Phenyl tetrazine

Bromo-6-phenyl- -tetrazine (334) gives the 3-hydroxy analog in quantitative yield after a few minutes at 95° in ethanolic potassium hydroxide or ethanolic ethoxide. As with other highly activated aikoxy-azines (cf. Section III,B,4,c and reference 582), the latter... 

A refluxing solution of 3-phenyl-2//-azirine (0.468 g, 4 mmol) in toluene (10 mL) was treated with 3,6-diphcnyl-l,2.4.5-tetrazine (0.702 g, 3 mmol) in toluene (10 mL) and the solution was boiled under reflux for 22 h. On cooling, the mixture deposited an orange precipitate, which was filtered off and washed with pentane. Further product was obtained from the mother liquor by chromatography (silica gel). The combined solids were recrystallized (benzene/pentane) to give the product yield 0.664 g (68%) orange plates mp 210 C. 

There is only one reported synthesis of a bcnzannulated 1,2,4-triazocine system. 2-Phenylbenz-azete (1), which can be generated from 4-phenyl-l,2,3-benzotriazine by pyrolysis, is reacted with tetrazine 2 to give a [4 + 2] adduct, which loses nitrogen and finally results in the eight-membered-ring derivative after valence isomerization.2... 

Hartung et al. [120] determined the crystal structure of the mesogenic 6-hexylamino-l,2,4,5-tetrazin-3-yl 4-pentyloxybenzoate. The plane of the bridging carboxylic group is inclined to those of the phenyl and the tetrazine rings by 12.1 and 76.3°, respectively. The molecules are arranged in sheets parallel to (021). 

The reaction of 3,6-diaryl-l,2,4,5-tetrazines (aryl = phenyl, 2-furyl or 2-thienyl) with 2 equivalents of Ru(acac)2(CH3CN)2 resulted in reductive tetrazine ring opening to yield diruthenium complexes <06IC821>. 

Thus, the recognition that nitrosoimidazoles and phenyl methylcarbazates can participate in an efficient condensation to give 2,8-dihydro-imidazo[5,l- 7][l,2,3,5]tetrazine-l-one derivatives 9 led to the elaboration of a new reaction pathway to this biologically active substance <2002J(P 1)1877> (Scheme 14). 

Synthetic approaches to representatives of this ring system have been discussed in CHEC-II(1996) <1996CHEC-II(8)496>. Research activity in this area has been considerably extended during the past years. Thus, the basic starting material is a 6,6-disubstituted tetrahydro[l,2,4,5]tetrazin-3-thione 52, which has been converted in three different ways reaction with phenacyl bromides led to 3,3-disubstituted 3,4-dihydro-6-phenyl-2//-thiazolo[3,2-4]-[l,2,4,5]tetrazines 53, reaction of 52 with 1,2-dibromoethane gave 3,4,6,7-tetrahydro-2//-thiazolo[3,2-7][l,2,4,5]tetra-zines 54, whereas transformation of 52 with chloroacetic acid in the presence of sodium acetate yields substituted 3,4-di hydro-1-2//-thiazolo[3,2- 1 [ 1,2,4,5]tctrazin-6(7//)-oncs 55 <2001IJB584> (Scheme 17). Details are shown in Table 2. 

The synthesis of pyrrolo[2,3- 7 pyridazines can be achieved by starting either with pyridazine, a tetrazine, or a pyrrole. Pyridazinone 80 reacts with bromomethyl derivatives to give poor yields of 81 <1996H(43)1863> (Equation 34), while 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone, after treatment with sarcosine ethyl ester for a brief time at room temperature, followed by acid hydrolysis afforded a good yield of 82 (70%) <1994S669>. 

Bei der Reaktion von Bis-[a-phenylhydrazono-benzyl]-disulfan mit Tetranitromethan in Dichlormethan bei 20 entsteht interessanterweise unter Schwefel-Abspaltung, RingschluB und aromatischer Nitrierung das 3,6-Bis-[4-nitro-phenyl]-l, 4-diphenyl-l, 4-dihydro-l, 2,4,5-tetrazin (Schmp. 308-315° aus Dichlormethan/Diethylether) in 20%iger Ausbeute1 ... 

