride effects protonation of the oxazinone ring (316) and subsequent ring-opening and ring-closure to the isoxazoles (315), as illustrated in path (c). 

Fukuyama used a phenylglycine-derived amino alcohol as a chiral auxiliary for diastereoseleclive additions to 5,6-dihydro-2H-l,4-oxazin-2-one 70 [66] (Scheme 11.10) [67]. This oxazinone template 70 was showcased with the TFA-catalyzed addition of the electron-rich phenol 69, affording adduct 71 as a single stereoisomer in 89% yield. The resulting adduct was utilized in Fukayama s total synthesis of the potent antitumor agent ectenascidin 743 (72). 

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