Oxazinones, preparation

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

The oxazinones 74 and 79, already described as chiral glycine templates in Section 11.11.6.3, have been prepared by the PET cyclisation of 252 by irradiation in the presence of 1,4-dicyanonaphthalene as the electron acceptor and methyl viologen as electron-transfer mediator. When the reaction was carried out under strictly anhydrous conditions, compound 79 was isolated, whereas when the reaction was carried out in wet MeCN, compound 74 was the exclusive product (Scheme 33). In any case, the products were obtained with high stereoselectivity, which is the condition required to use them as chiral auxiliaries <2000EJ0657>. 

Sharp less et al. also reported <2001AGE2004> the synthesis of one representative of the present class of compounds. In their studies on click chemistry, the substituted cyclohexyltriazole 302 was prepared, which, upon treatment with a base at reflux temperature, underwent lactonization to yield the fused oxazinone 303 in high yield. 

The carboacyclic C-nucleosides 988 were prepared by the cycloaddition of 987 with oxazinone 986 (91T10065). 

From the readily available benzotriazole derivative 76, Katritzky and Harris (90T987) prepared a diastereomeric mixture of the /3-amino ketone 77 with the lithium enolate of cyclohexanone. In the reduction of 77 with lithium aluminium hydride, a reductive cyclization took place, resulting in the two diastereomeric oxazinones 78 in a ratio of 5 2. This cyclization can be regarded as a variation of the chloroformate cyclization under alkaline conditions. 

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). 

A general type of [3 + 3] heterocyclization involves initial nucleophilic attack on the electrophilic three-membered heterocycle by a 1,3-electrophile-nucleophile. Aziridines (330) with either a-mercapto ketones (329) or with a mixture of a ketone and sulfur give 5,6-dihydro-1,4-thiazines (330 — 331 — 332). Azirines (333) can be used for the preparation of pyrazinones (334) from ot-amino esters R2CH(NH2)C02Et and of 1,4-oxazinones from a-hydroxy esters (83TL1153). 

The preparation of dihydro-4//-l,3-oxazinones (166) from mono-239,240 or disubstituted307 thiopseudoureas has been accomplished by their reaction with diketene. In one case,239 a 2-alkylthio intermediate in the... 

As with most camphor-based chiral auxiliaries, the size and steric congestion at the C-8 position of the camphor moiety can determine its efficiency. Through the formation of a connection between C-8 and C-2, a novel camphor-based oxazinone auxiliary 29, which can be prepared from camphor in 3 steps,52 becomes highly effective in directing stereoselective aldol reactions (Scheme 5.11).53... 

Seeking to emulate the benzylidene effect in p-mannosylation [68] (see Section 4.2.6), David Crich and Baolin Wu [87] and Hiromune Ando and coworkers [88] prepared 5-.V,7-(9-oxazinone-protecled thiosialosides 69 and 70 (Fig. 5.5). Unfortunately, both groups found this class of donors to be moderately p-selective under a variety of activating conditions and even in the presence of acetonitrile. 

Starting from the pyridazinocarboxyimidoyl chlorides (158) the corresponding ureas (159) were prepared and subsequently cyclized into the pyridazino[4,3-e][l,3]oxazinones (160) (Scheme 27) <88AP(321)527>. 

Matyus et al. reported the synthesis and cardiotonic activity of pyrimido[5,4-6][l,4]oxazinones <90JHC151>. The synthesis started from 6-amino-2,3-dimethyl-4(3//)-pyrimidinone. Also 4-sub-stituted pyrimido[5,4-6][l,4]oxazinones were transformed into pharmaceutically interesting products. Several compounds were prepared some showed an ionotropic effect, for example (208) and (209). 

The most straightforward method used to prepare pyridazine derivatives is the reaction of a 1,4-dicarbonyl compound with hydrazines . 1,4-Dicarbonyl compounds with a double bond in the 2,3-position 120 condense with hydrazine to give pyridazines 121 (Scheme 62). If one of the carbonyl groups in the starting material is part of a carboxyl group or a potential carboxyl group (e.g., 122), then reactions with hydrazines or hydroxylamine lead to pyridazinones 123 (Z = NH) or 1,2-oxazinones 123 (Z = O) (Scheme 63). Similarly a cyano group leads to an amino or imino product. 

Preparative Methods N-t-Boc- and Al-Cbz-3-bromo-5,6-diphenyl-2,3,5,6-tetrahydrooxazin-2-ones are not commercially available. They are prepared by addition of 1 equiv of N-Bromosuccinimide to a solution of the parent oxazinone (commercially available as the individual enantiomers or as racemates) in CCI4 at reflux. Upon cooling of the reaction mixture to 0 °C and filtering off the succinimide, the CCI4 is removed under reduced pressure and the bromooxazinone is obtained in essentially quantitative yield as a white solid and is used without further purification. ... 

Dipolar Cycloadditions. Highly substituted proline derivatives can be prepared by removal of the r-Boc protecting group from the oxazinone followed by condensation of the heterocycle with an aldehyde in the presence of p-Toluenesulfonic Acid in benzene. Under these conditions, Schiff base formation and ylide generation occur. Subsequent [3 + 2] cycloaddition with a dipolarophile affords the bicyclic heterocycle, which is then de-protected to yield the desired proline derivative (eqs 10 and 11). ... 

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>. 

The oxazinone I is prepared in several steps from ketopinic ethyl ester. 

With this efficient crystallization-induced resolution in place, a more concise preparation of racemic oxazinone 1 was desired. A modified variant of Scheme 4 was rapidly instituted (Scheme 6). 

A pyrrolo[l, 4]oxazinone has been prepared by cyclization of the )3-chloroethyl pyrrolecarboxylate anion (231) (Equation (90)) <70FRP1502066>, and a pyrrolo[l,3]thiazinedione (232) by lactam formation (Equation (91)) <87JMC498>. 

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