1.3.4- Oxadiazin-6-ones

The enthalpies ofall the annular tautomers of l,3,4-oxadiazin-5-ones 117 and -2-ones 118 were calculated using the MNDO method (88CB887). The results clearly indicated that in both cases the hydrazone-type tautomers 117a and 118a are the most stable, while the formation of the tautomer 118c is the least probable. 

Thermal condensation of a-chlorocarboxylic chlorides with amidoximes affords 1,2,4-oxadiazoles. However, in the presence of a strong base (NaH) l,2,4-oxadiazin-5-ones were isolated (Scheme 41) <87H(26)163>. 

Oxadiazin-5- and -6-ones are likewise thought to be the 477-tautomers shown. These compounds are lactams and lactones, respectively. The l,2,4-oxadiazin-5-ones are acidic they dissolve in aqueous alkali or ammonia and are regenerated on acidification. Their 5-lactam character is confirmed by their infrared spectra. 

Diaryl- and 2,5,6-triaryl-477-l,3,4-oxadiazines are stable solids which absorb at 3400, 1600-1590 and 1280-1250 cm-1 in the infrared.34,35 The l,3,4-oxadiazin-2-ones 2 are lactones their IR spectra show NH and carbonyl bands at ca. 3420 and 1730 cm-1, respectively.36 l,3,4-Oxadiazin-5-ones 3 are (5-lactams with vmax 1710-1700 cm-1 and 1,3,4-oxadiazin-6-ones 4 are acidic they exhibit <5-lactone carbonyl absorption at ca. 1800 cm-1. 

Formation of 1,2,4-oxadiazines occurs by acid-catalyzed ring expansion of a-aziridino oximes and dioximes, and by 1,3-dipolar cycloaddition of arylcarbonitrile oxides and 2-acyl-2//-azirines (Section 6.14.10). Preparation of l,2,4-oxadiazin-5-ones can be achieved by ring closure of A-carboxymethyl and A-alkoxycarbonylmethyl amidoximes (Section 6.14.9.1.1), by the acid-catalyzed condensation of arylaldehydes with O-alkyl-A-acylhydroxylamines (Section 6.14.9.2.3.1), and by reaction of A-hydroxyureas or amidoximes with a two-carbon fragment such as an a-halo ester or an acyl halide (Section 6.14.9.2.2.1). 

MNDO calculations have been used to determine the relative stabilities of the tautomeric 1,3,4-oxadiazin-5-ones (9) and (10) and the dipolar form (11), and also of the three isomeric 1,3,4-oxadiazin-2-ones (12)-(14) <88CB887>. Calculated AHf values are appended to the diagrams. 

The ring cleavage of hydrazide 308 in the presence of 2equiv of Bu OK, followed by alkylation, results in 1,3,4-oxadiazin-5-one derivatives 309 (Scheme 40) <2002TL1015>. 

Diaryl-4/7-l,3,4-oxadiazines can be prepared by hydration of l-aryl-2-phenacyl hydrazine derivatives (Section 9.08.8.1.1). 3/7-l,3,4-Oxadiazin-2-ones are obtained by cyclization of ethoxycarbonylhydrazones of a-hydroxy ketones (Section 9.08.8.1.1). 47/-l,3,4-Oxadiazin-5-ones are synthesized by ring closure of l-acetyl-2-chloroacetylhydrazines. 

Aryl-4-(chlorophenyl)-6i/-l,3,4-oxadiazin-5-ones 345 are a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists <2000W02000047567>. 

Diethyl azodicarboxylate and diphenylketene can he submitted to a [4 + 2] cycloaddition however, the initial l,3,4-oxadiazin-5-one product 503 react with a second mole of ketene to give a hicycHc product 504... 

Phenyl-3,6-dihydro-l,3,4-oxadiazin-2-one (50) is a high temperature blowing agent used primarily for polycarbonates (qv). It is prepared by the reaction of a-hydroxyacetophenone and methyl carbazate (52), made from hydrazine and dimethyl carbonate (175) ... 

Two Nitrogen Atoms and One Oxygen Atom Synthesis of 1,3,4-oxadiazines 98H(49)557. 

Dehydrogenation of piperidine derivative 329 with Hg(II)-EDTA reagent afforded a mixture of perhydropyrido[l,2-n]pyrimidin-2-one 330 and pyrido[],2-c][],2,5]oxadiazine 331 (99ZN(B)632). 

The formation of two fused oxadiazine ring systems and one fused dithiazine ring system is illustrated in Scheme 28. 

Reaction of a-aminoketoximes 374 with l,l -carbonyldiimidazole (GDI) in THE afforded l,2,5-oxadiazin-6-ones 375 in 41-65% yields (equation 163) °. 

