1.2.4- Triazines, 4,5-dihydro

In a review on dihydrotriazine chemistry, the possible isomeric dihydro-1,2,3-triazines have been categorized but no mention of their relative importance or the factual existence of some of them has been made, and only the preparation of some 2,5-dihydro-l,2,3-triazines has been mentioned briefly 1985AHC1 . 

There is only one case known about the reactivity of l,6-dihydro-l,2,3-triazines. Compound 35 reacts with an excess of sodium ethoxide in ethanol at reflux to effect ring contraction to l-(isopropylamino)-3,5-diphenylpyrazole 187 (Equation 62) 1996H(43)1759 . 

In addition to these cases, the oxidation of 4,6-disubstituted-2-methyl-2,5-dihydro-1,2,3-triazines 21q-s by I2 gives 2-methyl-l,2,3-triazinium iodides 114a-c 1990TL7193 , whereas the treatment of 21t-v with bromine followed by LTA generated the N-2-demethylated 1,2,3-triazines 17z and 188a and 188b (Equation 63) 1992CPB2283 . 

Oxidation of 2,5-dihydro-l,2,3-triazine 21g with ceric ammonium nitrate (CAN) gave almost complete decomposition of starting material products 119b and 17m were isolated in low yield 1996J(P1)2511 . Eor oxidations of 2-(Tchloroethoxycarbonyl)-2,5-dihydro-l,2,3-triazines 118 with the same reagent, see Section 9.01.5.4. 

6-dihydrophenanthridine has been treated in the same review 1978HC(33)3 as well as in 1984CHEC(3)369 . 

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Alkylation reactions were recently performed with all the thio derivatives of 6-azauraciI and 6-azathymine. In agreement with previous findings, the methylmercapto derivatives were obtained by alkylation of all these substances in alkaline solution. Thus, e.g., 3-ihethylmercapto-5-oxo-2,5-dihydro-1,2,4-triazine (96), 5-methylmer-capto-3-oxo-2,3-dihydro-l,2,4-triazine (90), and 3,5-dimethylmer-capto-1,2,4-triazine (91) were obtained. The last-named of these was... 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

The ring-chain isomerism was studied in a series of 4-hydroxy-3,4-dihydro-1,2,4-triazines 87, which are models for cr -adducts at the 3 position of the... 

The isomer lowest in energy is predicted to be the 2,5-dihydro-1,2,4-triazine 198g. The most stable structures always show two C=N double bonds. Moreover, in polar solvents, 198h should also be a dominant species [00PCCP2187]. The valence and Rydberg excited states of 1,2,3-triazine have been studied by multireference methods (MRD-CI) and the results are compared with experimental spectra [98CP39]. 

No data on the tautomerism of dihydro-1,2,4-triazines were available at the time of the previous reviews [76AHCS1 85AHC(38)1, p. 83] since then, however, much work has been done. For N-unsubstituted dihydro-1,2,4-triazines, nine possible isomers (92-100) could exist however, only some of them (92-95, 98, and 99) have been synthesized individually. 

The first systematic theoretical study on dihydro-1,2,4-triazines was recently carried out (98JOC5824) the stabilities of all the possible unsubstituted dihydro-1,2,4-triazines were calculated using various theoretical methods, all reliable calculation methods consistently show that the 2,5-dihydro isomer 98 is the most stable. This is in perfect agreement with the experimental observations all the synthetic methods used for the preparation of dihydro-1,2,4-triazines result in 2,5-dihydro isomer 98, provided the structures of the reactants and the reaction mechanism allow its formation. Thus, although Metze and Scherowsky (59CB2481) claimed the formation of 1,2-dihydro-1,2,4-triazine 92 (R = = Ph) in the reduction... 

In the ring-closure reaction of a-acylaminoketones with hydrazines, some dihydro-1,2,4-triazines were obtained. The possible 1,2-, 2,3-, or 5,6-dihydro structures were excluded by IR spectroscopic studies however, this method, as well as the attempted preparation of fixed derivatives, failed to distinguish between... 

Calculated Relative Energies oe Isomeric Dihydro-1,2,4-triazines Compared TO 2,5-Dihydro-1,2,4-triazine 98... 

