1.2.3- Triazines, fused reactions

In addition to the synthesis of industrially important azo dyes using heteroaromatic diazo components, intramolecular azo coupling reactions of heterocyclic diazonium ions also have interesting synthetic uses, because they lead to new fused-ring heterocycles, as shown by the diazotization of 2-amino-3-arylbenzimidazoles (12.7) in which, without isolation of the diazonium ion, a 1,2,4-triazine ring is formed (Kolodyazhnaya et al., 1973). Further examples of intramolecular azo couplings were reviewed by Tisler and Stanovnik (1980), and very extensively (403 references ) by Kishimoto et al. (1990). 

Triazinethiones have been used frequently for the syntheses of triazino-triazines in the literature. Reaction of 6-methyl-5-[substituted styryl]-2/7-[l,2,4]triazine-3-thiones 39 with thiourea or acetylthiourea in dimethylformamide (DMF) led to the formation of N,N -disubstituted thioureas 40. Heating the compound 40b with glacial acetic acid and fused sodium acetate under reflux led to the formation of the compounds 4,7-dimethyl-8-[2-ethenylfuran]-2-thioxo-l,3,5-triazino[5,6- ][l,2,4]triazine 22 (Scheme 6) <2003PS279>. 

Triazoles fused with larger aromatic systems can be also obtained this way. Thus, in an example given in Equation (30), 2i/-phenanthro[9,10-r/l-l,2,3-triazole 1221 is obtained in 84% yield from a reaction of 3-hydroxyphe-nanthro-l,2,4-triazine 1220 with NCS <2000H(53)203>. 

Ring-opening reactions with opening of the five-membered moiety can occur in the cases of several fused [l,2,3]triazines. Such transformations are depicted in Scheme 13. 

Concerning the transformation of substituents, a special note should be made on a series of ring-closure reactions carried out on the side chain of some [l,2,4]triazolo[4,3-r]benzo[l,2,3]triazines published by Moustafa <2001SC97>. The results are summarized in Scheme 18. This scheme shows that by transformation of the R group attached to the sulfur atom of derivative 97 a fairly large set of cyclic products - involving thiazolidone 97a, [l,2,4]triazole 97b, coumarone and its imine 97c and 97d, respectively, benzoxazylpyrane, 97e, thiophene 97f, and cyclopenta- or cyclohexa-fused protected pyrone 97g substituents - have been obtained. 

Reiter and co-workers found in the course of their extended research on fused [l,2,4]triazines <1994JHC997> that the N-protected methylthiotriazine derivative 110 when reacted with carbon disulfide under strongly basic conditions yields a mixture of two products 111 and 112. When this mixture was treated with dibromomethane, product 113 was easily removed from the reaction mixture, and workup of the mother liquor allowed the isolation of the [l,2,4]triazolo[l,5-c][l,3,5]thiadiazine derivative 114 in 49% yield (Scheme 21). The same authors carried out ring closure of the ring-closed semithiocarbazide 115 to the triazolothiadiazine derivative 118 as shown in Scheme 21 <1997JHC1575>. The starting compound was treated with triethyl orthoformiate. The authors assume that first intermediate 116 is formed which cyclizes to a second intermediate 117 and, finally, ethanol elimination yields the isolated product 118. 

Nagai et al. carried out various transformations with camphor-fused amino[l,2,4]triazine 191 <1998JHC293> (Scheme 39). Reaction of 191 with chlorocarbonylsulfenyl chloride yielded the fused thiadiazolone 192 in high yield (83%). The same starting compound also proved to be suitable for the synthesis of the fused triazole derivative 193. To this end, 191 was first subjected to two subsequent transformations first by dimethylformamide dimethylacetal followed by treatment with hydroxylamine hydrochloride to give an Ar-hydroxyamidine 193 in 90% overall yield, and then this compound was treated with polyphosphoric acid to yield the fused triazole product 194 in 92% yield. 

Most of the cyclizations of the five-membered ring relating this type of fused [l,2,4]triazines concern the synthesis of [l,3,4]thiadiazolo[2,3-c][l,2,4]triazines. These synthetic approaches are similar in respect to the starting compound, which is a substituted 4-amino-3-mercapto[l,2,4]triazine-5(477)one 218 in each case. The ring-closure reactions can be classified into four related categories according to the reagent used aldehyde, isothiocyanate, carbon disulfide, or an acid. 

The fused tetrazoles 10 containing various aryl groups in position 6 were boiled in acetic acid in the presence of either triphenylphosphine or copper and gave rise to the amino-substituted triazines 12. The reaction proceeds obviously via valence bond isomerization of 10 to the azide 11 and is regarded as a useful synthetic route to the diamino compounds 12. 

In Scheme 7, ring-opening reactions of some fused pyrazoles are shown. Thus, Baraldi et al. <1999S453> described that the pyrazolo[l,5-<7][l,2,4]triazine-dione derivative 72 is sensitive toward nucleophiles its reaction with benzylamine at room temperature gives rise to the acyl semicarbazide 73 in high yield (78%). 

Ring contraction reaction of the benzthiazolo[2,3-f][l,2,4]triazin-one derivative 95 has been reported by Kuberkar et al. <2005JCM632> (Scheme 13). This compound when heated in aqueous sodium hydroxide underwent ring opening and a subsequent ring closure to result in formation of the fused [l,2,4]triazole ring system 96 in good yield (60%). 

