1.2.4.5- Tetrazine ring, 1,4-dihydro

Dissolving 3-aryl(alkyl)-1,2,4,5-tetrazines (21) in liquid ammonia or primary aliphatic amines at — 35°C to — 40°C, followed by addition of potassium permanganate, gives 6-alkylamino-3-aryl-(alkyl)-1,2,4,5-tetrazines (23) in reasonable to excellent yields. This shows that, under the reaction conditions, addition of A-nucleophiles to the tetrazine ring must have occurred (Scheme 1) <8 JHC123>. The presumption of a 1,6-dihydro intermediate (22) rests on the experimental result that tetrazines can be transformed by sodium borohydride into the isolable 1,6-dihydro-1,2,4,5-tetrazines, which can be considered as neutral homoaromatic systems <8UOC2i38>. 

On the other hand, in dipropyl 3,6-diphenyl-l,2-dihydro-l,2,4,5-tetrazine-l,2-dicarboxylate <2003AXEo281> and diphenyl 3,6-bis(4-chlorophenyl)-l,2-dihydro-l,2,4,5-tetrazine-l,2-dicarboxylate <2005AXEol552>, the central tetrazine ring adopts a twist conformation, while in 3,6-bis( -chlorophenyl)-l,4-bis(/>-tolylsulfonyl)-l,4-dihydro-l,2,4,5-tetrazine the tetrazine ring is essentially planar <2005AXEo3152>. 

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>. 

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 ... 

For the synthetic studies on the bicyclic 6-6 systems 1-3, with one ring junction nitrogen and five extra heteroatoms, refer to CHEC-II(1996) <1996CHEC-II(8)743>. In the studies of the newly available compounds, a one-pot procedure for the synthesis of [l,2,4]triazino-[4,3- ][l,2,4,5]tetrazine 4 derivatives is discussed below. Refluxing of hydrazonoyl halides 10 in chloroform (or ethanol) in the presence of triethylamine for 6h with either 4-amino-2,3-dihydro-6-substituted-3-thioxo-[l,2,4]triazin-5(4//)-ones 8 or 4-amino-3-methylthio-6-substituted-[l,2,4]-triazin-5(4//)-ones 9 yielded compounds 4 (Equation 1) <2000JPR342>. 

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. 

Oxidation of 1,2-bishydrazones (494) is now known to give triazoles (495) and not dihydro-1,2,3,4-tetrazines. Possibly the latter are intermediates but are aromatized by ring contraction. 

The five-membered ring systems can also behave as electron-rich dienophiles in [n4 + 2] reactions. Indole and 1,2,4,5-tetrazines yield indolopyridazines (262) via [ 4 + 2] cycloaddition followed by extrusion of nitrogen and aromatization, whilst the dihydro adduct,... 

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). 

Cyclic enol ethers give first the intermediate bicyclic dihydro-pyridazine adducts that isomerize by ring cleavage to pyridazines with hydroxyalkyl or alkoxyalkyl substituents. Several other alkenes were also used in the reaction with tetrazines to give pyridazines. ... 

Much more is known about tetrahydro-l,2,4-tetrazines which can form tautomeric structures with more than one double bond in the ring. These include the tetrahydro-oxo(thioxo)-1,2,4-triazines and tetrahydro-dioxo(thioxo)-l,2,4-triazines, which, in the absence of a principal group of higher priority, are more usually named as dihydro-1,2,4-triazinones and dihydro-1,2,4-tri-azinethiones. Still better known are the tetrahydro-dioxo-l,2,4-triazines and their mono- and di-thiooxo analogues, because the 3,5-isomers [l,2,4-triazine-3,5(2//,4//)-diones, 1,2,4-triazine-3,5(2/7,4//)-dithiones, and dihydro-3/5-thioxo-l,2,4-triazin-5/3-ones] are aza-uracil derivatives. 

The fully conjugated tetrazine nucleus in principle cannot undergo rearrangement reactions. Ring transformations of dihydro, tetrahydro, and hexahydro 1,2,4,5-tetrazines under acidic and basic conditions (partial hydrolysis) are well known and were competently and extensively treated by NeunhoefiFer <84CHEC-I(3)53i>. Short surveys can be found in Sections 6.21.6 and 6.21.9. No new aspects seem to be worthy of discussion here. 

In Neunhoeffer s contribution to CHEC-I a detailed and very competent discussion is found of the synthesis of the tetrazine system <84CHEC-I(3)531>. All principal synthetic ways are described there, and no new method has been published in the meantime, especially for the fully conjugated system. Therefore the discussion in this contribution is limited to Scheme 57, which summarizes the most successful ways to the heterocyclic ring system via the dihydro compounds. 

The formation of the tetrazine is interpreted in terms of an initial [3 -I- 2] cycloaddition leading to unstable spiro compounds. Ring opening of the dihydro-1,2,3-triazole ring generates the zwitterions... 

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