Tetrazine heterocycles

A particularly interesting system where nitrogen is lost cheletropically after formation of the initial [4 + 2] cycloadduct involves the thermal reaction of azirines with tetrazines (82) (74CC45, 74TL2303, 74CC782, 75JHC183). A variety of heterocyclic products are produced depending on the structure of the azirine and tetrazine used and the reaction conditions. 

Certain trifluoromethyl-substituted 1,2,4,5 tetrazines [260, 26i] and 1,2,4 triazines [i06] can be used as cyclic hetero-1,3-dienes and provide efficient preparative routes to partially fluorinated heterocycles (equations 55 and 56)... 

Interestingly, in the inverse-electron-demand Diels-Alder reactions of oxepin with various enophiles such as cyclopentadienones and tetrazines the oxepin form, rather than the benzene oxide, undergoes the cycloaddition.234 236 Usually, the central C-C double bond acts as dienophile. Oxepin reacts with 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dienone to give the cycloadduct 6 across the 4,5-C-C double bond of the heterocycle.234 The adduct resists thermal carbon monoxide elimination but undergoes cycloreversion to oxepin and the cyclopenta-dienone.234... 

A new class of heterocyclic compounds, the 1,2,3,4-tetrazine-l,3-dioxides (6.62) was found by Churakov et al. (1990) on diazotization of 2-tert-butylazoxyaniline followed by oxidation with 3-chlorobenzoic peracid (Scheme 6-42). 

Another type of special diene, the polyaza benzene heterocyclics, such as triazines and tetrazines, is discussed in Section 6.6.2. 

Bertinotti, F., G. Giacomello, and A. M. Liquori. 1956. The Structure of Heterocyclic Compounds Containing Nitrogen. I. Crystal and Molecular Structure of s-Tetrazine. Acta Cryst. 9, 510. 

Refluxing a mixture of hydrazonoyl halides 13 and heterocyclic thiones 14 in ethanol in the presence of triethylamine resulted in the formation of 3-arylazo-l,4-dihydro-l,7-disubstituted-pyrimido[l,2,-3]-l,2,4,5-tetrazin-6-ones 8. The reaction starts with the initial formation of the hydrazidine derivatives 15, which in turn undergo cyclization with the elimination of thiolate to give the desired product 8 (Scheme 1)<2004JCM399>. 

Many of these heterocyclic systems are of biological importance but detailed information regarding their biological activities is still lacking. Pyrimido[l,2- ]-l,2,4,5-tetrazin-6-ones 21 have been identified as potent inhibitors of the... 

The unusual reaction of cyanoacetic acid esters with s-triazine monoazides afforded derivatives of a novel coupled heterocyclic system 2-[l,3,5]triazin-2-yl-l,2-dihydro[l,2,3,4]tetrazine-5-carboxylic acid esters <06CHE965>. 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

Pagoria and co-workers synthesized a number of thermally stable explosives from the reaction of the sodium salt of ANTA with chloro-substituted arylenes and A-heterocycles. These include the synthesis of (117) from picryl ehloride, PRAN (118) from 2-chloro-3,5-dinitropyridine, IHNX (119) from 2,4-dichloro-5-nitropyrimidine, (120) from 1,5-dichloro-2,4-dinitrobenzene, and (121) from 4-chloro-6-(3-nitro-l,2,4-triazolyl)-5-nitropyrimidine. Coburn and co-workers " reported the synthesis of the tetrazine (122) and the triazine (123) from the reaction of the sodium salt of ANTA with 3,6-dichlorotetrazine and cyanuric chloride respectively. 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

The pyrido[2,3- ]- and pyrido[3,4-< ]-l,2,3.4-tetrazines 9-11 constitute a new class of heterocycle to add those reported in CHEC-II(1996) <1996CHEC-II(7)785> and their H and C NMR assignments are therefore worthy of inclusion here and are shown in Table 5 <2004RCB2577>. 

Van der Waals complexes of C2v symmetry between 1,2,4,5-tetrazine and a number of light gases (He, Ar, H2) have been observed and characterized by laser spectroscopic studies of free supersonic jet expansion of the tetrazine in the carrier gas (84CHEC-(3)53l). In these complexes, one equivalent of noble gas sits on top of the aromatic TT-system of the heterocycle. 1,2,4,5-Tetrazine, its 3-methyl, and 3,6-dimethyl derivative as well as aminotetrazine have all been used as heterocycles with noble gases, water, HC1, benzene, and acetylene, playing the role of the second partner. 

Of all the aza-heterocycles, pyridine possesses the least electron deficiency. Because of this, pyridine itself does not form a a-complex in liquid ammonia and cannot be aminated under these conditions. By the contrast, highly ir-deficient polyaza-heterocycles (diazines, triazines, tetrazines, pteridines, etc.) undergo oxidative amination, sometimes even by liquid ammonia itself. Sodamide converts 4-methylpyrimidine successively into the 2-mono- and 2,6-di-amino derivatives, and pyrazine gives... 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

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. 

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