L,3,4-Oxadiazin-5-one

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. 

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. 

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) ... 

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. 

Dialkylaminopyridazine-l-oxides (87) have been prepared by condensation of l,3,4-oxadiazine-6-one 4-oxides with ynamines. The synthesis is regiospecific, and upon deoxygenation the corresponding 4-dialkylamino-pyridazines are obtained. 

Decomposition of 4 in the presence of l,3,4-oxadiazin-6-one 4-oxides, 267 (R = Me, Et, Ph), leads to the formation of benzofurans 272, benzofuranones 273, and the cyclic anhydrides 271, all of which can be rationalized in terms of an initial 1,3-cycloaddition of benzyne to 267, 1,3-sigmatropic rearrangement of 268 - 269, and subsequent decomposition steps as outlined in Scheme 26.120 Formation of 271 requires a cycloaddition of the benzyne precursor 5 to the ketene intermediate 270, which is supported by the observation of a similar capture of 5 by diphenylketene. 

Numerous l,3,4-oxadiazin-5(6//)-ones can be prepared by this type of cyclization. Examples arc 2-(l-ethyl-l-hydroxypropyl)-4-phenyl-4//-l,3,4-oxadiazin-5(6//)-one (6),40 4-phenyl-2-(4-tolyl)-4//-1,3,4-oxadiazin-5(6//)-one (7) (which is claimed to be useful as a miticide and nerna-tocide),41 4-cyanomethyl-, 4-(2-cyanoethyl)-, 4-(3-cyanopropyl)- and 4-(4-cyanobutyl)-6-methyl-2-phenyl-4//-l,3,4-oxadiazin-5(6//)-onc (8, n = 1, 2, 3 and 4, respectively) (which inhibit monoamine oxidase Type A and Type B),42 various 2,4-diaryl-4//-l,3,4-oxadiazin-5(6//)-ones 9 (which possess acaricidal activity),43 cardiotonic 2-aryl derivatives 10,44 and some heteroaryl-substituted compounds, such as 2-[4-(imida/.ol-l-yl)phenyl]-4f/-l,3,4-oxadiazin-5(6//)-one (11) (which is claimed to be cardiotonic and antihypertensive)45 and 2-(2-methylimidazo[l,2-a]pyridin-3-yl)-4//-l,3,4-oxadiazin-5(6//)-one (12) (which inhibits blood platelet aggrega-... 

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). 

Surprisingly, treatment of 2-(2-hydroxyphenyl)-4/7-l,3,4-oxadiazin-5(6//)-one (54) with ethyl bromoacetate in aqueous alkali results in regioselective alkylation at N-4 rather than at the phenolic hydroxy-group (Equation (4)) <91JIC574>. 

Diphenyl-3,6-dihydro-2i7-l,3,4-oxadiazin-2-one (37), in the presence of sodium hydride, is tosylated at N-3 <83TL4635>. 

Although 5,6-diaryl 3,4-dihydro-2//-l,3,4-oxadiazin-2-ones (71) are stable in dilute acid, under more forcing conditions they yield carbazates (72) by hydrolysis of the N4—C5—C6 enamine system as outlined in Scheme 7 <88CB887>. 

Electrophilic attack at carbon is a rare event, and generally involves an oxidative process. For example, 5,6-diphenyl-tetrahydro-2//-l,3,4-oxadiazin-2-one (74) (Section 6.17.7.2.1.1) is inert towards oxidation by HgO, whereas with lead tetraacetate fraws-stilbene is produced in 89% yield <65JA5716>. In contrast, under the same conditions, the dehydro-derivative (75) is oxidized more slowly and in much lower yield (14%) to diphenylethyne. 

Analogous ring-opening reactions are noted with 1,3,4-oxadiazin-6-ones and a /, 2 of 1 h has been measured for 2,5-diphenyl-l,3,4-oxadiazin-6-one in a mixture of carbon tetrachloride and methanol at 20°C <85CB2940>. 

Diphenyl-3-p-tosyl-3,6-dihydro-2Ef-l, 3,4-oxadiazin-2-one (90) (Section 6.17.5.2) on treatment with t-butyllithium at — 78 °C undergoes an orbital symmetry controlled ring collapse of the resulting unstable l,3,4-oxadiazin-2-one (91) to 1,2-diphenylethyne <83TL4635>. 

As expected, 2-ethoxycarbonyl-5-phenyl-l,3,4-oxadiazin-6-one (102 R = Ph, R = C02Et) shows enhanced diene reactivity over the 2,5-diphenyl compound (102 R = R = Ph) and will react with norbornadiene at room temperature. Additionally, in some cases (e.g. with norbomene) the initial cycloadducts (103 R = Ph, R = C02Et) are isolable <85AG(E)886,90CB2031>. 

In marked contrast, however, the less reactive 2,5-diaryl-l,3,4-oxadiazin-6-ones (133) behave as... 

Reaction of 2,3-dihydrofuran with 2,5-diphenyl-l,3,4-oxadiazin-6-one results in trapping of the y-ketoketene (136) by an excess of dihydrofuran and production of diastereoisomeric cyclobutanones (137) in 62% yield <85T283>. 

Diphenyl and 5-methyl-2-phenyl-l,3,4-oxadiazin-6-one with 1-pyrrolidinylcyclopentene in boiling benzene followed by chromatography on silica gel yield, in each case, benzaldehyde and the tetrahydrocyclopenta[c]pyrazole (144) <85T283>. However, with the diphenyl-oxadiazinone in benzene at room temperature the diazatriene (145 R = Ph) is formed (77 /o), which on heating in wet solvent forms benzaldehyde and the pyrazole (144) (Scheme 18). A mechanistic rationale is proposed. 

Diaryl-l,3,4-oxadiazin-6-ones (147) undergo a stepwise 1,3-dipolar cycloaddition with 2,4,6-trimethylbenzonitrile oxide to yield the bis-adducts (148) together with varying amounts of the hydrolysis products (149) (Scheme 20) <90JHC1425>. The adducts, whose structures are confirmed by x-ray analysis, arise by sequential addition of the nitrile oxide at the N4—C5 imine bond and the carbonyl group. 

Dihydro-6-(4-nitrophenyl)-2/f-l,3,4-oxadiazin-2-one can be reduced to the 4-aminophenyl derivative in low yield (37%) with hydrogen and palladium-charcoal in acetone at room temperature <88CB887>. Likewise, reduction of 3,6-dihydro-5-(4-nitrophenyl)-277-l,3,4-thiadiazin-2-one to the 4-aminophenyl compound is possible with tin(II) chloride in a mixture of hydrochloric and acetic acids <91JAP(K)03261773>. 

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