1.3- Oxazin-6-ones ketenes

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>. 

Treatment of benzoylisocyanate 1562 with trimethylsilyl ketene 1563 gives the oxazine 1564 which reacts, e.g., with enamines 1565 to give pyridine-2-ones 1567,... 

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 flash vacuum thermolysis of 4-hydroxy-2,5-diphenyl-l,3-oxazin-6-one resulted in carboxy(phenyl)ketene and benzonitrile as the major and benzoyl isocyanate as the minor product. This was interpreted in terms of the influence of the tautomeric forms on the thermal fragmentation pathways <2007JOC1399>. 

It is well known that l,3-thiazine-4,6-diones can exist in three tautomeric forms <1960CB671, 1976KGS1042>. Cycloaddition of chlorocarbonyl ketenes with thioamides has been reported to produce only the 4-hydroxy-l,3-thiazin-6-ones, whereas the same reaction with amides gives either 4-hydroxy-1,3-oxazin-6-ones or a mixture of tautomers depending on the substituents on the starting materials <2005ARK(xv)88>. 

Pharmaceutically important 3-substituted-[l,8]naphthyridine-2,4-diones have been prepared by the reaction of 2-methyl-477-pyrido[2,3-r/][3,l]oxazin-4-one with active methylene compounds (Scheme 66) <1997J(P1)1487, 2003JOC4567> and by the same group via an intramolecular azadiene-ketene electrocyclization reaction of amino-nicotinic acid derivatives in a related process <2001JOC4413>. 

Irradiation of pyran-2-one gives the ketene (46) reversibly. Similar reactions are known for aza and diaza analogues. Thus, l,3-oxazin-6-ones isomerize photochemically to ketene imines (47), and flash vacuum pyrolysis converts the oxadiazinone (48) reversibly into (49). 

Quinolone undergoes photochemical addition of tetramethylethylene to give (434) (70AHC(ii)50), l,3-oxazin-4-ones photocycloadd ketene acetals to give (435), and irradiation of 2,6-dimethylpyran-4-one yields the cage dimer (436). 2-Pyranones form [2 + 2] photodimers whose structure is similar to that of uracil dimers (432 or 433). 

Oxazin-4-ones are obtained by cycloadditions between isocyanates and ketenes (Scheme 37). Routes to 1,3-oxazinium salts consist of 1,4-cycloadditions either between a,(3-unsaturated (3-chlorocarbonyl compounds and nitriles or between /V-acylimidoyl chlorides and alkynes. Tin(IV) chloride is an effective catalyst for both reactions (c/. Scheme 38). 

Oxazin-4-ones and -thiazin-4-ones are well represented in the chemical literature. Thiazin-4-ones can be synthesized from 1,3-oxazinium salts by the action of hydrogen sulfide and potassium carbonate (81H(15)85l) and oxazin-4-ones are obtained by cycloadditions between isocyanates and ketenes (Scheme 73), or alkynes (Scheme 74), or between nitriles and acylketenes (Scheme 75). Similarly diketene is often used and affords oxazin-4-ones by its reactions with imidates and cyanamides (Scheme 76) (80H(14)1333>. 

Steglich et al.174 obtained 5,6-dihydro-4//-l,3-oxazin-6-one by pyrolysis (270°C) of ethyl j8-acylaminocrotonate. Ethanol is evolved and a ketene is formed as an intermediate. 

Oxazin-4-ones are obtained by cycloadditions between ketenes and isocyanates (Scheme 167). The benzoylphe-nylketene generated from diazo compound 359 forms [4 + 2] DielsAlder adducts 361 with the C=N group of aldehyde imines 360 (Scheme 168) <2001J(P1)2266, CHEC-III(8.05.9.2)417>. 

Acyl isocyanates react with ketene in nonpolar solvents to give 4-hydroxy-l,3-oxazin-6-ones (186) (Equation (9)), but the regioselectivity of the cycloadditions is changed if the A-acyl substituent is... 

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... 

Cycloaddition of aroyl isocyanates and trimethylsilyl ketene generates 4-trimethylsilyloxy-l,3-oxazin-6-ones 29 in situ, which smoothly react with cycloalkanone enamines to give 3,4-cycloalkeno-2-pyridones 30 [87] ... 

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 ... 

Reactions of azines with ketenes 4,5-Dihydro-l,3-oxazin-6-ones from 2 ketene molecules... 

Perhaps, the most common approach for the synthesis of the alkyl-substituent l,3-oxazin-6-ones 475 is the cycHzation of 3-acylaminoacrylic adds and esters, best conducted, under thermal conditions, in accordance with the rule. The reaction proceeds via the intermediate generation of acylimino ketenes 474, which can be subjected to electrocyclization into the 1,3-oxa-zin-6-one derivatives (Scheme 150(a)) (1996T3163, 1977TL1053). Cyclo-addition of acyhsocyanate 469 with the alkynyl ether was observed to give imidoylketene 474, which was in turn converted to compound 475 (1986JCS(P2)961). Results of computational studies indicate interconversion of the A/-formylazetinone 476 into l,3-oxazin-6-ones 475 via two... 

Keten 55-acetals are obtained from thioamides that have at least one hydrogen atom a- to the thiocarbonyl group by 5-methylation and treatment of the imidium ester with propane-1,3-dithiol. Treatment of the imidium esters from NN-disubstituted thioamides with 4-amino-4-methylpentan-2-ol gives 2-substituted 4,6,6-trimethyl-5,6-dihydro-l,3-oxazines, and with sodium azide they give alkylidenetriazenes (1,2,3-triazabutadienes) (77), not dihydrothia(5 )triazoles (78), as previously claimed (see Vol. 3, p. 399). Structure (77) was demonstrated by Z-ray studies. 

In their s-Z conformation, a-oxo-ketenes (e.g., 2) almost exclusively behave as 1-oxa-dienes in inverse demand oxa-Diels-Alder reactions." " In particular, their reactions with preformed imines led to 1,3-oxazin-4-ones (e.g., 4 and 8), a... 

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