1.2.5- Oxadiazine, 5-hydroxy

The 1,2-bishydroxylamine (494) with phosgene gives the 5-hydroxy-1,2,5-oxadiazine (495) (80AP35). Acid-catalyzed dehydration of A-(2-hydroxyethyl)-A -acylhydrazines (496) is a general route to 4,5-dihydro-1,3,4-oxadiazines (497) (64JOC668). 

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 oxadiazine 1, previously believed to be a diazetidine2, is obtained from indene and dialkyl diazenedicarboxylate1,3. The oxadiazine ring is cleaved by lithium aluminum hydride to afford the cw-(l,2-dihydro-3-hydroxy-2-indenyl)hydrazine 21,3, which is successively converted to hydroxyamine 3 by hydrogenolysis3. 

Ethoxycarbonylhydrazones of a-hydroxy ketones readily cyclize under basic conditions to 3//-l,3,4-oxadiazin-2(6/f)-ones, e.g. formation of 2.35... 

There is an unconfirmed report of the oxidation of 5-hydroxy-5,6-dihydro-4//-l,2,5-oxadiazines (25 R = H or Me) to 6//-l,2,5-oxadiazine-5-oxides (26) with lead dioxide in benzene at room temperature (Equation (2)) <70CHE1180>. 

Originally, the products from the acid-catalyzed self-condensation of ketoaldehyde monoximes were formulated as 5-acyl-4-hydroxyimino-4,5-dihydroisoxazolines (64) <1897CB1292>, structures which later were revised to 6-acyl-4-hydroxy-4//-l,2,5-oxadiazines (64) <23G3ii, 26G713). However, Polish workers, on the basis of chemical and spectroscopic evidence together with measurements,... 

Trifluoromethyl-3,6-dihydro-2/7-l,3,4-oxadiazines (51) with an excess of iodomethane in hot ethanol undergo ring scission to the 2-hydroxy-ketones (52) in high yields (Equation (3)) <88S208>. 

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>. 

A detailed study of this oxidative cyclization revealed that 6-hydroxy-6-trifluoromethyl-1,3,4-oxadiazines are produced in good yields (52-72%) if the oxidation is carried out with sodium periodate at 25 °C in a 2 3 THF-H2O mixture. In 2 1 THF-H2O solution, the reaction is much slower (5 days) and in some cases (197 Ar = Ph, 4-CIQH4, 4-NO2QH4, R = Me, = H) considerable quantities of the dehydroxylated products (199) are obtained <91H(32)I693>. 

Cyclocondensation of the iminotetrahydropyrazole (302) with ethanal yields the bicyclic 1,3,4-oxadiazine (303) in 52% yield <86JOU2038>. In a similar manner, ring-closure of the A-(j8-hydroxy-... 

Dimethyl-6-hydroxy-3,6-dihydro-2/f-l,3,4-oxadiazine (309), a cyclic hemiacetal, is formed by reaction of 2-methylhydrazonopropanal (MeNHN=C(Me)CHO) with aqueous methanal <85JCS(P1)81>. 

Aryl-6-trifluoromethyl-3,6-dihydro-2//-l,3,4-oxadiazines result from the trifluoroacetylation of arylaldehyde iV,iV-dialkylhydrazones, while oxidation of the hydrazones with sodium periodate yields the 6-hydroxy-6-trifluoromethyl derivatives (Section 6.17.7.1.1). 

Hydroxy-l,5,6-trimethyl-3-aryl-l//-benzo[l,3,4]oxadiazines and 9-hydroxy-l-phenyl-3-aryl-l//-naphtho[3,4-r ]-... 

R = Me2C=CH-CH2-CH2) with hydrazine hydrate leads to carbamate intermediates, which undergo cyclization to give 5-hydroxy-5.6-dihydro-4/f-l,3,4-oxadiazin-2(3//)-ones 311. The thermal dehydration of 311 gives 1,3,4-oxadiazin-2(3//)-ones 312 <2003CHE1057>. In contrast to the case with hydrazine hydrate, the reaction of aromatic hydrazines with l,3-dioxolan-2-ones 310 provides 3-arylamino-4-hydroxyoxazolidin-2(3//)-ones 313. 

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. 

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