Tetrahydro-1,2,4,5-tetrazines

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). 

Dihydro-1,2,4,5-tetrazines (41) can be reduced by hydrogen sulfide to tetrahydro-1,2,4,5-tetrazines (44) (72HCA1404), while with zinc in acetic acid, sodium in ethanol or diimide they afford 1,2,4-triazoles (118 Scheme 7) (78HC(33)1075, p. 1154). 

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). 

Another method for the preparation of tetrahydro-1,2,4,5-tetrazines is by the cyclization of formazans (248) with an aldehyde in the presence of acid to yield the verdazylium cation (252), which is reduced under basic conditions to give the verdazyl (253) and further to the tetrahydro-1,2,4,5-tetrazines (254) <78HC(33)1075, p. 1174, 74T2841, 80CB2049, 78KGS991, 78KGS1137). 

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. 

Dimethylcarbodihydrazide (280) reacts with aldehydes to afford 1,5-dimethyltetrahydro-l,2,4,5-tetrazin-6-ones (281), which can be oxidized by silver oxide, potassium ferricyanide or lead dioxide to yield radicals (282) related to the verdazyls these can be transformed into tetrahydro-1,2,4,5-tetrazines (283) by hydrogenation over palladium (80AG766). 

Reaction of azines 6 with hydrazine affords, together with other products, tetrahydro-1,2,4,5-tetrazines 7 in low yield (6-14%) which can be oxidized with sodium nitrite in acetic acid to give (trifluoromethyl)-l,2,4,5-tetrazines 8.169... 

In addition to the aromatic tetrazine system (1), dihydro-1,2,4,5-tetrazines, tetrahydro-1,2,4,5-tetrazines, and hexahydro-1,2,4,5-tetrazines are known. In almost all the cases which have been studied by x-ray diffraction the dihydro derivatives are best described as 1,4-dihydro isomers (2) structures such as 1,2- and 1,6-dihydro isomers, (3) and (4) respectively, are very rare. Tetrahydro and hexahydro tetrazines, such as (5) and (6), are also known. 

Chloroformy hydrazones (18) react with hydrazines to yield tetrahydro-1,2,4,5-tetrazin-3(2 -ones (19). Oxidation of the products (R= H) with lead dioxide gives stable tetrazinyl radicals as purple, high melting (> 140 C) crystalline solids [94JHC319],... 

Nitrohistidine, N-60028 Schmitz s compound, in D-80044 Tetrahydro-1,2,4,5-tetrazine-3,6-dione 1,5-Di-Ac, in T-70097... 

A new electrofluorescent switch was prepared with an electroactive fluorescent tetrazine blend of polymer electrolyte <06CC3612>. The structure and magnetic properties of the stable oxoverdazyl free radical 6-(4-acetamidophenyl)-1,4,5,6-tetrahydro-2,4-dimethyl-... 

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 stereoselective normal electron demand Diels-Alder reaction of chiral 13-diaza-13-butadienes 42, derived from acyclic carbohydrates, with diethyl azodicarboxylate 2 yields the corresponding functionalized l,23,6-tetrahydro-133,4-tetrazines 43. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1 3 - Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation <99JOC6297>. 

Arylidene-33-diethyl-3,4,6,7-tetrahydro-2//-thiazolo[3,2-/j][l, 4 ]-tetrazin-6-ones 53 have been synthesized in a single step by the condensation of tetrahydro-l, 4 -tetrazin-3-thione 52 with ethyl chloioacetate and aldehydes in the presence of pyridine and piperidine. Condensation of 53 with hydrazine afforded fused derivatives 54 <98IJC(B)819>. 

Cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 321 with l-methyl(acetyl)-l,2,5,6-tetrahydro-4-pyrrolidinopyridine 322 led to the formation of A -methyl(acetyl)pyridopyridazine 323 (Equation 26) <1994H(38)1845>. 

Di amino-sym-tetrazine (called 3.6-Diamr no-l 2 4.5-tetrazin or 3 6TDiimino-1.2.3 6T tetrahydro-l 2.4.5-tetrazin in Ger),... 

However, in many other series results have been obtained that are compatible with those from other methods and that gave the dipole-moment method an appearance of general reliability now known to be unjustified. Such compatible results include spiropiperidines (Section III,A,4), tropanes (Section III,B,4), 2-alkyltetrahydro-l,2-oxazines (Section III,C,2), perhydro-pyrido[l,2-c][l,3]oxazines (Section III,D,IX perhydropyrido[l,2-c][l,3]thi-azines (Section III,D,2), dialkylhexahydropyrimidines and perhydropyrido-[l,2-c]pyrimidines (Section III,D,3), 5-alkyldihydro-l,3,5-dithiazines (Section III,G,3), 3,5-dialkyltetrahydro-l,3,5-thiadiazines (Section III,G,4) and, in part, l,2,4,5-tetraalkylhexahydro-l,2,4,5-tetrazines (Section III,H,4) as well as piperidines, tetrahydro-l,3-oxazines, and tetrahydro-l,3-thiazines containing an N-H group. 

The antisymmetric structure 494 has been proposed for the (V,7V-diacetyl-2,5-dimethyltetrazine.377,378 High energy barriers (Table XXXI) have been found for a variety of l,2,3,4-tetrahydro-l,2,4,5-tetrazines (495).379... 

Fibinger (72JA8497). They isolated l,4-dimethyl-l,4,5,6-tetrahydro-l,2,3,4-tetrazine (4) in less than 5% yield from the oxidation of N1, 1 -dimethyl-1,2-dihydrazinoethane (3) with sodium hypochlorite in the presence of sodium hydroxide. 

In the following years further l,4,5,6-tetrahydro-l,2,3,4-tetrazines, their 2-oxides (5) and 2,3,4,5-tetrahydro-l,2,3,4-tetrazines (7) have been prepared. 

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-... 

UV, NMR and mass spectra of most of the known tetrahydro-l,2,3,4-tetrazines have been published. 

So far there are only four known methods for preparing tetrahydro-l,2,3,4-tetrazines. The method which gives the best yields of the 1,4,5,6-tetrahydro compounds is that from a-lithiated iV-alkylnitrosamines (19). These compounds decompose at -73 °C to yield the 1,4,5,6-tetrahydrotetrazine 2-oxides (5) which can be reduced by trimethyl phosphite or lithium aluminum hydride to the l,4(5,6-tetrahydro-l,2,3,4-tetrazines (11) (73AG504, 74GEP2327545, 78HCA1622). 

Tetrahydro-l,2,3,4-tetrazines (23) are made by cycloaddition of electron-deficient azo compounds to vinylazo compounds (79AG757). 

Dihydro-, tetrahydro- and hexahydro-1,2,4,5-tetrazines are less coloured than the aromatic 1,2,4,5-tetrazines. In most cases these substances are yellow, yellow-orange or colourless. Most dihydro-1,2,4,5-tetrazines have two absorption maxima but their positions depend on the substituents on the ring, and on the pattern of hydrogenation. Bands in the visible (ca. 430 nm e 400-600) are found with the 1,6-dihydro compounds (42) 1,4-dihydrotetrazines (41) absorb at somewhat shorter wavelength (ca. 300 nm, e 100) in ethanol (72HCA1404). 

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