Indian authors reported the ring closure of the imidazolylamidine 240 to the tricyclic fused triazine 241 <1998IJB1283>. The reaction with aliphatic orthoesters was carried out under reflux conditions to yield the products in excellent yields. 

Isoxazolo[5,4-, [l,2,4]triazine-4-ones are prepared by six-membered cyclizations of diazonium salts onto adjacent ester or amide substituents on the isoxazole ring (Section 10.13.9.1.2(i)). [l,2,5]Oxadiazolo[3,4- ]pyrazines (Section 10.13.9.1.2(ii)) and [l,2,5]oxadiazolo[3,4- pyridazines (Section 10.13.9.1.2(iii)) are traditionally accessed by reliable six-membered condensation reactions to give the fused pyrazine and pyridazine rings, respectively. 

The reaction of the pyrido-fused pyridazino[3,4-< ][l,2,4]triazinium compound 105 with secondary amines results in the ring-opening of the pyridine moiety to yield dienyl-substituted pyridazino[3,4-< ][l,2,4]triazines of which the pyrrolidine compound 106, shown in Scheme 15, is typical <2003ARK62, 1998AC0285, 1995JOC4919>. Compound 106 has been the subject of a detailed study and has been shown to react as a diene in the presence of fumaronitrile and A -phenylmaleinimide to give the Diels-Alder adducts 107 and 108, respectively <2003ARK62>,... 

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>. 

The arylfuro-fused pyrido[l,2-/ ][l,2,4]triazinium salt 179 undergoes reaction with methyl hydrazine to give the zwitterionic pyrido-fused pyridazino[3,4- ][l,2,4]triazine 31 as shown in Scheme 32 <2003ARK62, 1997CC757>. Nucleophilic attack of the hydrazine at the bridgehead results in the elimination of an enol that then allows ring closure via attack of the other hydrazine nitrogen onto the carbonyl of the keto tautomer. 

Methylation of compound 31 from Scheme 32 gives the N-methylated analogue 32 (see Section 10.20.5.3), shown in Equation (27), which is then able to function as a fused heterocyclic precursor for the synthesis of the pyrida-zino[3,4- ][l,2,4]triazine 106 after reaction with pyrrolidine <2003ARK62>. 

N 14-89%, OB to C02 -68.1%. It was prepd from reaction of 3 Me-l,5-dimtro 5 triazine with nitric.acid, trituration with EtgO and refluxing with fused NaAc in HAc (Ref 2) no props given. Ref 3 mentions a UV spectrum Refs 1) Beil — not found 2) F. Chapman,... 

Diazotization followed by cyclization has been used to prepare fused thiophene derivatives. Thus diazotization of 3-aminothiophene-2-carboxamides in cone. HC1 leads to thieno-1,2,3-triazines (Scheme 122) (75CRV241). A similar reaction was also observed with the 4-carboxamide derivatives. With 2,4-dicarboxamides as substrates the 3-diazo group preferred to cyclize with the 2-carboxamide group. 

Pyrimidines are expected to be much less reactive in cycloadditions of this type than triazines and tetrazines. Normally, the presence of electron-withdrawing substituents on the pyrimidine ring is essential. The best results are obtained with a nitro group in position 5. Reaction of 5-nitropyrimidine with various enamines affords fused nitropyridines (82TL3965 89T2693) (Scheme 59). The mechanism (89T2693) is in agreement with the usual expectations. 

The dominant influence of secondary orbital interactions is observed in the reaction of the cyclopenta[e][l,2,4]triazine ester (415) witl the two enamines (416) and (417). In the first case the fused pyridine (418) was obtained directly in the latter the dihydropyridine (419) was isolated, and aromatized, by iV-oxidation and Cope elimination, to (420) <82CB2807>. 

There have been a number of syntheses of a wide range of fused 1,3,5-triazine systems (see Section 2.20.4), but the chemistry of most of these compounds has yet to be fully investigated. The following discussion is limited to an outline of novel rearrangements of some fused 1,3,5-triazines and the reactions of cycl[3.3.3]azine derivatives. 

Coburn and Bhoosan reported the first synthesis of 1,3-disubstituted l,3,5-triazine-4,6-dione (82) and the corresponding thione derivative. The dione (82) is thermally stable, but forms ring-opened products on exposure to moisture. The reaction of (82) with dimethyl acetylenedicarboxylate gives the 1 1 adduct rather than the expected cycloaddition products (Scheme 50) (75JHC187). The fused system (83) reacts with ethylamine to produce the 1,3,5-triazine (84 equation 41) (81JCS(Pl)33l). 

Fused ring systems are usually formed by reaction of a 2-amino nitrogen heterocycle with an appropriate reagent to generate the 1,3,5-triazine rings. 

The reaction of 2-mercapto-5-(phenylazo)-4,6-dimethylpyridine-2-carbonitrile with appropriate halogeno compounds yields S-alkylated products which can be cyclised to yield pyridothieno-pyrimidines (61a) or -triazines (61b) [94PS(90)85]. Related reactions have been employed to yield further fused ring heterocycles [95PS(104)143]. 

It is also possible to generate the same triazine in situ as part of a one-pot reaction starting from ethyl thioamido oxalate followed by generation of the hydrazone and then addition of an a,/3-diketone ester and either norbornadiene or 2,3-dihydrofuran. The former diene yields the pyridine skeleton in 59-87% yield, while the latter gives fused pyridolactones in 39—44% yield (Scheme 56) <2004T8893>. 

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