1.2.4- Triazines, 2,5-dihydro-, reaction with

Dioxohexahydro-l,2,4-triazine (dihydro-6-azauracil) (128) yields a diacetyl derivative (129) which is relatively stable toward hydrolysis. The acetylation of the iV-methyl derivatives and the course of the reaction with diazomethane indicates that acetylation takes place here in positions 1 and 2 ... 

This ring system is represented by tricyclic ring system 533 (76JHC1249). Reaction of 3-hydrazino[l,2,4]triazin-5-ones 531 with 3-imi-nobutyronitrile afforded 6-methyl- (or phenyl-) 3-[3-methyl-5-aminopyra-zolyl]-2,5-dihydro[l,2,4]triazin-5-ones 532A, which may exist in tautomeric form 532B. Its reaction with diethoxymethyl acetate (DEMA) or ortho-esters afforded the tricyclic compounds 533. 

Tetrazines (484) undergo Diels-Alder reactions with C-N multiple bonds. Imidates (69JHC497) or, that is better, thioimidates (83JOC621,83TL4511,85JA5745) thus afford 1,2,4-triazines (487) which are formed via intermediate bicycles (485) and dihydro-1,2,4-triazines (486). 

Tetrazines (624) are reactive dienes in Diels-Alder reactions with inverse electron demand. They react with both C—C and C—N multiple bonds. Cycloaddition of (624) with imidates thus affords 1,2,4-triazines (625) which are formed via the bicyclic intermediates (626) and the dihydro-1,2,4-triazines (627) (69JHC497). Further studies have been made on the limitations of this reaction. 

The cyclization of a-hydrazinohydrazones (653) with ketones has been used for the synthesis of 4-amino-2,3,4,5-tetrahydro-l,2,4-triazines (654), and their reaction with phosgene affords 4-amino-4,5-dihydro-1,2,4-triazin-3-ones (655) (78HC(33)189, pp. 608, 656). 3-Thioxo-l,2,4-triazine-5,6-dione (657) was obtained when oxamohydrazide (656) reacted with thiophosgene (76ACS(B)7l). 

Triazine and its derivatives react with dienophiles by a [4 + 2] cycloaddition reaction (equation 4) (75CB3877). The l,2-dihydro-l,3,5-triazines (35) can also undergo Diels-Alder reactions with potent dienophiles (equation 5) (77KGS122). 

The photodecomposition of l,2-dihydro-2,4,6-triphenyl-s-triazine (140) in refluxing benzene takes a different course and yields 2,4,5-triphenylimidazole (141) and 2,4,6-triphenyl-s-triazine (142) along with ammonia, toluene, and benzonitrile.127 This is believed to be the result of an initial disproportionation reaction yielding hexahydro-and tetrahydro-2,4,6-triphenyl-s-triazine. 

In addition, the efficiency of inverse electron demand Diels-Alder reactions with 1,2,4-triazines has been improved to include microwave-activated procedures <07T8286>. The approach allows access to higher reaction temperatures, which results in shorter reaction times. Several highly substituted dihydrofuro- and dihydro-2//-pyranopyridines 25 are produced from alkylnol-substituted triazines 26 in excellent yields via a one-pot cycloaddition/ aromatization protocol. 

These Soviet workers also prepared a series of l,2-dihydro-l,3,5-triazines by reaction of aryl aldehydes,252,254 Shiff bases,255-257 or ketimines258 with amidines of different acids (usually benzoic, trichloro-, or trifluoroacetic). They proposed that the dihydrotriazines form via intermediate azadienes, which undergo cyclization via [4 + 2] cycloaddition, accompanied by elimination of an akylidenimine [Eq. (75)]. 

Starting from the 1,3,5-triazines, few syntheses of dihydro-1,3,5-triazines have been reported. Although many versatile synthetic approaches are available, most of them are yet to be tried. The known reactions involve preparation of dihydro-1,3,5-triazine derivatives from 2,4,6-triphenyl-1,3,5-triazine (153) via (a) lithium aluminum hydride reduction264 (b) treatment with potassium in tetrahydrofuran, followed by hydrolysis265 and (c) reaction with organolithium compounds and hydrolysis266 [Eq. (81)]. 

Burger et al. have shown that upon thermolysis dihydro-l,3,5-oxadiazines (174) undergo a retro Diels-Alder reaction with elimination of hexaflu-oroacetone.269,270 The intermediate product, 4,4-bis(trifluoromethyl)-l,3-diaza-1,3-diene, was transformed to the corresponding 1,4-dihydro-1,3,5-triazine (173) [Eq. (83)]. 

Interesting results were obtained by reaction of substituted 1,2-dihydro-1,3,5-triazines with esters of acetylenedicarboxylic acid (DMAD) and of propiolic acid.254 In the case of the reaction with DMAD, formation of the different products 175 and 176 has been reported,254 presumably due to differences in the nucleophilicity of the secondary nitrogen atom of the triazines. 

