1,2,4,5-Tetrazine, 3,6-diphenyl-, reaction

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). 

Different results were reported for the photolysis of dihydro-1,2,4,5-tetrazines. 3,6-Diphenyl-l,4-dihydro-l,2,4,5-tetrazine (80) afforded 3,5-diphenyl-l,2,4-triazole (124) on photolysis (70T2619,69JOC199), while the 3,6-dimethyl-1,6-dihydro compound (125) yielded acetaldehyde azine (126) and nitrogen on photolysis, as in the thermolysis reaction (72HCA1404). 

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). 

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. 

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>. 

Diphenyl-l,2,4,5-tetrazine on heating with hydrochloric acid yields 2,5-diphenyl-l,3,4-oxadiazole together with dihydrotetra-zine.111 This long-established reaction when carried out in the presence of peracetic acid and sodium acetate at 50-60° leads almost exclusively to the oxadiazole.112... 

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. 

Diaryl-l,2,4,5-tetrazines, when treated with bulky amides such as lithium di-isopropylamide, undergo two competing reactions. In the first, tetrazine is reduced with concomitant formation of an imine from the amide. The imine is then attacked further by amide to give a pyridazine. For example, 3,6-diphenyl-l,2,4,5-tetrazine is converted with lithium diethylamide into 3,6-diphenylpyridazine in low yield. With lithium di-isopropylamide, 4-methyl-3,6-diphenylpyridazine is obtained in moderate yield [83JCS(P1)1601]. 

When l,8-bis(dimethylamino)-4-vinylnaphthalene (121) is heated with 3,6-diphenyl-s-tetrazine (DFT), a [4 + 2]-cycloaddition reaction with reverse electron demands takes place to give the 1,4-dihydropyridazine derivative 208 (Scheme 37). The latter could be oxidized with chloranil or with excess of DFT to pyridazine 209118. A similar reaction with acenaphthylene proton sponge 107 gives directly the annelated pyridazine 139, since the intermediate dihydropyridazine is readily oxidized in air. It was established that the reactivity ratio of compounds 107, 121, 5-dimethylaminoacenaphthylene and acenaphthylene in the reaction with DFT is equal to 32 17 14 1, respectively. These data are in... 

Under anhydrous conditions 3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine isomerizes to the 4-amino-1,2,4-triazole derivative (326). Hydrolysis under the influence of acids or bases transforms the 1,4-dihydro-1,2,4,5-tetrazine system to diacylhydrazines (329), carboxylic acids (330), and hydrazine, 1,3,4-oxadiazoles (328), or 1,2,4-triazoles (327) depending on the reaction conditions <78HC(33)1077>. 

The azaphilic addition of organometallic reagents on 1,2,4,5-tetrazines has been studied. Depending on the nature of the metal, azaphilic addition, reduction of the tetrazine or simple complex formation, was the predominant transformation and usually high selectivity was observed <04T1991>. Reaction of 3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine with isobutyric anhydride yielded l-isobutyryl-3,6-diphenyl-l,4-dihydro-l,2,4,5-tetrazine and its structure was elucidated by X-ray analysis <04JCR(S)408>. 

Irradiation of 5-phenyltetrazole (73) at 254 nm resulted in evolution of one molecule of N2 and the formation of compound 74 along with lesser yields of the other products indicated in Eq. (I).135,136 Further photodecomposition of compound 74 was the origin of the benzonitrile and the 3,5-diphenyl-1,2,4-triazole in the mixture.133,136 The reaction is considered to involve loss of N2 from the 3- and 4-positions of the ring38 137 to yield a nitrilimine intermediate, Ph-C=N+—NH-, which dimerizes to the dihydrotetrazine 74, some of which is subsequently oxidized to the tetrazine form. 

Regitz and Maas (1986, Table 14.5) give 23 further examples of diazomethyl alkylation with aldehydes and ketones. A potential difficulty may be the dimerization of diazocarbonyl and related compounds in the presence of alkali hydroxides, by which l,4-dihydro-l,2,4,5-tetrazines are formed (see the discussion in Sect. 9.2). We know, however, of only one case in which this reaction interfered (Disterdorf and Regitz, 1976 diazomethyl(diphenyl)phosphine oxide, (H5C6)2P(0) —CH=N2). 

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