Triazines benzo

The synthesis of 9H-benzo[2,l-e]thiazolo-[2,3-c]-as-triazine (401) was achieved by oxydative cyclization of 2-imino-3-(o-aminophenyl)-4-phenyl-4-thiazoline (718, 719). This latter reacts also with paraformaldehyde in hot toluene yielding 3-phenyl-9H.10H-benzo[l,2-/]thiazolo-[2,3-d][l,3,5]triazepine (402) (720). This heterocyclic sytem is also formed when carboxylic acids replace paraformaldehyde (Scheme 230) (721). 

If diazomethane is added slowly to an etheral suspension of benzo-l,2,4-triazin-3-one, the 0-methyl derivative (cf. 161) is obtained in good yield, but, if the solid benzotriazinone is added to an etheral solution of diazomethane, approximately 50% of the A -methyl derivative (or, according to a later report, 70% of a mixture of two isomeric iV-methyl derivatives) is formed. These facts have been interpreted to indicate that the benzotriazinone exists as such in the solid state, i.e., as 162, and partially tautomerizes to 161 in solution. Similar results have been reported and similar conclusions drawn for the related 1-oxide 162a. ... 

In some cases, the position of the N-oxidation depends on the temperature. The reaction of 3-phenyl-1,2,4-benzotiiazine 172 with peracetic acid affords 3-phenyl-l,2,4-benzotriazine 1-oxide 173 at 50°C and 2-oxide 174 at room temperature (57JCS3186). Only the 1-oxide 175 was obtained by the oxidation of 3-unsubstituted 1,2,4-benzotriazine 176. The oxidation of 3-methyl-1,2,4-benzo-triazine 176 (R = Me) under the same conditions results in a mixture of 3-methyl-l,2,4-benzotriazine 1-oxide 175 and 2-oxide 177 in 25 and 10% yields, respectively. 

Chemical Name 5-(dimethylamino)-9-methyl-2-propyl-1 H-pyrazolo [ 1,2-a] [ 1,2,4] benzo-triazine-1,3(2H)-dione... 

The benzo analogue 684 of [1,2,4]triazino[3,2-6]thiazoles was prepared (88LA1089) by heating triazine derivative 632 with 2,4-dinitrochloroben-zene or picryl chloride in N,N-dimethyl formamide (Scheme 143). 

Benzo-l,2,3-triazin-4-ones with the general structure 6.54 (X = O, S, or H2) are obtained by diazotization of the appropriate aniline derivatives 6.53 (Scheme 6-38). In polar aprotic solvents (e. g., nitrobenzene) the reverse reaction takes place to give the diazonium ion (for an example see Kullick, 1966). Diazotization of 1,8-diamino-naphthalene yields l-i/-naphthol[l,8-cfe]triazine (6.55 Tavs et al., 1967). In concentrated HC1 the triazine ring is opened again. 

The synthetic method indicated in Scheme 6-38 is important for the preparation of heterocyclic analogues of benzo-l,2,3-triazin-4-ones. The cyclization products of... 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

Refluxing of benzo[l,2,4]triazine-3-thione 86 with epichlorohydrin in the presence of triethylamine in methanol for 14 h resulted in the formation of 3,4-dihydro-2H,97/-l-thia-4a,9,10-triaza-phenanthren-3-ol 87 <2003PS797> (Equation 7). 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

Isoindolo[2,l-c]benzo[l,2,4]triazines 85 have been described as a new ring system with antiproliferative activity <06BMC343>. 

Thus oxidation of both 6- and 7-substituted 3-amino-benzo-l,2,3-triazin-4-ones with lead tetraacetate in methanol produced a mixture of p- and m-substituted benzoates, clearly indicating that a symmetrical intermediate, i.e. benzocyclopropenone (166) was formed and underwent ring opening by attack of solvent121 ... 

The intervention of an intermediate with the symmetry of a benzocyclopropenone (166, R = Cl) is also demanded by the formation of methyl p-chlorobenzoate in the photolysis of the lithio derivative 173 of the chlorosubstituted 3-p-tolylsulpho-nylamino-benzo-l,2,3-triazin-4-one128) ... 

Pyridazino[2,3-h]benzo[l,2,4]triazine 197 was prepared (84CL1197) by boiling the triazolobenzotriazole 196 with dimethyl acetylenedicarboxylate in toluene. Compound 197 behaves as a stable free radical. 

The first representative of the [l,2,4]triazino[5,6-fc]diazepin-8-ones 583 was obtained by reaction of 6-amino-3-(p-tolyl)[l, 2,4]triazin-5(2//)-thione 581 with 2//-1,3-oxazine-2,6(3//)-dione [85LA(3)640]. The benzo analogue [l,2,4]triazino[5,6-b][l,4]benzodiazepinones 582 were similarly obtained by reaction of 581 with isatoic anhydride. 

Pyrazolo[3,2-c]pyrido[4,3- ][l,2,4]triazine oxides704 were prepared by cyclization of the hydrazone derivatives 703 with ethanolic sodium hydroxide. Subsequent reduction of 704 gave 705 (76JPR835). Hydrazone 703 was prepared by condensation of 4-hydrazino-3-nitropyridine with 702. The mass spectral fragmentation patterns for 704 and 705 and their benzo analogues were studied (77ZC142). 

Benzo-flw-triazine tri-N-oxides 384 (R = H, Me R1 = mesityl, 2,6-ClC6H3) are formed from the reaction of nitrile oxides R CNO with benzofuroxans 385. The structure of 384 (R = Me, R1 = mesityl) has been confirmed by X-ray crystal structure analysis (431). 

Finally, indolo[l,2-r ]benzo[l,2,3]triazines 46 proved to be fairly potent and selective inhibitors of Streptococcus and Staphylococcus, up to 80 times more potent than the reference drug streptomycin, and inhibited the growth of the above Gram-positive bacteria at concentrations far lower than those cytotoxic for animal cells <1999JME2561>. 

The exact stmcture of a cycloadduct 39 obtained by dipolar cycloadditions of a [l,2,4]triazolo[3,4-c]benzo[l,2,4]triazine-based azomethine imine has been determined by X-ray investigation <2005EJO3553> (Scheme 4). The data supported the unambiguous connectivity of the particular atoms (i.e., attachment of the />-anisyl carbon atom to N-l) and, furthermore, the fact that the central triazine ring had a quasi-envelope stmcture with the N l atom at the top. 

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. 

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. 

Costanzo etal. <1994JHC1369> published the synthesis of a series of pyrazolo[5, l-c]benzo[l,2,4]triazine-5-oxides 48 and compared the 13C NMR chemical shifts of these products. These values for a set of four derivatives are shown in Table 1. 

Table 1 13C NMR chemical shifts (300 MHz) of some pyrazolo[5,1 -c]benzo[1,2,4]triazine-5-oxides 48 measured...

LA Carpino, J Xia, A El-Faham. 3-Hydroxy-4-oxo-3,4-dihydro-5-aza-benzo-l,2,3-triazine. J Org Chem 69, 54, 2004. 

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