Tetrazines 1,5-disubstituted

The hetaryl displacement in 3,6-disubstituted 1,2,4,5-tetrazines with anhydro bases of N-methylquinaldiniums has been described <06MI99>. 

Earlier attempts to oxidize 3,6-disubstituted 1,2,4,5-tetrazines with peroxycarboxylic acids did not give the expected 1,2,4,5-tetrazine A-oxides, but 2,5-disubstituted 1,3,4-oxadiazoles (see Houben-Weyl, Vol. E8c, p 596).245 246... 

The prediction that electron-withdrawing substituents in tetrazines accelerate, and electron donors decrease the reaction rate was demonstrated by p values of + 1.24 and -1-2.51 for the combination of 3,6-disubstituted 1,2,4,5-tetrazines with styrene and a-methylstyrene respectively <80Mi 62i-oi> and was also confirmed using cyclooctyne as dienophile <83TL1481> for a number of nitrogen... 

Compounds 875 belonging to this class of C-nucleosides were synthesized by Diels-Alder cycloaddition with inverse electron demand of 3,6-disubstituted 1,2,4,5-tetrazines containing a highly reactive diazadiene system and /if-D-ribofuranosylacetylenes (305) (94AP365) (Scheme 248). 

Inverse electron demand cycloaddition of 1,2,4,5-tetrazine with alkenes and alkynes. Inverse electron demand Diels-Alder addition has also been employed for the synthesis of pyridazines and condensed pyridazines. The reaction of olefinic and acetylenic compounds with 3,6-disubstituted 1,2,4,5-tetrazines 142 to yield substituted pyridazines 144 by the intermediacy of 143 was first reported by Carboni and Lindsey (1959JA4342). Analogous reaction of 142 with a variety of aldehydes and ketones 145 in base at room temperature proceeded smoothly to yield the corresponding pyridazines 144. Compounds 146-148 are proposed nonisolable intermediates (1979JOC629 Scheme 26). 

Regarding the series of hetero aromatic pentacyclic compounds with three heteroatoms, an accelerated synthesis of 3,5-disubstituted 4-amino-1,2,4-triazoles 66 under microwave irradiation has been reported by thermic rearrangement of dihydro-1,2,4,5 tetrazine 65 (Scheme 22). This product was obtained by reaction of aromatic nitriles with hydrazine under microwave irradiation [53]. The main limitation of the method is that exclusively symmetrically 3,5-disubstituted (aromatic) triazoles can be obtained. 

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>. 

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

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. 

Only those compounds which do not have tautomeric aromatic triazole structures will be considered here, the others having been treated as triazoles. The triazolines are unstable and have been subjected to little study. Compounds which are disubstituted at the C(3) or C(5) atom are more stable than the mono- or unsubstituted analogues. The equilibrium has been observed by NMR spectroscopy between the six-membered tetrazine (75) and the triazolinethione (76) via the open-chain form, thus mirroring monosaccharide equilibria (Scheme 12) <90TL3927>. 

Predictably, treatment of the methiodides (495) with 1,1-disubstituted hydrazines (R R N.NH2) gives the meso-ionic l,2,4-triazole-3-thiones (496). An interesting variation is observed when the iodides (495) are treated with monosubstituted hydrazines (R NH.NHj). In this case the product is a tetrazine (497). ... 

Treatment of 3-hydrazino-l,2,4,5-tetrazine (47), obtained following the pathway shown below, with diethoxy methyl acetate yields the unknown parent ting system 1,2,4-triazolo [4,3-b][l,2,4,5]tetrazine (48), some 3,6-disubstituted derivatives being also described <98JHC1329>. 

Sodium borohydride reduction of 4,6-disubstituted 1,2,3-triazines in methanol afforded 2,5-dihydro-1,2,3-triazines (329) in good yields. 1,2,4,5-Tetrazines with mild reducing agents give dihydro derivatives. 

Basic hydrolysis of 1,4-disubstituted l,4-dihydro-l,2,4,5-tetrazines (87) resulted in the formation of 2,4-disubstituted 3-imino-1,2,4-triazoles (88) (78HC(33)1075, p. 1152), and aqueous base converted 3,6-disubstituted dihydro-1,2,4,5-tetrazines (89) into 3,5-disub-stituted 1,2,4-triazoles (90) (56JCS2253). 

The formation of 1,2,4,5-tetrazine Af-oxides (102) by oxidation of 1,2,4,5-tetrazines (39) has not yet been reported. Oxidation with peracetic acid resulted in the formation of 2,5-disubstituted 1,3,4-oxadiazoles (103) (62JOC1463, 73JCS(Pi)335). 

Thermolysis of 3,6-diphenyl-l,4-di(phenylsulfonyl)-l,4-dihydro-l,2,4,5-tetrazine (127) in boiling toluene gives benzenesulfonic anhydride (128), phenyl benzenethiosulfonate (129), small amounts of diphenyl disulfide (130), 3,6-diphenyl-l,2,4,5-tetrazine (51) and a rearrangement product, 3,6-diphenyl-l,2-di(phenylsulfonyl)-l,2-dihydro-l,2,4,5-tetrazine (79) (79BCJ483). 3,6-Disubstituted hexahydro-1,2,4,5-tetrazines (132) afforded aldehyde hydrazones (133) when heated at their melting point (63AG1204). 

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). 

Cyclization of the disubstituted hydrazidines (264) with phosgene and carbon disulfide was used to prepare dihydro-l,2,4,5-tetrazin-6-ones (265) (76CZ496) and dihydro-1,2,4,5-tetrazine-6-thiones (266) respectively (73CZ565). 

Like the oxadiazolium salts (288), 1,3,4-thiadiazolium salts (296) can also react with hydrazines to afford 1,4-disubstituted l,4-dihydro-l,2,4,5-tetrazines (290). By this method, 1,4-dihydro-1,2,4,5-tetrazines with four different substituents can be prepared this seems to be the only method for preparation of such compounds, and proceeds in yields of 70-99%. The 4-amino-l,2,4-triazoles were isolated as side-products (74ZOR377, 71DOK(200)134, 71MIP22100). 

Reaction of aldehydes with hydrazine, or mono- or 1,2-disubstituted hydrazines is the method used almost exclusively for the preparation of hexahydro-l,2,4,5-tetrazines (377). All types of hydrazines have been used hydrazine itself, monoalkyl-, monoaryl-, dialkyl-, diaryl-, alkylaryl-, alkylacyl- or arylacyl-hydrazines. The aldehydes used were mainly aliphatic aldehydes. An excellent review by Wiley of the literature on this reaction up to 1974 is available (78HC(33)1075, p. 1190). 

Tetradehydrodianthracene undergoes 4 + 2-cycloaddition with electron-deficient dienes such as 1,2,4,5-tetrazines.263 The Diels-Alder reactions of [3.3 ortho-anthracenophanes witli A-(p-nitro, chloro, or methoxy-substituted phenyl)malehnides yield approximately equal quantities of inside and outside adducts.264 The photooxidation of bulky water-soluble 1,4-disubstituted naphthalenes with singlet oxygen yields both the expected 1,4- and the unexpected 5,8-endoperoxides.265... 

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