Tetrazine Derivatives

Tetrazine Derivatives. 1,4,5,6-Hexahydro-l, 4-dimethyM, 2,3,4-tetrazine (396) has been prepared in 5 % yield by oxidation of the bishydrazine (397) with sodium hypochlorite in basic conditions. Its chemical properties as a c -tetra-alkyl-2-tetrazene were compared with those of the long-known rra/ij-2-tetrazene (398). The expected decrease in activation energy for thermal decomposition of (396) compared with the trans-mo6 (398) was not observed, and reaction products of low volatility were predominant. In contrast, the only organic product from room-temperature photolysis was the triazine (399), presumably arising from cleavage of the biradical (400). 

The oxidation potential of (396) is 570 mV anodic of (398), attributable to charge repulsion in the cw-tetrazene cation. 

Some new methods for preparing methyl- and phenyl-substituted hexa-hydro-l,2,4,5-tetrazines have been reported.  

Jensen and S. Hammerun, Acta Ghent. Scand., 1972, 26, 1258. 1 S. Hammerun, Tetrahedron Letters, 1972, 949. 

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Most of the l,2,4-triazino-l,2,4,5-tetrazine derivatives 4 have been evaluated in vitro for antitumor activity. Results showed that these compounds exhibited a moderate anticancer activity toward leukemia <2003PS2055>. For biological activities of the previous compounds discussed in CHEC-II(1996), please refer to the same <1996CHEC-II(8)743>. 

Other examples of the use of 1,2,4,5-tetrazine derivatives in [4+2] cycladditions have been reported <06T8169 06EJO3358>. 

Reaction of hydrazonoyl halides 40 with 4-amino-23-dihydro-6-substituted-3-thioxo-1,2,4-triazinones 39 gives l,2,4-triazino[43-h][l,2,4,5]tetrazine derivatives 41 <00JPR96>. 

Table 1 Calculated charges of nitrogen atoms in two triazolo[4,3-fa][1,2,4,5]tetrazine derivatives...

Hydrazine was first obtained by hydrolytic decomposition of bis-diazoacetic acid . The latter, a tetrazine derivative, is obtained from ethyl diazoacetate in the form of alkali salt by the (catalytic) action of strong alkali. Two molecules of the acid simply unite and, at the same time, the ester group is hydrolysed ... 

Derivatives of two pyrazolotetrazine ring systems have been synthesized. Thus, the pyrazolo[5,l-cT -l,2,3,5-tetrazine derivative (161) was formed up on reacting diazopyrazole (86) with isocyanates (79TL4253). 

Appropriately substituted azolyldieneamines were found to undergo double inverse electron demand Diels-Alder reactions with tetrazine derivatives, yielding azolylpyridazines and... 

Calculated values shifts for some monosubstituted tetrazine derivatives lie in the range 10.26-10.45 p.p.m. in ... 

The pyrazolo[3,4-( ][l,2,3,4]tetrazine derivative 49 has been reported to be formed by treatment of the hydrochloride salt of the amine 48 with sodium nitrite in aqueous ethanol at room temperature. Only a single example was described. Compound 49 was obtained as red crystals (m.p. >300°C). The product is presumed to form from the diazonium cation 50 which cyclizes via the hydrazone tautomer 51 (Scheme 2) <1998MI11>. 

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. 

The use of ammonia or amines instead of sodium hydroxide for the dimerization of ethyl diazoacetate leads to the formation of dihydro-1,2,4,5-tetrazine-3,6-dicarboxamides. The products isolated were formulated either as l,2-dihydro-l,2,4,5-tetrazine derivatives (314), as l,6-dihydro-l,2,4,5-tetrazine derivatives (315), or as mixtures of both. The dimerization is usually run in alcoholic solution at temperatures from cold to 100 °C (78HC 33)1075, pp. 1157, 1158, 76G1). 

Avalos et al. has reported the microwave-assisted synthesis of tetrazine derivatives by a hetero Diels-Alder reaction of homochiral 1,2-diaza-l,3-butadienes with diethyl azodicarboxylate (Scheme 3.40)65. Under conventional conditions, reactions could be performed in benzene solution at room temperature. However, under microwave heating conditions, the reaction was significantly accelerated (by a factor of 1000) when carried out solvent free. The observed stereoselectivity was identical for the hetero Diels-Alder reaction under both microwave-heated and conventional conditions. 

In a different pattern, by using silylated acetylenes, substituted pyridazines are obtainable217 from the tetrazine derivative 401 in a diene-type reaction, first introduced by Carboni and Lindsey218. Via this reaction 4-TMS- (402) and 4,5-bis(TMS)-3,6-bis(methoxycarbonyl)pyridazine (403) can be achieved in very high yield, being inert against acid catalyzed desilylation (Scheme 59). 

