1,3,5-Triazines dihydro— from

Dihydro-1,2,4-triazines resulting from the addition of Grignard reagents at C-5 are supposed to exist in solution in two tautomeric forms, 12 and IS however, the structure of 2,5-dihydro-l,2,4-triazines 12 is considered to be preferred over the 4,5-dihydro structure 15. This is probably due to the fact that when isolated from the rection mixture as crystalline products these C-5 adducts proved to have the 2,5-dihydro structure (84MI3 85AHC1). Indeed, unequivocal evidence for the structure of 2,5-dihydro-3-methylthio-5-phenyl-l,2,4-triazine in a crystalline state has been obtained by X-ray analysis (80JOC4587 81BCJ41). 

Shvaika and Fomenko demonstrated the formation of 4,5-dihydro-1,2,4-triazines (149) from recyclization reactions of 1,3-oxazolium salts (148a),236... 

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)]. 

Reaction of bis(arylidene)- or bis(alkylidenc)acetone with guanidin-2-amine affords hydra-zones these can be cyclized to give the 4,5-dihydro-l,2,4-triazines 9, from which elimination of RMe is observed, leading to 5-unsubstituted l,2,4-triazin-3-amines 10.116... 

The dihydro-1,2.4-triazine obtained from the reduction of 3-(methylsulfanyl)-1,2,4-triazines 3 with sodium borohydride were formulated by Mansour et al.370 as the 4,5-dihydro-l, 2,4-triazi-nes, and as the 2,5-dihydro-l,2,4-triazines by Sasaki etal.371 It is not certain which of these tautomeric forms is predominant, but it has been shown by X-ray crystallography that the product of methylation of 3-(methylsulfanyl)-5,6-diphenyldihydro-1,2,4-triazine is 2-methyl-3-(methylsulfanyl)-5,6-diphenyl-2,5-dihydro-l,2,4-triazine.371... 

The synthesis of the triazine ring from [3+3] fragments is not as widely used as the [4+2] approach nevertheless, several successful examples have been reported during the last decade. One of these is the reaction of nitrilimines, generated from chloroamidrazones 204, with ethyl isocyanoacetate, which results in the formation of either 2-aryl-3-ethoxycarbo-nyl-2,3-dihydro-l,2,4-triazines 205 or l,2,4-triazolo[4,5- -l,2,4-triazines 206 (Scheme 119) <2002M1165>. 

The course of methylation of all the thio derivatives with diazomethane was then investigated. These mcthylations generally result in mixtures of substances it may be deduced from the products isolated, however, that this reaction proceeds first at the nitrogen atom (in contrast with alkaline methylation) and only then at the sulfur one. The methylation of the 3-methylmercapto derivative to 4-methyl-3-methylmercapto-5-oxo-4,5-dihydro-l,2,4-triazine (95) is of interest in this connection. 

The triazine ring could be formed by reaction [82S853 83BSF(2)226] of alkyl (2-aryl-4-thioxo-3,4-dihydro-2//-quinazolin-3-yl)acetates 477, prepared from 476, with hydrazine to yield 6-aryl-2,4-dihydro[l,2,4]tria-zino[4,3-c]quinazolin-3-ones 478. 

A new cyclization method for [l,2,4]triazolo[5,l-c]triazines (ring system 26) starting from trifluoromethylated 1,2,3-triketones and resulting in formation of 4,7-dihydro derivatives has recently been published <2005JFC1230>. The structure of one representative derivative has also been investigated by X-ray crystallography. 

The observations suggest that the two condensations are direct and distinct. Had the base-catalysed reaction first given the aryl-dihydro-triazine (CXXXIV) which, under the prevailing basic conditions rearranged to the anilino-dihydro-triazine (CXXXV), an equilibrium mixture of the two would have been expected. Since, however, the pure anilino-dihydrotriazine (CXXXV) was isolated, its formation is considered to be direct and independent of that of its isomer (ffS). The formation of (CXXXIII) from 1-aryl-l-alkylbiguanides (see preceding Section), which cannot proceed by way of an aryl-dihydrotriazine, bears out this conclusion. 

