5- Substituted 1,2,4-triazine 4-oxides

The reaction of 1,2,4-triazine 4-oxides 55 with CH-active 1,3-diketones (dime-done, indanedione, iV.iV -dimethylbarbituric acid) in the presence of trifluoroacetic acid (substrate activation by protonation) or KOH (activation of the nucleophile) leads to stable cr -adducts 63, whose oxidative aromatization by the action of KMn04 results in 5-substituted 1,2,4-triazine 4-oxides 64 (98MI). 

Addition of electron-rich aromatic systems to the 1,2,4-triazine ring can easily be achieved by preliminary activation of the heterocyclic system by protonation or alkylation. Addition of the following nucleophiles to the 1,2,4-triazinium ion (129) has been observed indoles, pyrroles, anilines, phenols, and aminothiazoles. The 1,6-dihydro-1,2,4-triazines (130) can be isolated in most cases and oxidized in a second step to the aromatic 1,2,4-triazine system (Scheme 20). 1,2,4-Triazin-5(2i/)-ones also undergo this reaction. 5-Unsubstituted 1,2,4-triazine 4-oxides (131) can be transformed into 5-substituted 1,2,4-triazine 4-oxides (Equation (14)) <86KGS1535, 92H(33)93l, 95UP 611-01>. 

Amination of azaaromatic compounds using liquid ammonia-potassium permanganate (85S884 86MI1) has been found to be a successful method for preparing a number of 5-amino-l,2,4-triazines (Scheme 73). This SNH reaction is based on the ability of 3- and 6-substituted triazines to form amino adducts 22 at C-5 in liquid ammonia (see Section III,A,2 and Scheme 18). These adducts can be oxidized into 5-amino-1,2,4-triazines 126. A number of 1,2,4-triazines containing substituents at C-3 and C-6,... 

Triazine (1) is highly 7c-electron deficient and readily attacked by nucleophiles. The parent triazine (la) slowly decomposed in methanol at room temperature, which suggested that nucleophilic attack of methanol occurred in the solution. The NMR spectrum of (la) in CD3OD measured at — 50°C in the presence of a base indicated that attack of methoxide ion on the 4-position was succeeded by ring-opening accompanied by the elimination of nitrogen (Equation (14)) <92H(33)63l >. All attempts failed to oxidize the intermediate 1,4-dihydro adducts to form 4-substituted triazines. 

In addition to the examples cited above, in which l,2,4-triazine-4-oxides have been converted into 4-C-substituted-l,2,4-triazines, there have been recent reports in which the N-oxide functionality can be retained or eliminated depending on the conditions. Rusinov s group (03PJC1157) has shown that Grignard reagents can be reacted with triazine-4-oxides of type 53 to 3deld either the substituted triazine-4-oxide 55 or the parent triazine 56, via the 4-hydroxy-4,5-dihydro-l,2,4-triazines 54 (Scheme 19). 

Phenanthro[l,2-d][l,2,3]selenadiazole, 10,11 dihydro- H NMR, 6, 348 synthesis, 6, 353 Phenanthro[b]thiophenes synthesis, 4, 914 Phenanthro[4,5-bcd]thiophenes synthesis, 4, 883, 907, 914 Phenanthro[9,10-ej[l, 2,4]triazines synthesis, 3, 434 Phenarsazin synthesis, 1, 561 Phenazine dyes, 3, 196-197 nitration, 3, 177 UV Spectra, 2, 127 Phenazine, 3-amino-2-hydroxy-in colour photography, 1, 374 Phenazine, 1-chloro-nucleophilic substitution, 3, 164-165 5-oxide... 

Triazole has been prepared by the oxidation of substituted 1,2,4-triazoles, by the treatment of urazole with phosphorus pentasulfide, by heating equimolar quantities of formyl-hydrazine and formamide, by removal of the amino function of 4-amino-l,2,4-triazole, by oxidation of l,2,4-triazole-3(5)-thiol with hydrogen peroxide, by decarboxylation of 1,2,4-triazole-3(5)-carboxylic acid, by heating hydrazine salts with form-amide,by rapidly distilling hydrazine hydrate mixed with two molar equivalents of formamide, i by heating N,N -diformyl-hydrazine with excess ammonia in an autoclave at 200° for 24 hours, and by the reaction of 1,3,5-triazine and hydrazine monohydrochloride. ... 

