2.3- Dihydro- 1,2,4-triazines, production

A new synthesis of 6-arylamino-2-heteroarylimino-l,2-dihydro-l,3,5-triazines from 2,4-bis-(heteroarylimino)-l,3-diazetidines and amidines has been developed by Molina et al. The formation of the triazines was explained as an initial addition of the imino nitrogen of the amidine to the exocyclic C=N bond, followed by formation of an open chain intermediate. This intermediate cyclized, followed by elimination of 4-amino-6-methyl-3-methylthio-l,2,4-triazin-5(47/)-one to give the triazine product (Scheme 62) <87S150>. 1,3,5-Triazines (207) and (208) have been prepared from 2-acylimino-l,3-thiazetidines (204) by treatment with iso thioureas or guanidines respectively (Scheme 63) <91JHC177>. 

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. 

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). 

Hydrogenation of the product 147 removes the benzyl protecting groups and at the same time reduces the triazine to its dihydro derivative 148. A roundabout scheme is required for dehydrogenation due to the sensitivity of the intermediates. The product is thus converted to its silyl ether 149 exposure to air results in oxidation and desilylation. There is thus obtained the antineoplastic agent fazarabine (150), also known as ara-A C. 

The presence of a 5-oxo group in the 1,2,4-triazines, as in 3-hydrazino-2,5-dihydro-5-oxo[l,2,4]triazines, does not alter the direction of cycliza-tion by the action of nitrous acid. The initial products are azido compounds 1016, which can cyclize spontaneously to tetrazolo[l,5-b][l,2,4]triazines 1017 (77JHC1221, 77JOC1866) rather than the previously reported isomeric structure. On the other hand, when the cyclization onto N-2 is impossible, as in derivative 1018, the azidotetrazolo equilibrium 1018 1019 exists (76JOC2860 77JOC1866). It exists in the solid state at least as the tetrazole derivative (Scheme 190). 

Two types of addition to pyrimidine bases appear to exist. The first, the formation of pyrimidine photohydrates, has been the subject of a detailed review.251 Results suggest that two reactive species may be involved in the photohydration of 1,3-dimethyluracil.252 A recent example of this type of addition is to be found in 6-azacytosine (308) which forms a photohydration product (309) analogous to that found in cytosine.253 The second type of addition proceeds via radical intermediates and is illustrated by the addition of propan-2-ol to the trimethylcytosine 310 to give the alcohol 311 and the dihydro derivative 312.254 The same adduct is formed by a di-tert-butyl peroxide-initiated free radical reaction. Numerous other photoreactions involving the formation by hydrogen abstraction of hydroxyalkyl radicals and their subsequent addition to heterocycles have been reported. Systems studied include 3-aminopyrido[4,3-c]us-triazine,255 02,2 -anhydrouri-dine,256 and sym-triazolo[4,3-fe]pyridazine.257 The photoaddition of alcohols to purines is also a well-documented transformation. The stereospecific addition of methanol to the purine 313, for example, is an important step in the synthesis of coformycin.258 These reactions are frequently more... 

A considerably large set of N-acylated 6,7-dihydro[l,3,4]thiadiazolo[3,2-tf][l,3,5]triazine-5-thiones has been prepared by an Indian team <2003IJB2583>. Acylation of 49 has been carried out in chloroform under heating for 3 h to yield the iV-acyl products 50 in medium yields (35-40%) (Scheme 6). 

Some 4,5-dihydro[l,2,4]triazolo[3,4-r-]benzo[l,2,4]triazines 57 easily reacted with aromatic aldehydes to result in the formation of synthetically valuable azomethine imines 58 <2005EJO3553>. The transformation took place at room temperature in the presence of tetrafluoroboric acid in 10 min in high yields. The product 58 was conveniently prepared and stored in the form of tetrafluoroborate salt, and was subjected to further reactions (e.g., 1,3-dipolar cycoadditions see Section 11.19.5.4.) by in situ liberation of the free base prior to transformation. 

A Greek team also reported on oxidation of partially saturated heterocycles to fully heteroaromatic rings <1996JHC599> 5-/>-anisyl-4,5-dihydro[l,2,3]triazolo[5,l-/][l,2,4]triazine 91, when treated with cerium ammonium nitrate, underwent an oxidative hydrolysis giving heteroaromatic product 92 in poor yield (20%). 

