1.4- Dihydro-l ,2,4,5-tetrazines

MIP22100). This reaction probably proceeds via the intermediates (289). Similarly, 2-methylmercapto-l,3,4-oxadiazolium salts (291) and hydrazines afford the 1,4-dihydro-l,2,4,5-tetrazin-6(5//)-ones (292) (76CZ496). 

Electrochemical oxidation of hydrazidoyl halides (330) also affords 1,4-dihydro-l,2,4,5-tetrazines (104). A nitrilimine intermediate is not suggested for this reaction. The main process is the dehydrodimerization of the initially formed hydrazonyl radical, while a concurrent side-reaction leads to the 1,4-dihydro-l,2,4,5-tetrazines (104), which are transformed into the corresponding cation radicals (336) on further oxidation (77IZV393, B- 75MI22102). 

The second (3 + 3) fragment method concerns reactions which can be explained as dimerization of nitrile imines 8. Since in most cases R2 is a substituent and not a proton, these reactions give 1,4-disubstituted 1,4-dihydro-l,2,4,5-tetrazines 9 which cannot be transformed into aromatic 1,2,4,5-tetrazines 10. These reactions will not be discussed in detail. 

Thermal or photochemical elimination of nitrogen from tetrazoles 1 affords nitrile imines 8 (see Houben-Weyl, Vol E8d, p774ff) which dimerize to give 1,4-dihydro-l,2,4,5-tetrazines 9 which are oxidized under the reaction conditions to 1,2,4,5-tetrazines 10 (when R2 = H).175-179... 

Unsymmetrically substituted 1,2,4,5-tetrazines 24 were prepared by reaction of a mixture of imidates 19 and amidines 20 with hydrazine204-210 or by reaction of two different amidines 21 and 22 with hydrazine211,212 to give the unsymmetrically substituted 1,4-dihydro-l,2,4,5-tetrazines 23 which were oxidized to 24. 

The 1,2,4,5-tetrazine system is readily reduced to dihydro-1,2,4,5-tetrazines. In particular reduction oft with hydrogen sulfide or sodium dithionite affords l,4-dihydro-l,2,4,5-tetrazines 2 in high yields.154,247 251 1,4-Dihydro-l, 2,4,5-tetrazines 2 are also obtained by treatment of 1 with lithium diisopropylamide252 and by irradiation with UV light in methanol.253... 

C2,HjgBr4N. 3.6-Diphenybi. 4>bis> [4>hrom. phenyi]>1.4-dihydro.l.2.4.5>tetrazin 26II220. 

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). 

Methylthio-1,3,4-thiadiazolium salts (297) were treated with hydrazines in the ratio 1 2 to afford l,4-dihydro-l,2,4,5-tetrazine-6(5//)-thiones (298). In most cases the acyclic intermediate could not be isolated (73CZ565,73CZ566,01CB2311). 

Other methods for the synthesis of l,4-dihydro-l,2,4,5-tetrazines 9 which can be explained by intermediate formation of nitrile imines 8 are the photolysis of 1,2,3-triazoles 2181 and sydnones 3,182 reaction of tetrazoles 4180 with tosyl chloride, elimination of pyridine from the pyridinium compounds 5,189-190 of hydrogen chloride from the hydrazonic acid chlorides 1 s.3-i88 or elimination 0f sulfinate from the a-sulfonyl hydrazone 7.189... 

Hydrazide-hydrazones 1 are cyclized by treatment with orthocarboxylates, imidates, or ami-dines in methanol to give l,4-dihydro-l,2,4,5-tetrazines 2 (see Houben-Weyl, Vol. E8c, p 622), which are oxidized by manganese(IV) oxide, mercury(II) oxide, 1,4-benzoquinonc, or air to afford 1,2,4,5-tetrazines 4 the yield is always below 10%.156 The predominant products of the reactions of 1 arc 1.2,4-triazol-4-amines 3.157... 

A frequently used method for the synthesis of l,4-dihydro-l,2,4,5-tetrazines 17 and, hence, for the preparation of 1,2,4,5-tetrazines 18 is the dimerization of activated hydrazidic acid derivatives, such as hydrazinoyl chlorides 1, thiohydrazides 4, amidrazones 10, selenohydrazides 12, hydrazonic esters 15, hydrazidines 16 or thiohydrazonic esters 13. This corresponds to a synthesis by a (3 + 3) fragment method. 

