1.2.4.5- Tetrazine ring

Acid-catalyzed 1,2,4,5-tetrazine ring contraction of the pyrimido[l,2-h]l,2,4,5-tetrazines 116 led to the formation of the 8-amino-l,2,4-tria-... 

Another class of 1,2,4,5-tetrazine compounds which is well known and intensively studied is the stable radicals verdazyls (48), also called 1,2,4,5-tetrazin-1 (2H)-yls. Benzo derivatives of the 1,2,4,5-tetrazine system are not possible since in all cases the second ring has to be condensed to the 1,2,4,5-tetrazine ring either by two nitrogen atoms as in (49), or by one carbon and one nitrogen atom as in (50). 

Van der Waals complexes between 1,2,4,5-tetrazine (38) and a number of light gases (He, Ar, H2) were observed and characterized by laser spectroscopic studies of free supersonic expansion of (38) in the carrier gas. The observed complexes are of the form X (38) or X2- (38), where X is He, Ar or H2. The spectra are consistent with the gas in both types of complexes being bound on or near the out of plane C2 axis on top of and/or below the 1,2,4,5-tetrazine ring. For the He and H2 complexes, analysis of the rotational structure indicates that the van der Waals bond length is 3.3 A (78JCP(68)2487,79JCP(7l)4757). 

Substituents bound to the 1,2,4,5-tetrazine ring behave very much as expected. Heterosubstituents can be exchanged by nucleophilic substitution as is shown in Scheme... 

Only for compound lj a very slight, but significant deviation from planarity toward a boat conformation was reported for the 1,2,4,5-tetrazine ring.24... 

The experimental bond lengths and the angles in the 1,2,4,5-tetrazine ring of la and lc-lk are given in the table below. 

Apparently, no alkylation, arylation, acylation or /V-amination of a heteroaromatic 1,2,4,5-tetrazine ring has been reported so far, but alkylation or acylation of substituents bound to the 1,2,4,5-tetrazine ring are known (see Section 5.1.4.6.). Treatment of 1,2,4,5-tetrazines with acids affords ring-opened products in the presence of water or alcohols a protonated 1,2,4,5-tetrazinium salt may be an intermediate in this reaction. 

Three methods have been reported for the introduction of hydrogen into the 1,2,4,5-tetrazine ring reduction of 3-halo-l,2,4,5-tetrazines l,152 oxidation of 1,2,4,5-tetrazine-3-hydrazines 3 2i9,225,242 an(j decarboxylation of 1,2,4,5-tetrazine-3-carboxylic acids 5.235 240... 

Exchange of leaving groups bound to the 1,2,4,5-tetrazine ring by nucleophiles is a well-known and often used reaction in 1,2,4,5-tetrazine chemistry. All types of reactions known from other azabenzene systems have also been observed with 1,2,4,5-tetrazines. Most reported exchange reactions and modifications of substituents are illustrated and compiled with references. In case where R1 is also a leaving group, one or both substituents can be replaced by a nucleophile. 

Most 1,2,4,5-tetrazines are unstable to acids as well as to bases and nucleophiles. In most cases the 1,2,4,5-tetrazine ring is opened, but in a number of cases the opened product can cyclize to another heterocyclic system. 

In addition to intermolecular cycloaddition reactions of 1,2,4,5-tetrazines with various dienophiles, intramolecular cycloaddition reactions with alkene367 and acetylene 360 367 dienophiles or nitrile groups355-356 have also been reported. By this method condensed pyrid-azines 15 or 1,2,4-triazines 16 (see Section B.2.2.1.3.) are obtained. In most cases the side chain is bound to the 1,2,4,5-tetrazine ring by a heteroatom (O, S or In ). In a few cases the side chain is bound by a carbon atom or contains an additional heteroatom. The general reaction scheme is shown. 

Reports describing 1,2,4,5-tetrazine ring contractions are scarce. However, photochemically induced ring contraction of 3,6-diphenyl-l,2-dihydro-l,2,4,5-tetrazine 363 into triazole 364 has been reported in the presence of hydrochloric acid <2000JPR281>. Similarly, thermal rearrangement of 3,6-bis(trifluoromethyl)-l,2-dihydro-l,2,4,5-tetrazine 365 in acetic acid afforded 1,2,4-triazoles 366 and 367 (Scheme 89) <1995JFC(72)95>. 

There has been considerable interest in the study of the reactivity and properties of various tetrazine derivatives. The 1,2,4,5-tetrazine ring system is electroactive and has a high electron affinity. Tetrazines possess high positive heats of formation and large crystal densities—properties important in energetic materials appfications. Additionally, they seem to be insensitive to destructive stimuli such as friction, impact, and electrostatic discharge. 

N. Haider and R. Wanko [41] developed a method for the synthesis of pyridazino[4,5-b]indoles omitting the intermediate stage of oxo derivative production (Scheme 13). The target heteroc cle (124) was formed as a result of attachment of indole pyrrole ring(121) as in the case of dienophile to azadiene - to 1,2,4,5-tetrazine ring of compound 122. The reaction is carried out in one stage without the adduct 123. 

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