1.2.3.4- Tetrazines

The hydrazination of aza-aromatics, using sodium hydrazide, has been reported, but no detailed mechanism was given (64AG206). On treatment of 3-i -l,2,4,5-tetrazines R = CH3, C2H5, C6H5) with 3 equiv of 

To investigate whether in the formation of these hydrazino compounds an Sn(ANRORC) mechanism would be involved, the reaction was studied with N-labeled hydrazine(78JHC445). If ring opening occurs, one could 

5-tetrazine (140A). Evidence was presented that at the pH of the solution, adduct 140A is present in its anionic form 140B (81JOC5102). NMR signals of the starting material could not be detected, nor could those of the 2,3-dihydro-3-hydrazino-3-R-l,2,4,5-tetrazine 142. The presence of the 6-hydrazino adduct 140 was further proved by NMR spectroscopic 

Based on this assumption, it can easily be understood why in the case of R = t-C4H ) no incorporation of the label in the 6-hydrazino compound was found. The addition at C-3, the required initial step for incorporation in the tetrazine ring, is prevented by the strained conformation in 142 (R = t-C4H9). 

Sn(ANRORC) Reactions in Azaheterocycles Containing an Inside Leaving Group 

A new electrofluorescent switch was prepared with an electroactive fluorescent tetrazine blend of polymer electrolyte 06CC3612 . The structure and magnetic properties of the stable oxoverdazyl free radical 6-(4-acetamidophenyl)-1,4,5,6-tetrahydro-2,4-dimethyl- 

5- tetrazin-3(2//)-one has been reported 06POL2433 . The synthesis and characterization of two new tetrathiafulvalene (TTF) derivatives bearing pyridine-based substitutents and l,5 -dimethyl-6-oxoverdazyl radicals have been described 06JOC2750 . 

New high-nitrogen materials with 3-amino-6-nitroamino-tetrazine (ANAT) as the anion have been synthesized and their properties studied 06CC4007 . 

The reaction of 3,6-diaryl-l,2,4,5-tetrazines (aryl = phenyl, 2-furyl or 2-thienyl) with 2 equivalents of Ru(acac)2(CH3CN)2 resulted in reductive tetrazine ring opening to yield diruthenium complexes 06IC821 . 

Complexes involving the 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine (bptz) ligand have been obtained 06JA5895 06MI1498 . 

Tetrazine acaricides are derivatives of tetrazine. Clofentezine is an acaricide/ovicide for eggs of various phytophagous mites on deciduous fruits, citrus, cotton, vines, and ornamentals. Its oral LD50 in rats is 5200 mg/kg. 

Several reports have dealt with pharmacological applications of 1,3,5-triazme derivatives  

2-Chloro-4,6-dimethoxy-l,3,5-triazines have been employed as reagents for the synthesis of 4,4-dimethyloxazolines from carboxylic acids and 2-amino-2-methyl-l-propanol 

Several reports have dealt with the 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine (bptz) ligand reactions of bptz with first-row transition metals have been explored 05JA12909 the synthesis and crystallographic study of a dinuclear iridium complex have been published 051CA1317 and a new molecular propeller compoimd prepared from the reaction of bptz with Ag[AsFe] has been reported 05CC46 . 

New tetrazines 42—46 bearing heteroatom substituents have been synthesized. The electrochemical and fluorescence properties of these compounds have also been reported 

The synthesis of 1,5-diisopropyl substituted 6-oxo-verdazyls 49 has been accomplished starting from 2,4-diisopropylcarbonohydrazide bis-hydrochloride 47. The introduction of isopropyl groups results in free radicals more stable and soluble than their methyl counterparts 05OBC4258 . 

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Figure 9.46 shows an example of a fluorescence excitation spectmm of hydrogen bonded dimers of x-tetrazine (1,2,4,5-tetraazabenzene). The pressure of x-tetrazine seeded into helium carrier gas at 4 atm pressure was about 0.001 atm. Expansion was through a 100 pm diameter nozzle. A high-resolution (0.005 cm ) dye laser crossed the supersonic jet 5 mm downstream from the nozzle. 

Figure 9.46 Rotational structure of the Ojj bands in the fluorescence excitation spectra of s-tetrazine dimers at about 552 run. Bottom Ojj band of planar dimer. Middle Ojj band of T-shaped dimer with transition in monomer unit in stem of T. Top Ojj band of T-shaped dimer with transition in monomer unit in top of T. (Reproduced, with permission, from Haynam, C. A., Brumbaugh, D. V and Levy, D. H., J. Chem. Phys., 79, f58f, f983)...

C2F12C12F2 (1,2-dichloro-l, 2-difluoroethane) symmetry elements, 83 CF13C3CN (methyl cyanoacetylene) interstellar, 120 2142X4 (s-tetrazine) fl S3 — X Ag transition, 3971F F1COOCF13 (methyl formate) interstellar, 120... 

X4)2 (s-tetrazine dimer) electronic spectrum, 397tf... 

Among the molecules that have received greatest attention are 2,6-bis(picry1amino)-3,5-dinitropyridine (PYX) 3,6-dinitro-j -tetrazine ... 

Although all the rings in Figure 1 contain six tt-electrons, the accumulation of electronegative nitrogen atoms in the polyaza structures leads to hydrolytic as well as thermal instability. This is noticeable in pyrimidine, and marked in the triazines and tetrazine. Some stability can be conferred by appropriate substitution, as we shall outline later. 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

Benzo[Z)]thiophene reacts with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate in a cyclo-addition-fragmentation reaction to yield (143), whereas benzo[A]furan and N- methylindole yield products (144) arising from ring opening and recyclization (76AP679). 

H-Azepine derivatives form a diene complex with tricarbonyliron, leaving uncomplexed the third of the double bonds. If the 3-position is substituted, two different such complexes are possible, and are in equilibrium, as seen in the NMR spectrum. An ester group in the 1-position of the complex can be removed by hydrolysis, to give an NH compound which, in contrast to the free 1/f-azepine, is stable. The 1-position can then be derivatized in the manner usual for amines (Scheme 22). The same tricarbonyliron complex can, by virtue of the uncomplexed 2,3-double bond, serve as the dienophile with 1,2,4,5-tetrazines. The uncomplexed N-ethoxycarbonylazepine also adds the tetrazine, but to the 5,6-double... 

The 27T-electrons of the carbon-nitrogen double bond of 1-azirines can participate in thermal symmetry-allowed [4 + 2] cycloadditions with a variety of substrates such as cyclo-pentadienones, isobenzofurans, triazines and tetrazines 71AHC(13)45). Cycloadditions also occur with heterocumulenes such as ketenes, ketenimines, isocyanates and carbon disulfide. It is also possible for the 27r-electrons of 1-azirines to participate in ene reactions 73HCA1351). 

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. 

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