L,4- oxazin-2-one,

A new synthetic route for functionalized polyhydroxyalkyl-pyrimidines starting from unprotected aldoses and based on montmorillonite K-10 catalysis and solvent-free microwave irradiation conditions, has been reported by Yadav et al,m Thus, reaction of D-glucose and D-xylose with semicarbazide or thiosemicarbazide (186) in the presence of montmorillonite K-10, under microwave irradiation, proceeded via domino cycloisomerization, dehydrazination, and dehydration of the intermediate semi- or thiosemicarbazones (187) to afford l,3-oxazin-2-ones or l,3-oxazine-2-thiones (188) in one single step and in yields between 79% and 85% (Scheme 34). Other mineral catalysts tested, such as silica gel and basic alumina, were far less effective for this transformation and only silica gel was active at all, giving low yields (15-28%) of compounds 188a-d. The l,3-oxazin-2-ones(thiones) thus synthesized were subsequently converted into the target pyrimidines by reaction with aromatic... 

SCHEME 34. Synthesis of l,3-oxazin-2-ones and 1,3-0xazin-2-thiones from unprotected aldoses... 

SCHEME 35. Montmorillonite K-10-catalyzed cyclodehydration of the l,3-oxazin-2-one and 1,3-oxazin-2-thione derivatives 189 into bicyclic compounds 190. 

The l,3-oxazin-2-ones and 1,3-oxazine-2-thiones previously synthesized were used to prepare various N- and O-heterocyclic systems fused with 1,3-oxazine rings.172 For example, furan-l,3-oxazin-2-one or furan-l,3-oxazine-2-thiones (190a,b) and pyran-l,3-oxazin-2-ones or pyran-l,3-oxazine-2-thiones (190c,d) were prepared in very good yields, ranging from 83% to 90%, by montmorillonite K-10 clay-catalyzed cyclodehydration of 189a,b and 189c,d, respectively (Scheme 35). 

Cadogan and coworkers160 developed a fructose-derived l,3-oxazin-2-one chiral auxiliary which they applied in the Diels-Alder reactions of its iV-enoyl derivatives 246 with cyclopentadiene using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded mixtures of endo 247 and exo 248 (equation 68). The catalyst binds to the chiral dienophile in a bidentate fashion (co-ordination to both carbonyl groups). As a consequence, the dienophile is constrained to a rigid conformation which accounts for the almost complete diastereofacial selectivities observed. 

Oxazine derivatives are formed from unsaturated AAs. Vinylglycine, after epoxidation at the double bond, yielded methyl l,3-oxazin-2-one-4-carboxylate after treatment with sodium methoxide or p-chlorophenol (90TL2291). Similarly, some alkenes react with methyl a-methoxyhippurate and cyclization occurs with BF3-Et20 (75TL3737). In sulfuric acid butyro-lactones are formed. 

The following l,3-oxazin-2-one syntheses have been applied individually. 

Bobowsky and Shavel found an interesting intramolecular reductive transacylation reaction, in which substituted cyclopent[e][l,3]oxazin-2-ones and l,3-perhydrobenzoxazin-2-ones (90) were formed (80JHC277). In the reactions of 4-(2 -oxocycloalkyl)-3,4-dihydro-3-methyl-2//-l,3-benzoxazin-2-ones 88 and potassium borohydride, the 2 -hydroxycycloalkyl products 89 obtained underwent intramolecular transacylation reactions, resulting in the dihydro-1,3-oxazine derivatives 90. In this way, the 4-(2 -oxocycloalkyl)... 

Lithium aluminum hydride reduction of tetrahydro-l,3-oxazin-2-ones 434 results in the corresponding A -methyl-substituted 1,3-amino alcohols 435 (60JA4656 87TL1623). 

Methyl substituents at position 6 caused a change in the solid-state conformations of 4-phenyltetrahydro-l,3-oxazin-2-ones 80 and 81. In the 6-unsubstituted heterocycle 80, the 4-phenyl group was situated in an axial position, whereas 1,3-interactions arising from the presence of geminal methyl groups at position 6 of 81 led to an equatorial orientation for the 4-phenyl substituent <2006OBC2753>. 

No loss of optical purity was observed in the mild acidic hydrolysis of the enantiomerically pure 6-alkoxy -phenyl-5,6-dihydro-4/7-l,3-oxazine 132, which resulted in formation of (R)-3-benzoylamino-3-phenylpropanal 133 in excellent yield (Scheme 20). Hydrolysis of the analogous tetrahydro-l,3-oxazin-2-one 134 to 133 required a stronger acidic medium and took place only in poor yield, but without any decrease in the optical purity <20000L585, 2003JOC4338, 2004TL9589>. 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

The D-fructose-derived, chiral, nonracemic l,3-oxazin-2-one derivative 260 exerted smooth stereocontrol, resulting in high levels of asymmetric induction and good chemical yields in various synthetic transformations. The chiral fragments 256 and 261 formed in the aldol or a-bromination reactions of the A -propionyl derivative 257 could easily be removed from the parent auxiliary by mild hydrolysis (Scheme 48). The Diels-Alder cyloadditions of the A -acryloyl and A -cinnamoyl derivatives of 260 were also characterized by excellent diasterofacial selectivity <1998T9765>. 