Amino-1 -p-chlorophenyl-4-dimethylamino-1,2-dihydro-2,2-dimethyl-s-triazine (CXXXVII) was obtained from acetone and 1-p-chlorophenyl-5,5-dimethylbiguanide under acid conditions, and was isomerised by alkali to 6-p-chloroanilino-4-dimethylamino-l,2-dihydro-2,2-dimethyl-s-triazine (CXXXVIII), which also arose directly under basic conditions (95). Piperidine was found useful in promoting an analogous condensation (534). 

Grignard reagents add to 1,2,4-triazines. Initial attack at the 5-position is favored (277 — 278 — 279) if this position is substituted the nucleophile adds to the 6-position, and finally to the 3-position. Starting from the parent 1,2,4-triazine, 3,5,6-triaryl-l,2,4-triazines (280) have been prepared by successive addition of Grignard reagents to the ring and oxidation of the dihydro-1,2,4-triazine so formed. 

Data on the structures of monocyclic dihydro- or hexahydro-1,2,3-triazines, on 1,2,3-triazine tV-oxides and 1,2,3-triazinones are not yet available. From studies on the one-electron reduction of the tetrahydro-l,2,3-triazinium salts (7) it was concluded that the heterocyclic ring is flexible and not planar (80LA285). No detailed information on the structure of 3-benzyl-l,5-diphenyl-l,2-dihydro-l,2,3-triazine-4,6(3//,5f/)-dione (8) or of the 6-hydroxy-4-oxo-l,4-dihydro-l,2,3-triazinium hydroxide inner salts (9) seems to be available. 

From the reaction of 6-phenyl-l,2,4-triazine-3,5-dione (157) with phenylmagnesium bromide, 5,6-diphenyl-1,2,4-triazin-3-one (27), 3,5,6-triphenyl-l,2,4-triazine (147), 3,3,5,6-tetraphenyl-2,3-dihydro-l,2,4-triazine (158), 2,4,6-triphenyl-l,3,5-triazine (148) and 2,4,4,5-tetraphenylimidazole (149) were isolated (71JPR699). From the results obtained in the reaction of 3,5,6-triphenyl-l,2,4-triazine (147) with phenylmagnesium-bromide it can be supposed that the last two compounds were formed via the intermediate formation of (147). 

Reaction of 5,6-diphenyl-1,2,4-triazin-3-one (215) or 5,6-diphenyl-l,2,4-triazine-3-thione (216) with benzene under Friedel-Crafts conditions led to the isolation of 5,5,6-triphenyl-4,5-dihydro-l,2,4-triazin-3-one (217) and -3-thione (218) respectively (76IJC(B)273). Reacting under similar conditions (C6H6/A1C13) the 6-styryl compounds (219-221) are converted into the corresponding 6-(2,2-diphenylethyl) derivatives, e.g. (222) from (219) (75IJC1098). 

Reduction with zinc and acetic acid affords 1,2-dihydro-1,2,4-triazines (263) and imidazoles (264). The latter are secondary products, formed from (263) (57T103, 59CB2481, 63JCS1628). The compounds obtained by electrochemical reduction of 1,2,4-triazines have been shown to be 1,2-dihydro- (263) and 4,5-dihydro-l,2,4-triazines (265) (72CLU85, 72CJC1581). Reduction of l-methyl-3,5,6-triphenyl-l,2,4-triazinium iodide (266) with zinc and acetic acid affords 2,4,5-triphenylimidazole (267) and methylamine (63JCS1628). 

Interaction of 1,3,5-triazine (241) with hydrazine affords 1,2-diformylhydrazine dihy-drazone (242) which is a light-sensitive compound which turns pink, especially in the presence of air. The color is attributed to the formation of 1,2,4,5-tetrazine (38) but due to its high volatility the tetrazine could not be isolated. Heating (242) for two hours with acetic anhydride again affords an unisolated red, volatile product formulated as (38), and 1,2-diacetyl-l,2-dihydro-1,2,4,5-tetrazine (243). Since compound (242) is prepared from hydrazine and (241) this preparation is in the final analysis a [2+ 1+ 2 + 1] method (57JA2839). 

---