1.3.4- Oxadiazines, fused

Early studies on tautomerism of benzo-fused 1,3,4-oxadiazines (70CB331 76AHCS1, p. 79) suggested the predominance of the 2H tautomer 119a, which, however, easily tautomerizes to the 4H isomer 119b on treatment with sodium alkoxide (Scheme 31). 

Three triazole-fused oxadiazines have been synthesized during the recent period, as shown in Scheme 19. 

Two other synthetic routes to derivatives of this ring system should be mentioned here, and the transformations are shown in Scheme 54. The phenanthrene-fused fV-aryldihydro[1.2.4]triazine 274 was found to undergo 1,3-dipolar cycloaddition with diarylnitrilimine to give the cycloadduct 275 <1997J(P1)1047. This transformation is entirely analogous to that taking place with a fused oxadiazine derivative, as discussed in Section 11.19.6.1. 

The compilation of ring systems in Scheme 1 consists of all the ring systems discussed in this chapter. The first three lines of structures are fused oxadiazines, dithiazines, and thiadiazines, these ring systems are followed by various fused... 

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

The labile cycloadduct 262 of azodibenzoyl to cyclopentadiene rearranges to the fused oxadiazine 263 on heating. The process involves dissociation of 262 into its components, followed by a Diels-Alder reaction in which the azo compound functions as a hetero diene (equation 142)135. 

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>. 

Pyrazolo[4,3- ][l,3,4]oxadiazine 78, whose preparation is given in Section 10.13.9.1.2(iv), was condensed with various amines to give pyrazolo[3,4- ][l,2,4]triazines 101 (Scheme 78 Table 9) <2002IJB664>. This ring system was earlier reported by synthesis of the fused six-membered ring, through condensation onto pyrazolediones <1996CHEC-II(7)489>. 

The reaction of 1,3-dithietane 92f substituted with a diethylphosphoryl group with G-nucleophiles is analogous to the previously reported reaction. Its condensation with different C-nucleophiles, such as cyclic and acyclic a-carbonyl-methylenes and a-carbonylhydrazones, gave a number of [2,l-3]fused phosphono-substituted thioxopyranes 97, 100, 103, 107, oxadiazine 109, and thiazine 105 (Scheme 12), which are of potential biological interest <2002PS1885>. 

Bifunctional nucleophilic compounds can add to TV-alkylpyrazinium salts, and the benzo fused pyrazino[2,3-e][l,3,4]thiadiazine (471) as well as the benzo fused pyrazino[2,3-e]-l,2,4-oxadiazine (472) can be made by this method (Scheme 40). A closely related reaction is exemplified by the preparation of the pyrazino[2,3-e]-1,2,4-triazine (473) (Equation (94)) <87KGS557, 87KGS1118). The pyrimido[5,4-c][l,2,5]oxadiazine (475) can be prepared by treatment of the uracil derivative (474) with isoamyl nitrite (Equation (95)). Presumably the reaction proceeds by cyclization of an initially formed 5-nitrosopyrimidine intermediate (64ZC454). 

New fused 6,8a-dihydro-4/7-pyrrolo[l,2- ][l,2,5]oxadiazines 1176 and 5,7a-dihydro-37/-pyrrolo[l,2- ]imidazole 1-oxides 1177 were obtained via hetero-Diels-Alder reactions ([4-1-2] and 1,3-dipolar) adding 277-pyrrole 1174 to substituted nitrosoalkenes [CH2=C(R)N=0], generated in situ thorough base-mediated dehydrohalogenations of ot-bromooximes 1175 (Equation 268) <2002T1507>. 

On the other hand, the [4 +- 2] cycloaddition of diethyl diazenedicarboxylate and cyclic enol ethers is performed efficiently under UV irradiation. Without irradiation and by increasing concentration, the ene reaction product can be obtained from the substrates. The oxadiazine structure, as well as the stereochemistry of the cycloadduct 13 obtained from a cyclopropane-fused dihydrofuran and diethyl diazenedicarboxylate, was established by X-ray29. 

S,5-Dimethylsulphimides (readily prepared from the primary amine, dimethyl sulphide and AT-chlorosuccinimide) react with nitrile oxides (review [B-43]) under mild conditions to form a fused oxadiazine. 

The ring closure of acylhydrazines can be applied to the synthesis of numerous 1,3,4-oxadi-azines fused to heterocyclic rings. Thus condensation of 2-chloro-3,5-dinitropyridine with l-benzoyl-2-phenylhydrazine, followed by cyclization as described above yields 7-nitro-2,4-diphenyl-4//-pyrido[2,3-e][l,3,4]oxadiazine (6) in 85% yield.55... 

Dihydro-4 f-l,2,5-oxadiazines (21) (see Section 6.15.6.2.3.1) have been used as masked acyl groups for the stereoselective synthesis of 3(a)-(l-hydroxyethyl)-4( )-benzoyl- -lactams (24) (Scheme 2) <88EUP265169>. Condensation of the oxadiazine (21) with (2R,3R)-epoxy-butanoic acid in the presence of dicyclohexylcarbodiimide yields the A(-acyl derivative (22), which on treatment with lithium bis(trimethylsilyl)amide in THE undergoes stereoselective ring closure to the fused azetidinone (23). Hydrolysis with 1 M sulfuric acid in acetone ruptures the oxadiazine ring and forms the -lactam (24). 

Systematic studies of the cycloaddition of l,3,4-oxadiazin-6-ones with a variety of alkenes have been carried out. With benzvalene the tetracyclic ketone (110) is the major product (75%) accompanied in some instances (R = Ph, = C02Me) by a small amount of the fused ) -lactone (111) (Scheme 13—path a). Cycloaddition with the less reactive norbomene (Scheme 13—path b) yields ultimately the reduced a-pyrone (112), an enol-lactone <81AG(E)674, 85CB2940, 85JHC61, 90CB203i>. The enol-lactone is found to be produced more quickly and at a lower temperature if cycloaddition is carried out in the presence of trifluoroacetic acid. 

Acid-catalyzed condensation of l,l-bis-(jS-hydroxyethyl)hydrazine with 4-nitrobenzaldehyde in hot methanal yields mainly the hydrazone (306) (48%) together with a small amount (6.5%) of the hydro-1,3,4-oxadiazino[3,4-c][l,3,4]oxadiazine (307). However, with a two-fold excess of aldehyde, the yield of the fused oxadiazine increases to 17% <85JOU832>. 

The fused oxadiazine (249) is formed, in excellent yield, by heating the nitroso-compound (248) in light petroleum... 

When the perhydropyrido[l,2-r/ [l,3,4]oxadiazines 170 are treated with sodium hydride, followed by methyl iodide, the 2-(Af-aryl-Af-methylamino) derivatives 171 are formed (Scheme 25) <1997H(45)927>. The NMR spectra and X-ray crystallographic analysis indicated that the 1,3,4-oxadiazines adopt rigid cis- or /ra r-fused ring conformations. It was found that for the 1,3,4-oxadiazines 170 involving a potential tautomeric equilibrium, the amino form is most likely to be predominant. 

The condensation of acenaphthenequinone 291 with hydrazine in ethanol furnishes a monohydrazone derivative which, by heating with a half equivalent of 1,3-dithietane 292, provides the fused 1,3,4-oxadiazine 293 (Equation 49) <2002PS1885>. The treatment of 3,5-di-/r r/-butylbenzoquinonehydrazone or l,3-indandione-2-hydrazone with... 

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