Synthesis of benzo[c]furans and isoindoles (181) is also possible by the addition of benzyne to the respective monocycles (178), followed by reduction (179 — 180) and pyrolysis. In an alternative procedure, (179) is reacted with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine, which affords (181) under far less vigorous conditions via a retro Diels-Alder reaction of the intermediate (182). 4-Phenyl-1,2,4-triazoles pyrolyze to form isoindoles (Section 3.4.3.12.2). 

The only known representative of 1,2,3,4-tetrazines (502) has been obtained with 81% yield on oxidation of l-amino-5-phenyl-l,2,3-triazolo[4,5-cn-l,2,3-triazole (501) with lead tetraacetate (88CC1608). 

Only about 20 compounds with the tetrahydro-l,2,3,4-tetrazine structure are known, but two X-ray crystallographic analyses have been reported. The structure of 1,4-dimethyl-l,4,5,6-tetrahydro-l,2,3,4-tetrazine 2-oxide (6) is a twisted boat conformation with non-planar terminal nitrogen atoms, which reflects the repulsion in the four-atom six-electron N—N=N—N system. The bond distances and angles are given in Figure 1 (78HCA1622). A similar study of dimethyl 2-phenyl-2,3,4,4a,5,6,7,8-octahydrobenzo-l,2,3,4-tetrazine-... 

Treatment of verdazyls (48) with mineral acids resulted in disproportionation to 1,2,3,4-tetrahydro-1,2,4,5-tetrazines (75) and l,6-dihydro-l,2,4,5-tetrazinium salts (76). Here one molecule of the verdazyl is reduced to (75) and the other is oxidized to (76). The mechanism of this reaction has been studied by Polumbrik and his group (72ZOR1925). Heating 3-phenyl-1,2-dihydro-1,2,4,5-tetrazine-6(5/f)-thione (77) in 2N hydrochloric acid led to the isolation of 3-phenyl-l,2,4-triazole-5-thione (78) (77KGS1564). 

Basic hydrolysis of 3-phenyl-l,2,4,5-tetrazine (81) led to the isolation of benzalazine (82) in 80% yield (71KGS708). In most other cases studied the isolated product was an aldehyde acylhydrazone (83), indicating that during the basic hydrolysis one carbon atom of the tetrazine ring is reduced from the acid oxidation level to an aldehyde level (78HC<33)1075, p. 1094). A mechanism for the reaction has been proposed by Libmann and Slack (56JCS2253). Benzalazine (82) was also isolated when 3-azido-6-phenyl-l,2,4,5-tetrazine (84) was hydrolyzed by base (71KGS711). 

Treatment of 3-phenyl-l,6-dihydro-l,2,4,5-tetrazin-6-one (94) with base led to the isolation of benzalazine (82) (69KGS566). Alkaline hydrolysis of hexahydro-1,2,4,5-tetrazines (74) gave an aldehyde hydrazone or an aldehyde and hydrazine as with the acidic hydrolysis <78HC(33)1075, p. 1213). 

Thermolysis of 3,6-diphenyl-l,4-di(phenylsulfonyl)-l,4-dihydro-l,2,4,5-tetrazine (127) in boiling toluene gives benzenesulfonic anhydride (128), phenyl benzenethiosulfonate (129), small amounts of diphenyl disulfide (130), 3,6-diphenyl-l,2,4,5-tetrazine (51) and a rearrangement product, 3,6-diphenyl-l,2-di(phenylsulfonyl)-l,2-dihydro-l,2,4,5-tetrazine (79) (79BCJ483). 3,6-Disubstituted hexahydro-1,2,4,5-tetrazines (132) afforded aldehyde hydrazones (133) when heated at their melting point (63AG1204). 

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