In most cases these C,N2 fragments are prepared by reaction of activated carboxylic acid derivatives (C, fragment), such as dithiocarboxylates 2, thioesters 3. nitriles 5, imidates 6, amidines 7, thioamides 8, selenoamides 9, selenoesters 11, orthocarboxylates 14, with hydrazine (N2 fragment) and are transformed to l,4-dihydro-l,2,4,5-tetrazines 17 without isolation. Therefore, these syntheses are treated as a (2 + 1 +2+1) fragment method. 

Reaction of l,l-dichloro-2-sulfonylcthcncs with hydrazine in ethanol at reflux affords a mixture of l,4-dihydro-l,2,4,5-tetrazines and l,2,4-triazol-4-amines. l,4-Dihydro-l,2,4,5-tetra-zines are oxidized by hydrogen peroxide to yield 1,2,4,5-tetrazines.214... 

Further reports on 1,4-dihydro-1,2,4,5-tetrazine structures by x-ray diffraction are found for the 3-(p-chlorophenyl)-6-trifluoromethyl derivative <85JHC643>, l,3,6-triphenyl-l,4-dihydro-l,2,4,5-tetrazine <90JCS(Pl)2527>, 6-bromo-l,4-dihydro-l,4-di(o-tolyl)-l,2,4,5-tetrazin-3(27/)-one, and 3,6-dibromo-1,4-dihydro-l,4-bis(p-methoxyphenyl)-1,2,4,5-tetrazine <94AX(C)l78l>. Finally, there are reports on the crystal structures of the heterocyclic betaine l,4-dimethyl-6-oxo-1,2,4,5-tetrazin-l-ium-3-olate (17) <84TL629> and tetramethyl-p-urazine (18), from which cation radicals could be formed <9UOC1045>. 

Kaim reports on the photoelectron spectroscopy and cyclic voltammetry of 1,4-dihydro-1,2,4,5-tetrazine, the parent compound as well as its 1,4-dimethyl- and l,4-bis(trimethylsilyl) derivatives <85JCS(P2)I633>. 

A few typical reactions of l,4-dihydro-l,2,4,5-tetrazines are listed in Scheme 55.1,4-Dihydrotetra-zines (2) are easily oxidized to 1,2,4,5-tetrazines (1) by nitrous acid, nitric acid, oxygen, halogens, iron(III) chloride, hydrogen peroxide, and lead tetraacetate <78HC(33)1077>. In contrast, 1,2,4,5-tetrazines are strong oxidants, as the half wave reduction potentials of Table 4 show. The redox system is quite mobile. 

Treatment of Y -(benzylidene)benzohydrazonoyl chlorides 38 with titanium tetrachloride in chloroform produced symmetrically substituted 3,6-diaryl-l,4-dihydro-l,2,4,5-tetrazines 2 in moderate yields. The authors suggest that cyclocondensation between two molecules of hydrazonoyl chloride takes place first, followed by elimination of two molecules of an aldehyde during hydrolytic workup. Oxidation of the dihydrotetrazines 2 with nitrous acid afforded the fully conjugated tetrazines 1 in 32-56% yields (Scheme 8) <2000MI37>. 

Dihydro-l,2.4.5-tetrazin-dioarbon= saure-(3.6)-bis-methylamid 26, 666. 1-Athyl-l. 8-dihydTO-1.2.4.5-tetrazin-dicar> bonsauTe-(3.6)-diamid 26, 687. 

The partial inhibition of the hydrolysis observed at pH < 4, and the negative salt effect, may be attributed to a specific cation-anion interaction. The proposed mechanism receives further support from the observed effects on the hydrolysis rates of increased viscosity of the medium and of added inorganic nucleophiles. Hydrazine or alkylhydrazines cleave and recyclize 1,3,4-thiadiazolium salts (114) to 1,2- or l,4-dihydro-l,2,4,5-tetrazines (115) in high yield. The action of arylhydrazine results in the alternative recyclization of the probable intermediate ArNHN=CR2NR N=CR SH, to 4-amino-1,2,4-triazolium salts (116). 5-Amino-2-imino-3-phenacyl-l,3,4-thiadiazolines (117) isomerize in boiling ethanol to 5-amino-3-mercapto-l-phenacyl-l,2,4-triazoles (118). This example... 

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). 

Cyclization of the disubstituted hydrazidines (264) with phosgene and carbon disulfide was used to prepare dihydro-l,2,4,5-tetrazin-6-ones (265) (76CZ496) and dihydro-1,2,4,5-tetrazine-6-thiones (266) respectively (73CZ565). 

Treatment of verdazyls (48) with mineral acids resulted in disproportionation to 1,2,3,4-tetrahydro-l,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//)-thione (77) in 2N hydrochloric acid led to the isolation of 3-phenyl-l,2,4-triazole-5-thione (78) (77KGS1564). 

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