Tetrazines are reactive dienes in Diels-Alder reactions with inverse electron demand and react not only with C—C multiple bonds, but also with C-N triple and C—N double bonds (see Section C.5.2.5.1.). In 1969 Roffey and Verge192 reported the reaction of 1,2,4,5-tetrazines with imidates 2 (X = O) to give 1,2,4-triazines 5 via the bicyclic intermediate 3 and the dihydro-1,2,4-triazine 4. Further studies, in particular by Boger and coworkers have shown that much better yields of 1,2,4-triazines are obtained when thioimidates 2 (X = s) are used as the dienophile.193-195... 

Reaction of phenols and hexahydro-l,3,5-triazines at 150°C also provides access to dihydro-1,3-benzoxazines (272) (Equation (24)). Similar constructions use hexamethylenetetramine, rather than hexahydro-l,3,5-triazines, but now the products are 3-benzyl derivatives (e.g. 273) (Equation (25)) <85ZOR2243>. It seems likely that, in these reactions, the nitrogen-containing reagents act as sources of methylenimine, which convert the phenols into the corresponding benzylamines. Further reactions with more methylenimine then results in cyclization if so these preparations are closely related to those which employ hydroxybenzylamines and carbonyl compounds. 

Nucleophilic addition using organometallics showed that the C-4 position of (la) is a hard reaction site, whereas the C-5 position has soft reactivity (Equation (15)) <85CC1370>. These results are in accord with those from MO calculations. Softer nucleophiles such as organocopper reagents underwent a redox reaction with triazine to give 2,5-dihydro derivatives without ring substitution. 

A related attack on ring nitrogen also occurred with 4,5,6-tris(perfluoroisopropyl)-l,2,3-triazine (52) <87CC1697, 90JCS(Pl)2379>. When (52) was treated with a large excess of 2,3-dimethylbutadiene at 70 °C, a spirotriazinium zwitterion (53) was obtained whose structure was confirmed by x-ray crystallography. The reaction with 2,3-dimethylbut-2-ene resulted in a 2-substituted 2,5-dihydro derivative (54) (Scheme 5). 

The reactions studied are Addition of ammonia to 1,2,4-triazines and oxidation of the amino-dihydro compounds with potassium permanganate to amino-1,2,4-triazines (Scheme 15) addition of Grignard reagents or other carbanions to 1,2,4-triazines and oxidation of the dihydro adducts with potassium permanganate or potassium hexacyanoferrate(III) (Scheme 17) and addition of... 

Most dihydro-l,2,4-triazinones can be converted into the corresponding thiones, and into chloro-dihydrotriazines, and they can be alkylated by the usual methods. These reactions are also known for the diones. As was mentioned earlier, in these reactions the 5-position is the most reactive. Treatment of 1,2,4-triazine-3,5-diones (258) with phosphorus pentasulfide leads firstly to the 5-thioxo-4,5-dihydro-l,2,4-triazin-3-ones (259), and then to the l,2,4-triazine-3,5-dithiones (260). Further reactions reported for l,2,4-triazine-3,5-diones (258) are bromination in the 6-position to give (261), replacement of one (262) or both oxygens by chlorine (263) on reaction with SOCI2,... 

N-l, N-2- and 7V-4-substituted amidrazones (358)-(360) can be used for the synthesis of 1-, 2-, or 4-substituted dihydro-1,2,4-triazines <82CB2807>. Reactions of 1,2-dicarbonyl compounds with hydrazidines (361) have been used for the synthesis of 4-amino-dihydro-1,2,4-triazines <85LA78>. The examples shown (Scheme 67), employing the cyclopentanedione (362), result in a variety of reduced cyclopenta[c]-l, 2,4-triazines. 

Amino-1,2,4-triazine-5,6-diones (398), 4-amino-4,5-dihydro-1,2,4-triazines (399), 4-amino-5-imino-l,2,4-triazines (400) and 4,6-diamino-l,2,4-triazin-5-ones (401) were prepared from hydra-zidines (361) by reaction with oxalates, a-bromo-ketones (385 Y = Br), acyl cyanides (381) and thiooxamides, respectively <85LA78,92LA115>. 

Several chapters in Advances in Heterocyclic Chemistry deal with aspects of 1,3,5-triazine chemistry reactions of ring nitrogen atoms with electrophiles <88AHC(43)I27> dihydro-l,3,5-triazines <85AHC(38)9l> halogenation of 1,3,5-triazines <93AHC(58)323> conformation of hexahydro-1,3,5-triazines <84AHC(36)160>. 

Methyl-l,3-oxazine-2,4(3//)-diones (218) combine with ureas or thioureas under phase-transfer catalytic conditions to give 1,3,5-triazines. Unfortunately the yields in the reactions with ureas were very low and therefore not synthetically useful. However, reaction with thioureas provided 5,6-dihydro-6-thioxo-l,3,5-triazine-2,4(l/f,3//)-diones (220) in better yields. Two pathways are possible for the formation of (220), either directly to (220) or via the intermediate (219) which implies the involvement of sulfur. The failure of S -methylisothiourea to react with (218) and the absence of this mode of cyclization in the reactions with biprotic ureas supported the pathway via (219). The participation of sulfur is therefore invoked, followed by loss of acetone (detected as its 2,4-DNPH... 

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