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

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 ... 

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. 

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). 

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). 

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). 

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... 

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]. 

In a similar approach, (3,6-diphenyl-l,2,4,5-tetrazin-l-ium-l-yl)(propyl)amide 43 was obtained in a one-pot reaction by treatment of Y -(chloro(phenyl)methylene)benzohydrazonoyl chloride 39 with 1 equiv of sodium azide under phase-transfer conditions, followed by addition of 1 equiv of 1-propanethiol and triethylamine (Scheme 9) <2000JA2087>. 

Long reaction times, which are usually required in [4-1-2] cycloadditions of 1,2,4,5-tetrazines to various alkenes under classical heating, were shortened drastically by microwave-assisted reactions supported on graphite. In contrast to conventional conditions, microwave-assisted cycloadditions of 3,6-diphenyl-l,2,4,5-tetrazine 23 furnished fully conjugated pyridazines 212 (Scheme 54) <1996LA739>. 

Cycloaddition of 3,6-diphenyl-l,2,4,5-tetrazine 23 to the enolate of 281 produced molecular clefts 283 (Scheme 69) <1996T13531>. 

Sol 16. (i) 3,6-Diphenyl-l,2,4,5-tetrazine (I) undergoes Diels—Alder reaction with acrylonitrile to give a bicyclic product (II), which undergoes retro Diels—Alder reaction generating a 4,5-dihydropyridazine (III), which on tautomerization gives a 1,4-dihydropyridazine (IV). 

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