1,2,4,5-Tetrazine ring synthesis

Because of the clinical application of temozolomide 9a, the synthesis of a nC derivative 41 labeled at position 1 (i.e., the carbonyl carbon atom in the tetrazine ring) of these compounds has also been published (Scheme 13). 

Synthesis of derivatives (36) of the [l,2,4]triazolo[l,5-c][l,2,3,5]tetrazine ring system was accomplished by treatment of the 7V-hydrazino[l,2,4]triazolethione compound (35) with isocyanates <88MI 821-01 >. 

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. 

There is only one reported synthesis of a bcnzannulated 1,2,4-triazocine system. 2-Phenylbenz-azete (1), which can be generated from 4-phenyl-l,2,3-benzotriazine by pyrolysis, is reacted with tetrazine 2 to give a [4 + 2] adduct, which loses nitrogen and finally results in the eight-membered-ring derivative after valence isomerization.2... 

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>. 

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. 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

The only ring system with a 0 3 nitrogen atom arrangement that has been studied in the past period is pyrrolo[2,l- /] [l,2,3,5]tetrazine, which was not synthesized earlier. The first synthesis was presented by Cirrincione et al. in two successive publications <1999S2082, 2003BMC2371>. The results are depicted in Scheme 36. 

In the course of studies on the synthesis of [l,2,4]triazolo[3,4-A][l,2,4,5]tetrazines, Kotschy et al. investigated the alkylation of the morpholino derivative 13 of this ring system <2000ARK259>. It has been found that ethylation carried out with triethyloxonium tetrafluoroborate took place exclusively on the five-membered ring and yielded a mixture of 1-ethyl 14 and 2-ethyl 15 quaternary salts. 

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. 

Elimination of nitrogen from Diels-Alder adducts of certain heteroaromatic rings has been useful in the synthesis of substituted aromatic compounds.224 Pyridazines, triazines, and tetrazines react with electron-rich dienophiles in inverse-electron-demand cycloadditions. The adducts then rearomatize with loss of nitrogen and the dienophile substituent.225... 

Two complementary routes to the synthesis of pyrido[, y-i/ pyridazines have been developed, the first of which begins by constructing the pyridine ring, and the second by constmcting the pyridazine ring. In addition, ring transformations of pyrrolopyridine, pyridooxazine, pyridopyrimidine, and tetrazine derivatives to the pyrido[x,y-t7 pyridazines have also been reported. 

Synthesis and ring-chain tautomerism of hexahydro-1,2,4,5-tetrazine-3-thiones 93KGS991. 

The synthesis and characterization of a new 6-phosphoverdazyl radical incorporated into a spirocyclic framework containing a cyclotriphosphazane ring has been reported <02CJC1501>. Verdazyl-3-carboxylic acid (35) was prepared by condensation of carbonic acid bis(l-methylhydrazide) (33) with glyoxylic acid, to give tetrazine (34), and subsequent oxidation with benzoquinone. The coordination chemistry of this water-soluble verdazyl derivative was explored <02CC1688>. 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

The synthesis of pyrano[3,4-Z>]pyrroles was achieved utilizing a zinc-mediated ring contraction of pyridazines 07EJ03296 07SL403>. The pyridazines were formed by the cycloaddition of alkynes with tetrazines. 

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