2- -l,3,5-triazines

Cyclization of hydrazide 954, with triethyl orthoformate gave a mixture of triazolo[4,3-[Pg.144]

A series of functionalizations of the ring system tetrazolo[l,5- ][l,2,4]triazine 1 have been reported by Rusinov et al. 

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... 

Seitz and co-workers (84AP237) reported that 2-pyrazolines (132) react with tetrazines (133) to yield pyrazolo[l,5-rf]-l,2,4-triazines (135), most likely via intermediate cycloadduct 134 (Scheme 18). Addition of py-razoles to 133 has been reported to also yield pyrazolo[l, 5-[Pg.245]

The reaction of aminoguanidine with ethyl 2,4-dioxopentanoate afforded pyrazole 137 at pH 2. When the reaction was carried out at pH 4, pyrazolo[l,5- /]-l,2,4-triazine (136) was formed upon further reaction of 137 with aminoguanidine (76MI2) (Scheme 19). 

The reaction of 3-aryl-l,2,4-triazines 100 with thioamides in acetic anhydride was reported to occur regioselectively at room temperature resulting in simultaneous A -acetylation and annelation of the thiazole ring to form 1,4,4 ,7 -tetrahydrothiazolo[4,5-( ][l,2,4]triazines 38 (Scheme 74 Table 8) <2004RCB1279>. 

Only a few nonazapteridines have had their UV spectra reported since CHEC-II(1996). Thus, the imidazo-fused pyridazino[6,5-( ]-l,2,4-triazines 23 show XmaiL values (dioxane) at 325 and 410nm <1999CHE376, 1999KGS426>, and the l,3-oxazino[4,5-( ]-l,2,4-triazines 25 show maximum absorption at 290nm <2003ARK98>. 

Azapteridines (pyrimido[4,5- ]-l,2,4-triazines) are stable solids with good thermal stability. Thus, the 3,6-diaryl-pyrimido[5,4- ]-l,2,4-triazines 18 (R = Ar) show melting points in excess of 350°C without decomposition after recrystallization from ethanol. The corresponding 6-unsubstituted system 18 (R = H) shows decomposition at 325°C <2003CCC965>. These systems are soluble in chloroform. 

Nucleophilic attack on the chloro-substituted pyrimido[4,5- ]-l,2,4-triazines 35 by amines allows the synthesis of the corresponding amino-substituted systems 36 as shown in Equation (5) <1996T3037>. 

A similar process was found to occur with the fervenulin-3-carboxyl chloride 54, which upon treatment with an amine gave the bis-adduct intermediate 55, which ring-closed to the imidazo[4,5- ]-l,2,4-triazine bis-carboxamides 56 as shown in Scheme 5 <1996JHC949>. The structure of the products 56 was confirmed by X-ray crystallographic analysis. 

Methylfervenulone 12 is a natural product that undergoes nucleophilic attack of water at the nonconjugated ring to give the imidazo[4,5-< ]-l,2,4-triazine 59 via the mechanistic pathway shown in Scheme 8 <2000JNP1641>. 

The 5-0X0 substituent of the 3-alkylfervenulins 24 reacts with aqueous potassium permanganate to give the imidazo[4,5 ]-l,2,4-triazin-6-ones 66 via the ring-opening-ting-closure process suggested in Scheme 10 <1996JHC949>. 

The pyrimido[4,5- ][l,2,4]triazines (6-azapteridines) 18a and 18b, shown in Scheme 18, were formed upon the reaction of the ethyl l,2,4-triazine-6-carboxylates 121 with benzamidine, a reaction which proceeds via the action of boiling acetic acid upon the characterized intermediate salt 122 <2003CCC965>. The same researchers (Scheme 19) also showed that the 5-amino-l,2,4-triazine-6-carboxamide 123 (R =OMe) can undergo reaction in neat benzaldehyde to furnish a low yield of the 6-azapteridine 18b. More importantly, the 5-amino-l,2,4-triazine-6-carboxamides 123 were found to undergo reaction with triethyl orthoformate to yield the 6-unsubstituted-3-arylpyr-imido[4,5-( ][l,2,4]triazines 18c and 18d, also shown in Scheme 19 (R = H) <2003CCC965>, one of only a few entries to such compounds. 

The pyrazolo-fused pyrimido[4,5-< ]-l,2,4-triazine 35 was synthesized using the 5-amino-6-cyano triazine 131 (Scheme 21) as the precursor. Reaction with phosgeniminium chloride gave the amide halide intermediate 132 which in turn produced the pyrimido[4,5-< ]-l,2,4-triazine 35 upon treatment with gaseous hydrogen chloride <1996T3037>. 

Only one nonazapteridine (pyrimido[4,5- ]-l,2,4-triazine) derivative has been synthesized by the methods covered in this section. Thus, the reaction of the 5-amino-l,2,4-triazine-6-carboxylate 128a with triphenylphosphine/hexa-chloroethane produced the iminophosphorane 133 which underwent aza-Wittig reaction in hot benzoyl chloride in the presence of catalytic 4-dimethylaminopyridine (DMAP) to give the oxazino[6,5-< ]-l,2,4-triazine 134 as shown in Scheme 22 <2003ARK98>, which, as discussed in Section 10.20.1, constitutes an addition to the 44 ring systems covered by the remit of this chapter that were known at the time of CHEC-II(1996) <1996CHEC-II(7)785>. 

The reaction of the cyanoimino-5-diazopyrimidine 2,4-dione 155 with a large excess of propanethiol gave the 3-aminopyrimido[4,5- ]-l,2,4-triazine 6,8-dione (6-azapteridine) 156 as shown in Scheme 26. The mechanistic pathway is also shown in Scheme 26 and relies upon the addition of propanethiol to the cyanoimino group followed by propanethiol-mediated cyclization and loss of a disulfide <2001JHC141>. 

The reaction of 6-aminouracils 157 with dimethyl Ai-cyanodithioimidocarbonate, shown in Scheme 27, gave the intermediates 158 which on coupling to phenyldiazonium salt, followed by elimination of methanethiol, gave the 5,7-disubstituted-2-phenylpyrimido[4,5- ]-l,2,4-triazines 159 (Ar = Ph) in the isolated yields shown in Table 10 (entries... 

Three classes of compound dominate this section, namely the 6-azapteridines or pyrimido[4,5- ][l,2,4]triazines, the 7-azapteridines or pyrimido[5,4-i ][l,2,4]triazines, and the pyrazinothiadiazines, particularly the pyrazino[2,3-r ][l,2,6]thiadiazine 2,2-dioxides. None of the other systems that have appeared in this chapter show important applications. 

---