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... 

Hydrolytic cleavage of condensed 1,2,3-triazine derivatives is normally a straightforward, high-jneld process which results in production of one or other of several distinct types of product. 3-Alkyl- and 3-aryl-3,4-dihydro-l,2,3-benzotriazines, for example, undergo facile hydrolysis in concentrated hydrochloric acid to give, via the diazonium compound, A(-alkyl- and W-aryl-substituted o-chlorobenzylamines (100, R = Cl). If the reaction is carried out in water or in dilute mineral acid, the corresponding -alkyl and iV-aryl-substituted o-hydroxybenzylamines (100, R = OH) are obtained. 

Alkylation and acylation of 6-halo-l,2,4-triazine-3,5-diones yields 2- and 4-alkylated and -acylated derivatives. With trimethylchlorosilane they afford the 6-haIo-3,5-bis(trimethylsilyloxy)-l,2,4-triazines. l,6-Dihydro-l,2,4-triazine-3,5-diones (204) are acylated at N-l and N-2 and the diacylated product (205) can then be methylated by diazomethane at N-4 to afford compound (206) (63CCC2527). 

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). 

Substituted 3-thioxo-l,2,4-triazin-5-ones (76 R4 = H) are stable toward sodium amalgam, but the 4-substituted derivatives (76 R2 = H) are reduced to the 1,6-dihydro compounds (282). Hydrogenation of (76 R2 = H) affords ring-opened products. 3-Methyl-thio-l,2,4-triazin-5-ones (78) are reduced by sodium amalgam to 3-methylthio-3,4-dihydro-... 

Irradiation of 5,6-diphenyl-3-p-tolyl-l,2,4-triazine (358) in methanol with UV light afforded three products, 2,4-diphenyl-6-p-tolyl-l,3,5-triazine (359), 5,6-diphenyl-3-p-tolyl-2,5-dihydro-l,2,4-triazine (360) and 4,5-diphenyl-2-p-tolylimidazole (361) (72UP21900). 

Aromatic aldazines when treated in boiling toluene with potassium r-butoxide, furnished 3,5,6-triaryl-l,2,4-triazines (632) and their 2,5-dihydro (633) and 1,2,5,6-tetrahydro derivatives (634), besides triazoles, which were the major products (76JCS(Pl)207). The formation of the triazines is best explained by a [4+2] cycloaddition or a two-step process via the carbanion (631) and elimination of benzalimine to give (633), which can be oxidized to (632 Scheme 21). TTie formation of (634) is still in doubt. 

Thioxo-4,5-dihydro-l,2,4-triazin-6-ones (708) are reported to be prepared by treatment of a-(4-thiosemicarbazido)acetates (707) with sodium ethoxide (64CB994) there is, however, some doubt about the structure of these products (68CCC2087). 

The a-hydrogens of 2,4,6-trialkyl-1,3,5-triazines are readily chlorinated or brominated in the presence of acid. The reaction is believed to occur via an ionic mechanism. The final products using an excess of chlorine or bromine are strongly dependent on the reaction conditions used (Scheme 19) (64JOC1527). 2-Alkyl-l,2-dihydro-l,3,5-triazines (36) may be rearranged in good yields to pyrimidines (Scheme 20) (79TL1241). 

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). 

The residual crude crystalline ip-D-ribofuranosyl-4-methoxy-l,2-dihydro-l,3,5-triazin-2-one is dissolved in a 10% solution of dry ammonia in absolute methanol (4 ml) and the whole reaction mixture is allowed to stand in a stoppered flask for 30 min at room temperature (the product begins to deposit in the course of 5 min) and for 12 h in a refrigerator at -10°C. The resulting 5-azacytidine is collected with suction, washed with methanol and dried under reduced pressure. A yield of 0.216 g (88.6%) of 5-azacytidine, that is [l-p-D-ribofuranosyl-4-amino-l,3,5-triazin-2(lH)-one], melting point 232°-234°C (dec.), is obtained. 

An attempt to isolate the tetrahydro (246) or dihydro (247) derivatives of the pyrido[3,4-e]-1,2,4-triazine ring system from the cyclization of the pyridine (248) failed in that the only isolable product was the aminoimidazolone (249). This product (249), however, is postulated to be derived from the desired compound (246) via an intramolecular reaction (Scheme 20) <76JHC60l>. 

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