The l,3,4-oxadiazin-6-one (240) undergoes cycloaddition followed by a remarkable rearrangement to give the triazole A(-imine 241 and an open-chain product (136). Cycloadditions have also been carried out with the following ring systems 1,2-dihydroisoquinoline (242) (137) dihydro-1,3-oxazine (243) (138,139), 2H-, 3-benzothiazine (244) (140,141), and 27/-l-pyran-2-thione (245) (142). 

The addition of hydrazine to diphenylvinylene carbonate 92 quantitatively affords a 1 1 mixture of perhydro-l,3,4-oxadiazin-2-one 93 and 2-oxazolidinone 94 derivatives, both of which are smoothly dehydrated with P2O5 to afford 1,3,4-oxadiazin-2-one 95 and 3-amino-2(3//)-oxazolone 96 (Fig. 5.24), respectively. Addition of primary amines to diphenylvinylene carbonate results in exclusive formation of 3-aIkyl-2(3//)-oxazolones, previously investigated as amino protecting groups in peptide synthesis. 

A novel approach to the formation of the fused [l,3,4]oxadiazine ring in this heterocyclic system involved treatment of pyrazol-3-one 77 with acetic anhydride and hydrazine hydrate to give oxadiazine 78 in high yield (Scheme 55) <2002IJB664>. 

The NMR spectrum of oxadiazine derivative 129 shows (84ZOR717) only one signal for the acetyl group probably only the -conformer is present. 

Carbonyl-substituted isocyanates have been reported to add [2 + 2] to carbodiimides, although in one case the reported 4-imino-l,3-diazetidin-2-one (64AP623) was reassigned an oxadiazine structure (72BCJ1534). It is clear that the initially formed [2 + 2] kinetically favored adducts are thermally unstable and ultimately form more stable [4 + 2] products, oxadiazines (Scheme 13) (79BSF(2)499). 

Treatment of TV.A -disubstituted ureas with methanal followed by cyclodehydration of the resulting Ar,Ar -bis(hydroxymethyl)ureas (531) with P205 furnishes 3,5-dialkyl-5,6-dihydro-2H-1,3,5-oxadiazin-4(3//)-ones (532) in high yields (85JAP(K)6067471, 85JAP(K)6067472, 85JAP(K)60104075, 85JAP(K)60104076). 

Freeman et al.524 have shown that l,3,4-oxadiazin-6-one 4-oxides (114)525 react with a variety of acetylenes to produce acylbutenolides... 

A [1,5]-sigmatropic shift of hydrogen from an A-methyl group to the carbonyl carbon atom in protonated 3-(A,A-dialkylhydrazono)-l,l,l-trifluoroalkan-2-ones has been found to be a key step for the acid-catalysed cyclization of these ketones to 6-trifluoromethyl-3,6-dihydro-2//-[l,3,4]oxadiazines.58 Gas-phase kinetic studies on interconversions of monodeuterocyclohexadienes have given activation parameters in reasonable agreement with previous experimental and theoretical data.59... 

The reaction of 5-arylimino-l,2,3-dithiazoles 56 with hydroxylamine proceeds smoothly to give A -arylcyanoform-amidoximes 98 (Equation 19), which can be utilized as starting materials for the synthesis of 4-substituted-2-cyanoquinazolines and 4-aryl-3-cyano-l,2,4-oxadiazin-5(67/)-ones <1999H(51)2653>. 

Methyl 6-oxo-5-phenyl-6/M,3,4-oxadiazine-2-carboxylate 657 reacts with alkenes to yield 2//-pyran-2-ones. The reaction proceeds via cycloaddition of 657 to the alkene to form the y-oxoketene intermediate 658 addition of bromine and bis-elimination of HBr then affords 2//-pyran-2-ones (Scheme 154 and 155) <1998J(P1)2031>. 

The introduction of only one methyl group on the a-carbon atom with respect to the hydroxy group (37, R4 = Me) stabilizes the cyclic tautomer. The presence of two methyl groups (37, R4 = R5 = Me) exerts a less well expressed stabilizing effect when R1 = R3 = Me and R2 = H, but an entirely opposite effect when R1 = R2 = R3 = Me. This is presumed (89TH1) to be caused by nonbonded 2,6-diaxial (2-Me and 6-Me) interactions in the chair conformer of perhydro-l,3,4-oxadiazine 37B. 

The addition of a second equivalent of cyclopropene can then also occur 224). In the case of 3,3 -bicyclopropenyls (288), this provides a ready route to semibullvalenes, the epimeric intermediate cyclopropenes equilibrating and allowing intramolecular cycloaddition to occur 225). Addition also occurs to oxadiazin-6-ones 226), to 5-phenyl-... 

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