3,6-Diphenyl-7,2,4,5-tetrazine

The formation of dihydro or tetrahydrotetrazine intermediates in Pellizzari type reactions carried out at high temperatures has long been suspected. The conversion of diphenyl-tetrazine (275) into 3,5-diphenyltriazole (276) by reduction (62LA(654)146) occurs in two stages (Scheme 121). Formation of the aminotriazole (277) may be interpreted as an intramolecular leacylation of the amidrazone analogue derived from (275) followed by reductive cleavage of N(4)—NH2. The conversion of (275) into (276) with ethanolic alkali also is consistent with the known lability of N(4)—NH2. 

Like lV-methyl-2-phenylbenzothiazoliiim iodide (76KGS635), the salt 19 reacts with hydrazine hydrate to give 3,6-diphenyl-l,2-dihydro-l,2,4,5-tetrazine and di(o-lV-methylaminophenyl) ditelluride (92MI1). 

Cycloaddition-cyclorevcrsion reaction of 9-oxabicyclo[6.1.0]nona-2,4,6-triene (6) with 3,6-diphenyl-1,2,4,5-tetrazine followed by dehydrogenation with tetrachloro-1,2-benzoquinone (o-chloranil) yields the annulated oxonin 7.8... 

In an analogous reaction, treatment of 9 (R = Ac, C02Me) with 2,6-diphenyl-l,2,4,5-tetrazine leads to the annulated system 10.15... 

Several dihydrotetrazine materials have been promoted as oxygen scavengers, including 3,6-dimethyl,1-2-dihydro,1,2,4,5-tetrazine, and the diethyl- and diphenyl-derivatives. 3,6-Dimethyl,1-2-dihydro,1,2,4,5-tetrazine is a six-sided ring with a formula H3C-CN2C-CH3NHNH its MW equals 102. Its basic reaction with oxygen is shown here ... 

Among the dienes known as weakly reactive are anthracene (1), metacrolein di-methylhydrazone (2) and 3,6-diphenyl-l,2,4,5-tetrazine (3). DA cycloadditions with these dienes require long reaction times under classical heating conditions (Tab. 7.1). 

Diphenyl-l,2,4,5-tetrazin wird beim Erhitzen mit Salzsaure oder ethanolischer Kalilauge zu 2,5-Diphenyl-J, 3,4-oxadiazol und 3,6-Diphenyl-],4-dihydro-tetrazin umgewandelt558. Fiihrt man diese Reaktion mit Peressigsaure und Natriumacetat bei 50-60 durch, so erhalt man meist ausschliefilich 2,5-Diaryl-l, 3,4-oxadiazole559 ... 

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 ... 

The only report in the literature of the preparation of a tetrazine from a thiourea is that of Naik,270 who claimed to have isolated hexahydro-l,2,4,5-tetraphenyl-l,2,4,5-tetrazine-3,6-dithione (133) on treatment of l,3-diphenyl-2-thiourea with sulfur monochloride in refluxing benzene. Since the only evidence presented for structure 133... 

Pyrrolidinobenzo[6]furan (228) can function as a dienophile and by inverse electron demand it forms the [4 + 2] adduct (291 70%) with 1,4-diphenyl-s-tetrazine. With DMAD a [2 + 2] adduct (292) is formed which is easily converted into the benzoxepin (293) on heating (74RTC321). 

The X-ray crystallographic analysis of 3,6-diphenyl-l,2,4,5-tetrazine (51) was published in 1972 (72AX(B)739). The observed bond distances and angles are in the same range as were found for the parent compound (38 Figure 2). In both cases the heterocyclic ring is planar as expected for a molecule with some degree of electron delocalization. 

Treatment of 3,6-diphenyl-l,2-di(phenylsulfonyl)-l,2-dihydro-l,2,4,5-tetrazine (79) with concentrated sulfuric acid affords 3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine (80) in good yield (79BCJ483). 

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). 

Boiling the 1,3,5-trisubstituted verdazyls (134) for five hours in acetone afforded 1,3-disubstituted 5-amino-1,2,4-triazoles (135, 136) (78KGS1137) and tetrahydro-1,2,4,5-tetrazines (137) (64M457,72CB549) at higher temperatures, besides the triazoles (135,136), 1,3-diphenyl-1,2,4-triazole (138) and aniline were obtained (72CB549). 

No photolyses of hexahydro-1,2,4,5-tetrazines have been published. The kinetics of the photodecomposition of 1,3,5-triphenylverdazyl (61) was studied by Soviet authors in various hydrocarbons. The rate depends on the solvent. The excited radical is consumed by H extraction from the solvent and by dissociation at the N—N bond, forming the product 1,3-diphenyl-l,2,4-triazole (138), which catalyzes the decomposition of the verdazyl radical (74IZV2204). The dipole moment of (61) in the excited state is 9 1 D in the ground state it is 2.94 D. 