The reaction of 3-methoxy-1,2,4-triazine 1-oxide 20 with the carbanion generated from chloromethyl phenyl sulfone proceeds as the vicarious nucleophilic substitution (VNS) of hydrogen (Scheme 1, path B) via addition of the carbanion at position 5 of the heterocycle. Following base-induced elimination of HCl and protonation, 3-methoxy-5-phenylsulfonyl-1,2,4-triazine 4-oxides 65 result (88LA627). 

The reaction of 3,6-diphenyl-1,2,4-triazine 4-oxide 58 with benzoylacetone under basic conditions affords substituted 1,2,4-triazine 74 in low yield (96MC116). 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

Pyridine A-oxides were converted to tetrazolo[l,5-a]pyridines 172 by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent <06JOC9540>. 3-R-5-Trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-ones 173 have been prepared from the alkylation of 5-trinitromethyltetrazolo[l,5-a]-l,3,5-triazin-7-one silver salt with different alkylation agents <06CHE417>. The use of 2-fluorophenylisocyanide in the combinatorial Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution afforded tricylic tetrazolo[l,5-a]quinoxaline 174 in good yields and with high diversity <06TL2041>. 

The reactivity and use of 1,2,4-triazine 4-oxide have been described <06OM2972>. Thus, readily available (3-pyridyl)-1,2,4-triazine 4-oxides 13 were used to prepare 2,2 -bipyridines 15. The reaction course involves a nucleophilic substitution of hydrogen and an aza Diels-Alder (DA) reaction <06TL869>. 

Thus oxidation of both 6- and 7-substituted 3-amino-benzo-l,2,3-triazin-4-ones with lead tetraacetate in methanol produced a mixture of p- and m-substituted benzoates, clearly indicating that a symmetrical intermediate, i.e. benzocyclopropenone (166) was formed and underwent ring opening by attack of solvent121 ... 

Snyder and coworkers followed a completely different path to canthin-6-one (Fig. 23). Earlier they had shown that indole-substituted 1,24-triazine 66 could be heated in refluxing triisopropylbenzene (bp = 232 °C) to give /3-carboline 67 via an intramolecular cycloaddition/cycloreversion reaction [58]. Selective oxidation of 67 at C-6 was achieved through the use of triethylbenzylammonium permanganate [59]. Success of the reaction proved to be very sensitive to the solvent chosen. Heating 67 for 4 h at 70 °C in a 5 1 mixture of dichloromethane and acetic acid gave a 65% yield of 63, yet use of increasing amounts of dichloromethane slowed the reaction down (no reaction occurred in pure dichloromethane), while use of pure acetic acid led to an intractable mixture. 

These authors found that nucleophilic additions to the unsubstituted ring system 1 can be carried out to yield a number of 7-substituted dihydro products or, in some cases, where an oxidation can follow this addition, also 7-substituted heteroaromatic derivatives (Scheme 6). Thus, reaction of 1 with indole under acidic conditions (in trifluoroacetic acid) yields 7-(177-indol-3-yl)-7,8-dihydrotetrazolo[l,5- ][l,2,4]triazine 24 <1998ZOR450>. Reaction of 1 with 3,4-difluoroacetophenone in the presence of potassium /frt-butoxide in tetrahydrofuran followed by... 

Acid hydrolysis of 3-methyl-6-phenyl-l,2,4-triazine 4-oxide (827) yields 4-phenyl-1,2,3-triazole through an acyclic intermediate (828) (Scheme 168) <89AHC(46)73>. 1,2,4-Triazine 2-oxides (829) undergo rearrangement in basic conditions (Equation (80)) to form 4-substituted 2//-1,2,3-triazoles <89AHC(46)73>. l-(2-Nitrophenyl)-5-aryltetrazoles (830) and l-aryl-5-(2-nitrophenyl)tetrazoles are converted into 2-arylbenzotriazoles (831) by refluxing in nitrobenzene (Equation (81)) <81AJC69l>. 

The synthetic applications of substituted 1,2,3-triazole 1-oxides and 1,2,3-triazolium-l-imides in the preparations of 1,2,3-triazines, 1,3,4,5-oxo- and -thia-triazines, and 1,2,3,5-tetrazines have been discussed in Section 4.01.4.12. Conversions of 1,2,3-triazolines into aziridines either thermally or photochemically were described in detail in CHEC-I <84CHEC-1(5)691 > and in a review <84AHC(37)217>. Some recent developments are discussed in Section 4.01.5. 

As substitute for hydrogen cyanide, which does not add aromatic nitrile oxides, 1,3,5-triazine has been recommended for the preparation of 5-unsubstituted 1,2,4-oxadiazoles <78BCJ1484). 

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