Another tetrazine derivative, 3,6-bis(lH-l,2,3,4-tetrazole-5-ylamino)-s-tetrazine, has recently been prepared from (Ms(pyrazolyl)tetrazine (Fig. 1.16). It is interesting to note that the tetrazine derivatives potentially form strong intermolecular interac-... 

Significantly, the oxygenation pattern found in the two aryl groups, as in 24, would be expected to increase the nucleophilic character of the acetylene and improve what is a typically poor reactivity of alkynes toward 1,2,4,5-tetrazine derivatives <65CB1435> for an inverse electron demand Diels-Alder cycloaddition. 

Middleton established that reaction of 1,2-dialkylhydrazines with sulfur and reduction of sulfinylhydrazines (R2N—N=S=0) with lithium aluminium hydride yielded highly colored N-thionitrosoamines (95), which are stable at < ca. -30°C (66JA3842). However, it was deduced from spectroscopic data that these were not true RN=S species a high contribution from the dipolar resonance form accounts for their stability. Nonetheless, compound 95 will act as a 277 component in an inverse electron demand Diels-Alder reaction with a tetrazine derivative to yield triazole 96 (79CZ230). 

Tetrazine derivatives have been used widely in making pyridazines by inverse electron-demand Diels-Alder reactions with dienophiles (see Scheme 10), followed by loss of nitrogen from the usually unstable intermediate if the dienophile has a triple bond or potential triple bond properties, the final pyridazines will be aromatic. From the coordination chemistry point of view 3,6-dipyridin-2 -yl-l,2,4,5-tetrazine and dimethyl 1,2,4,5-tetrazinedicarboxylate and their analogs are probably the most useful starting compounds for making relevant ligands. 

The true Dithio-p-urazine and some related Sym-tetrazine Derivatives. 

Two reports deal with the synthesis and antitumor activity of 3,6-disubstituted 1,4-dihydro-1,2,4,5-tetrazine derivatives <05JCR(S)91 05BMCL3174>. In the latter,... 

When 3Ph2Tz ( ed = 1.09 0.04 V versus SCE) is replaced by a tetrazine derivative that has a slightly higher reduction potential of 3(ClPh)2Tz (l ed = 1.11 0.05 V versus SCE), AcrH is also generated by hydrogen transfer from AcrH2 to 3(ClPh)2Tz. 48 In contrast to the case of 3Ph2Tz, however, only a small primary kinetic isotope effect (/cH//cD = 1.11 0.08) is observed.48 No deuterium kinetic isotope effect is observed when 3(ClPh)2Tz ( ed = 1.11 0.05 V versus SCE) is... 

On treatment with diluted hydrochloric acid or sulfuric acid at 40 "C, compound 1 forms amidinobiuret 4 (73%) with loss of nitrogen. When anhydrous hydrochloric acid is added to a solution of the potassium salt of 1 in anhydrous acetone and the resulting precipitate is treated with water, 6-chloro-l,3,5-triazine-2,4-diamine (5) can be obtained. Treatment of 1 with aqueous potassium hydroxide for 24 hours leads to the isolation of 2,4-diamino-l,3,5-triazin-6(l/7)-one 6 (45%). Reaction of 1 with cyanamide in aqueous potassium carbonate solution affords 2, which gives l,3,5-triazine-2,4,6-triamine (7, melamine, 88%) together with ammonia, carbon dioxide and nitrogen when heated in diluted mineral acid. Product 7 can be obtained similarly from tetrazine derivative 3.3 See also Section B.2.3 on 1,3,5-triazines. 

Trifluoroacetaldehyde azine, prepared from trifluoroacetaldehyde hydrate and hydrazine monohydrate, reacts with triethylamine in methanol to give the 1,4-dihydro-1,2,4,5-tetrazine derivatives 28, whose structure is confirmed by X-ray analysis (95BCJ2085) (Scheme 28). 

In Neunhoeffer s contribution to CHEC-I a large body of detailed data was compiled, for x-ray diffraction, H and C NMR, ESR, UV/VIS, fluorescence, phosphorescence, and photoelectron spectroscopy <84CHEC-i(3)531>. It is not possible within the limited space of this contribution to go back to the roots. There are many individual reports of spectral data on a variety of tetrazine derivatives, but it would be inappropriate to tabulate them here. The principal aspects of different types of spectroscopy have been well described by Neunhoeffer in . A few new results are presented in this chapter. 

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