The number of 1,2,4,5-tetrazines used in these cycloaddition reactions is limited. The most frequently used are the 3,6-dicarboxylates, the 3,6-diphenyl, 3,6-dimethyl, 3,6-di(2-pyridyl) and bis(perfluoroalkyl) compounds a few others have also been used. The most reactive substances seem to be the 1,2,4,5-tetrazinedicarboxylates, possessing the extra electron-withdrawing effect of the two carboxylate groups. 

The cycloaddition of 3,6-diphenyl-l,2,4,5-tetrazine (51) with 6-dimethylaminofulvene (195) has been studied by Sasaki et al. (75JOC1201) and by Neunhoeffer and Bachmann (79LA675). The Japanese group claim to have isolated 4,7-diphenyl-5,6-diazaazulene (196), produced via a [6 + 4] cycloaddition and dimethylamine elimination, but Neunhoeffer and Bachmann found that the reaction proceeds by a [4 + 2] cycloaddition, then loss of nitrogen and dehydrogenation, to form 5-dimethylaminomethylene-l,4-diphenyl-5//-cyclopenta[ /]pyridazine (197). 

Heating compound (244) for several minutes with copper(II) sulfate in pyridine led to the isolation of 3,6-diphenyl-l,2,4,5-tetrazine (51). The mechanism of this reaction seems to be cyclization of (244) to give the intermediate (245) which eliminates prussic acid, affording the dihydro tetrazine (80), which is oxidized by copper (II) sulfate (60AC(R)277). 

Although Wuyts and Lacourts (36BSB685) have reported the formation of 3,6-diphenyl-1,2,4,5-tetrazine (51) on oxidation of the azine (246), this was later shown by Lutz (B-67MI22101) to be incorrect the isolated 1,2,4,5-tetrazine (51) was formed by oxidation of the dihydrotetrazine (80), an impurity in the starting azine (246). 

Another method for the preparation of the 1,2,4,5-tetrazine system from a diazo compound was reported by Staudinger and Meyer (19HCA619). They reacted diaryldiazomethanes (321) with triethylphosphine and isolated the phosphazines (322). In moist benzene or chloroform these compounds were transformed into 3,3,6,6-tetraaryl-l,2,3,6-tetrahydro-1,2,4,5-tetrazines (323). This result was only obtained when triethylphosphine was used. The intermediate formation of hydrazones seems unlikely, since these compounds are stable and do not dimerize. A reaction which has a certain similarity to the above was reported by Merrill and Shechter (75TL4527). They obtained 3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine (80) when the phosphazine (324) was hydrolyzed. 

When chloride 28a was treated wtih a base in the absence of a suitable dipolarophile, the resulting nitrilimine dimerized to give l,4-diphenyl-3,6-(di-2-thienyl)-l,4-dihydro-l,2,4,5-tetrazine 341 (87JHC1665). Also, tet-razine derivatives 342 were isolated on heating hydrazonoyl bromides 13b in 50% aqueous ethanol (57JOC692). 

In the first step the formation of 5-phenyl-2-TMS-l, 2,3,4,-tetrazole (374) occurs which can either be hydrolyzed to 5-phenyl-l,2,3,4-tetrazole (375) or pyrolysed to give a N-TMS-benzaldehydehydrazonium compound (376). 376 can furthermore either dimerize to form 3,6-diphenyl-l,2,5-bis(TMS)-2,5-dihydro-l,2,4,5-tetrazine (377) and after subsequent hydrolysis and oxidation 3,6-diphenyl-l,2,4,5-tetrazine (3 79) or on the other hand react with a further equivalent 373 yielding in the last step 3,5-diphenyl-l, 2,4-triazole (381)214 (Scheme 55). 

In order to confirm the stmcture of the tricyclic thietane 60, it underwent several reactions <20040L1313>, which were performed on the substituent of the ring carbon atom. The thietane 60 underwent hydrogenation on palladium-on-charcoal to give the fully saturated compound 61. The presence of a double bond in compound 60 was also confirmed by [4+2] Diels-Alder cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate as well as of diphenyl-isobenzofuran, which led to the formation of cycloadducts 62 and 63, respectively (Scheme 10) <20040L1313>. 

The mesoionic 4,5-diphenyl-l,3,4-thiadiazolium-2-thiolate (114) reacts with methyl azodicarboxylate to yield the azothiadiazole (115) and not the tetrazine betaine (116) as previously claimed. Compound (115) can also be prepared from 2-amino-5-phenyl-l,3,4-thiadiazole and nitrosobenzene (71CC837). 

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