In the reactions of (i )-0-vinylpantolactone 307 and iV-BOC-0-methyl-iV,0-acetals 310, the corresponding tetra-hydro-l,3-oxazin-2-ones were formed as a result of loss of the tert-huVf group. The heterocycloadditions took place with high facial selectivity, leading to isomers 311 as the main products (Equation 29). Compounds 311 could also be utilized in the synthesis of /3-aminoaldehyde derivatives (see Section 8.05.6.3) <2004TL9589, 2006EJ03309>. 

Bromopropylamine was reported to form tetrahydro-l,3-oxazin-2-one in moderate yield when treated with the carboxylating reagent (O2 /C02) formed by the electrochemical reduction of oxygen in acetonitrile in the presence of carbon dioxide <1997JOC6754>. 

An elegant cyclization-cleavage strategy has been devised for the removal of resin-bound 1,3-amino alcohol derivatives 392 as l,3-oxazin-2-ones 393 upon treatment with lithium hexamethyldisilazide (LiHMDS) (Equation 42) <20010L3177>. 

Dibenzothiophene carbamate 396 was converted to the corresponding l,3-oxazin-2-one derivatives 397 in a two-step, one-pot procedure. Lithiation of 396 gave a bis-anion intermediate, treatment of which with ketones led to cyclization to tetracyclic l,3-oxazin-2-ones 397 (Equation 43). In the similar reaction of the analogous dibenzofuran carbamate, a hydroxymethyl-substituted acylic compound was formed <1998J(P1)457>. 

Late transition metal-catalyzed processes also proved to be very useful tools for formation of the C-O bond of the 1,3-oxazine ring from the corresponding alkynes. In the presence of 1-5 mol% of a cationic gold(l) complex, A -BOC-protected alkynylamines 450 were converted to 6-alkylidene-l,3-oxazin-2-ones 451 under very mild conditions (Equation 49) <2006JOC5023>. 

The iodocyclizations of 2-alkoxycarbonylamino-3-alken-l-ols proved to be highly stereoselective processes resulting in either l,3-oxazin-2-one or THF derivatives, depending on the substituents at the double bond and the nitrogen protecting group <2000TA3769>. 

The palladium-phosphine-catalyzed cycloaddition reactions of vinyloxetanes 530 with aryl isocyanates or diaryl-carbodiimides led to 4-vinyl-l,3-oxazin-2-ones 531 or l,3-oxazin-2-imines 532, respectively (Scheme 101). In the absence of phosphine ligands (PPhs, bis(diphenylphosphino)ethane (DPPE), l,3-bis(diphenylphosphino)propane (dppp), no conversion of heterocumulenes was observed. Starting from fused-bicyclic vinyloxetanes, both types of cycloadditions proceeded in a highly stereoselective fashion, affording only the r-isomers of alicycle-condensed 1,3-oxazine derivatives <1999JOC4152>. 

Cyclobutane-fused hexahydropyrimidine-2,4-dione 569 was converted to the corresponding l,3-oxazin-2-one derivative 571 in a two-step procedure (Scheme 109). Compound 569 was reduced with NaBH4 to give ureidoalco-hol 570 in excellent yield, the diazotization of which provided the cyclic carbamate derivative 571 <2006TL5981>. 

Maytansine 588 is a macrocyclic tetrahydro-l,3-oxazin-2-one derivative isolated from higher plants, mosses, and an actinomycete, kctinosynnema pretiosum. Despite the extraordinary antitumor activity found for many maytansine derivatives, the Phase II clinical trials with maytansine turned out to be disappointing. The chemistry and biology of maytansinoids have recently been reviewed <2004CPB1>. 

The Rh-catalyzed reaction of isoxazolidine 240 at 150-170 °C and65atmofCOgave tetrahydro-l,3-oxazin-2-one 241 in good yields, wherein the insertion of CO took place selectively into the N-O bond of isoxazolidine (Scheme 34). 

Routes to AH-1,3-oxazines and -thiazines involve the cyclization of amides or thioamides with acidic reagents (Scheme 35) (78AHC(23)l). l,3-Oxazin-2-ones can be made by the thermolysis of carbonyl azides (262 Scheme 36) (79CC719). 

Trimethylsilyloxyfuran (274) reacts with ethoxycarbonylnitrene to give 3-ethoxycarbonyl-3,4-dihydro-l,3-oxazin-2-one (276) via aziridine intermediate (275) (89TL5025). 

Annelated 2/f-l,3-oxazin-2-ones and -thiones of type (420) can be obtained by cycliza-tion of o-hydroxyimidic acid derivatives (e.g. 419) with A TV -carbonyldiimidazole (X=0) or thiophosgene (X = S) (Scheme 122) (78CB314). 

Breslow94 introduced an interesting method of forming 2-oxo compounds, which was based on his earlier work.95 Thermolysis of n-octadecyl azidoformate gives some tetrahydro-l,3-oxazin-2-one (23) [Eq. (14)]. 

Farrissey and Nashu105 reported that the reaction of an epoxide with phenyl isocyanate, which previously had been claimed to yield a tetrahydro-l,3-oxazin-2-one,1,106 produced, in fact, a 2-oxazolidone derivative. 

Kurtev and co-workers27 examined the conformation of trans-4,5-diphenyltetrahydro-l,3-oxazin-2-one (121) by NMR. They concluded... 

Oxazinomycin (l)5 is a 1,3-oxazine antibiotic. There are five other antileukemic antibiotic macrolides of known tetrahydro-l,3-oxazine-2-one structures. Maytansine, Maytanprine, and Maytanbutine were found by Kupchan et a/.278,278 in Maytenus ovatus and Maytenus buchananii, and in Maytenus serrata by Meyers et al.,277 and Calubrinol... 

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