Azine A-oxides

Azine A-oxides and azine A-imides undergo a deep ring transformation on interaction with various dipolarophiles. Thus, fervenulin-4-oxides (423) react with DMAD to afford derivatives of pyrrolo[3,2-first step of the reaction is assumed to involve the formation of cycloaddition products (424) which transform by subsequent multi-stage process into (425) (79JOC3830). 

Lithium derivatives of azine A-oxides are likewise considered in Section 3.2.1.8.1 because they are generally prepared by direct lithiation of the A-oxide, and again are seldom isolated. 

Imidazole and benzimidazole A-oxides are thermally unstable and may be explosive. However, more substituted imidazole A-oxides behave much like azine A-oxides, as illustrated by a couple of examples in Scheme 182 <1998HCA1585, 2000HGA728, 2002AGE2290>. 

Treatment of pyridine with NaOD/D20 at elevated temperatures results in eventual replacement of all hydrogen atoms by deuterium. This process presumably involves deprotonation followed by rapid deuteration of the intermediate negatively charged species cf. equation 21) in a sequential manner. Azine A-oxides are deuterated in a similar way, positions adjacent to the /V-oxide exchanging particularly rapidly. Controlled deprotonation of ring carbon atoms a and y to the heteroatom can be accomplished by the use of strong, non-nucleophilic bases and the intermediate carbanions may be trapped by electrophiles (equation 27). The yields in these reactions are in most cases only moderate, however. As expected, deprotonation occurs more easily if the heteroatom is positively charged. 

A particular example of reductive group elimination is elimination of a A-oxide function. Because of the rich chemistry of azine A-oxide it is often expedient to carry over useful functionalizations at the A-oxide level and then to reduce such a... 

Catalytic hydrogenation of a nitro ketone under mild conditions leads to an azine A -oxide, but the nature of the ketone moiety has an effect on the relative amounts of A-oxide and the free base which is otherwise a minor byproduct. 

Loska, R. Makosza, M. New synthesis of 2-heteroarylperfluoropropionic acids derivatives by reaction of azine A-oxides with hexafluoropropene. Chem. Eur. J. 2008, i4(8), 2577-2589. 

Palladium-catalyzed direct arylation of heteroaromatic Af-oxides using aryl triflates was reported to afford the corresponding 2-aryl heteroaromatic Af-oxides (Scheme 5) [21]. The reaction was carried out with a range of both azine Af-oxides and aryl triflates. The arylation can also be carried out as a sequence of reactions to yield various diarylated products. The regioselectivity and scope for the direct arylation of 3-substimted azine A -oxides have been investigated. The method can be apphed for the synthesis of compounds that exhibit antimalarial [22] and antimicrobial [23] activities. 

As for alkynylation of heteroaromatic A-oxides, it has been reported that azine A-oxides react with lithium and/or potassium acetylenides to give the corresprMiding ethynylazines. It is worth noting that the reaction with lithium acetylenide requires a subsequent acylation of the intermediate anionic adduct for rearomatizatiOTi, whereas in case of potassium acetylenide, the aMto-aromatization takes place (Scheme 35) [73],... 

Carbon nucleophiles are able to react with heteroaromatic W-oxides, and these addition-elimination transformations have been found to proceed effectively in the presence of the phosphonium salt PyBroP (Scheme 36) [74]. A series of carbonyl compounds capable of enolization have been involved in the reaction with pyridine A-oxides to give 2-substituted pyridines in moderate yields, and in all these cases, it proved necessary to use threefold excess of nucleophile relative to the A-oxide in order to avoid further addition of the reaction product to the starting azine A-oxide. 

Sun H-Y, Gorelsky SI, Stuart DR, Campeau L-C, Fagnou K (2010) Mechanistic analysis of azine A-oxide direct arylation evidence for a critical role of acetate in the Pd(OAc)2 precatalyst. J Org Chem 75 8180-8189... 

A related effect is observed on quaternization, but in this case the operation of a (3-substituent effect results in the overall change at the a carbon atom normally being small (Table 5). A further important general trend in the azines arises on A-oxidation, which... 

The first possibility for aromatization of the cr -adduets of azine iV-oxides is their oxidation with oxidizing agents, resulting in the eorresponding substituted azine iV-oxides with the retention of the iV-oxide group (Seheme 1, pathway A). When (T -adduets eontain an auxiliary leaving group, autoaromatization takes... 

The treatment of 3-amino-1,2,4-triazine 2-oxides 1 or 3-amino-1,2,4-benzotri-azine 1-oxides 29 with nitrous acid proceeds as a diazotization reaction, but the diazo compounds have never been isolated owing to the easy displacement of the di-azo group with nucleophiles. Thus the reaction of 3-amino-1,2,4-triazine 2-oxides 1 with sodium nitrite in hydrochloric or hydrobromic acids leads to the corresponding 3-halogen-1,2,4-tiiazine 2-oxides 119 or 3-bromo-l,2,4-benzotriazine 1-oxides 120 (77JOC546, 82JOC3886). 

The nonconjugated 1,4-oxazines covered in this chapter are shown in Figure 2. The dihydrooxazines included are compounds of the types 11-21. They include the 2//-5,6-dihydrooxazine 11 and its A -oxide 13 and 2/7-3,4-dihydroox-azine 12. Also included are the isomeric dihydrooxazinones 14-16, 2//-5,6-dihydrooxazin-2-one iV-oxide 17, 2//-3,4-dihydrooxazine-2,3-dione 18, benzodihydrooxazine 19, and the isomeric benzodihydrooxazinones 20 and 21. 

One very important method for the indirect oxidation of a 2-methyl substituent group in particular, in the azines, is the reaction of the corresponding A-oxide with acetic anhydride. This process, outlined in equation (75), gives initially the corresponding 2-acetoxymethyl derivative yields are generally good to excellent with only minor amounts... 

Azine oxides are versatile starting materials for heterocyclic synthesis and are frequently used for regioselective ring substitution reactions, most of which proceed with loss of the oxide substituent. Occasionally some unusual selectivities are observed. For example, treatment of 3-methoxypyrazine A-oxide with equimolar amounts of diethylcarbamoyl chloride and 4-methoxytoluene-a-thiol in refluxing acetonitrile gave 2-methoxy-6-(4-methoxybenzylthio)-pyrazine as the sole product in 60% yield. 

D.A. Peters et al., Structures of 3-methoxypyrazine 1-oxide (la) and 3-methoxy-5-methylpyr-azine 1-oxide (lb). Acta Crystallogr. C 48, 307-311 (1992)... 

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