If the formation of a 2,5-dihydro isomer 98 is not allowed, other dihydro-1,2,4-triazines are formed aeeording to their order of stability ealeulated by various theoretieal methods (see Table III) (98JOC5824). 

Although 1,4-dihydro-1,2,4-triazines 93 have long been assumed to be intermediates in eleetroehemieal and photoehemieal reaetions, the first representative of this series was isolated only reeently as its AA-diaeetyl derivative (99EJOC685). 

Dihydro-1,2,4-triazines 95 were obtained by base-indueed ring expansion of 1-alkyl-1,2,3-triazolium salts, and their strueture in the solid state was eonfirmed by X-ray analysis [92JCS(P1)147]. 

Dihydro-as 1.2.4) triazine-3.5-diol (called 3-5-Dioxo-hexahydro-1.2.4-triazin or 3-5-Dioxy-1.6-dihydro-1.2.4-triazin in Ger),... 

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. 

Various extensions are possible (see CHEC 2.19 for full details). Use of aminoguanidines, semicarbazide and thiosemicarbazide gives respectively the 3-amino-1,2,4-triazine, and the 3-one and 3-thione derivatives. Use of a-keto esters and a-keto cyanides gives 5-ones and 5-amino derivatives, respectively. a-Hydroxy ketones afford dihydro-1,2,4-triazines. Intermediates (479) and (480) can sometimes be isolated. 

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). 

Dihydro-1,2,4-triazine-3,5 (2H,4H )-dione (139) rearranges with aldehydes, with which they form N-aminoimidazoledione derivatives (140) (68CCC2087). 

Reaction of l,2,4-triazin-5-ones (151, 152) or 5-methoxy-l,2,4-triazines (156) with Grignard reagents afford, depending on the structure of the 1,2,4-triazine used, 1,2,4-triazines (153), 3,4-dihydro- (154), or 1,6-dihydro-1,2,4-triazin-5-ones (155) (73JHC559). 

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). 

The reaction of 1,3-dicarbonyl compounds (515) with azodicarboxamidine (516) affords l-amidino-3-amino-1,2-dihydro-1,2,4-triazines (517) (73AP697, 73AP801). 

Amino-l,2,4-triazine-5,6-diones (534), 4-amino-4,5-dihydro-1,2,4-triazines (535), 4-amino-5-imino-l,2,4-triazines (536) and 4,6-diamino-1,2,4-triazin-5-ones (537) were prepared by reaction of hydrazidines (526) with oxalates, a-bromo ketones, acyl cyanides (485) and thioxamidates, respectively (80UP21900). 

Reaction of the oxazolium salts (591) with methylhydrazine led to the isolation of 6-hydroxytetrahydro-l,2,4-triazines (592) (74ZOR2429), while the oxazolium or thiazolium salts (593 X = 0,S) with hydrazine gave dihydro-1,2,4-triazines (594) (78HC(33)189, p.576). 2-Amino-3-phenacyloxadiazolium salts (595) and hydrazine afforded the 3,4-diamino compounds (596) (71LA(749)125>. 

Azirine-3-carboxamides with a second substituent in the 3-position (599) were used by Nishikawa and Sato for the synthesis of dihydro-1,2,4-triazin-6-ones (600) (71JCS(C)2648). 

With a-hydrazinocarboxylates (613) instead of hydrazonocarboxylic acids, imidates give the dihydro-1,2,4-triazin-5-ones (614) (1895CB1223,64LA(676)l2l). 

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). 

A compound formulated as 5-methyl-1,4-dihydro-1,2,4-triazin-3(2//)-one (696) was obtained by sodium hydroxide treatment of compound (697). Reacting (697) with thallium ethoxide led to the isolation of diethyl 5-methyl-3-oxo-l,2,3,4-tetrahydro-l,2,4-triazine-1,6-dicarboxylate (698) (70JOC3792). Since compound (697) is formed by reaction of aminocrotonic ester with diethyl azodicarboxylate, these reactions can also be treated as [3 + 3] atom component preparations. 

The semicarbazone of phenacylhydrazine (699) yielded 4-amino-6-phenyl-4,5-dihydro-1,2,4-triazin-3-one (700) on treatment with base (36JPR(144)273). 

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