Nitriles 1,2,4,5-tetrazines

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. 

Reaction of dichorobenzaldoxazine with sodium azide followed by 1-propa-nethiol-triethylamine gave the tetrazine imide 367 as the major product. Its formation is thought to involve the reaction sequence shown which includes an unprecedented electrocyclization of the nitrile imine 366 as the final step (210). 

Tetrazines (39) form nitriles and nitrogen on thermal degradation (59JA4342). Pyrolysis of Af-unsubstituted dihydro-1,2,4,5-tetrazines (41) is reported to lead to the tetrazines (39) but this reaction was probably an oxidation since oxygen was not excluded. 

Heating 4-amino-3-azido-4//-1,2,4-triazoles (229) in chlorobenzene to 110 °C gives the 3-amino-l,2,4,5-tetrazines (232). This reaction is explained by the intermediate formation of the nitrene (230) which opens to the formazane (231) and subsequent ring closure by nucleophilic attack of the hydrazono group on the nitrile function (66TL5369). 

The observation of very small substituent splittings in a series of tetrazine anion-radicals (55), (R = Me, Et, i-Pr, cyclo-Pr, Ph2CH, and Ph) confirms that the singly occupied orbital is as in 54 the heterocycle, and not the nitrile groups, remains the primary site for the unpaired electron in 55 (R = CN).141-144 By contrast, principal foci of spin density are outside the... 

Indoles have been prepared from reactions of o-aminophenylketones with reactive , or stable " arsonium ylides. Oxo-stabilized ylides reacted with 2-chloro-oximes to give trans-5-acyl-A -isoxazolines, and isoxazoles have been obtained from reactive arsonium ylides and a-isonitrosoketones, and from triphenylarsonium methylide and nitrile oxides The latter ylide reacts similarly with nitrile imines to give pyrazoles. With triphenylarsonium benzylides and benzoylylides,benzene diazonium salts give 1,3,4,6-substituted 1,4-dihydro-1,2,4,5-tetrazines in a reaction in which initial coupling of the reagents is followed by a dimerisation. ... 

The preparation of amide hydrazones is quite simple, by mixing corresponding nitriles (or dinitriles) and hydrazine (1 1.5 molar ratio) in ethanol at room temperature and then allowing the mixture to stand overnight. This is called the direct method. The yield by this method is normally good (>90%). If this method does not work, the so-called indirect method can be used, in which a nitrile, e.g., malononitrile, is converted into its imidate then reacted with hydrazine. In early references (e.g., Case, 1965150), anhydrous or 95% hydrazine was employed. We have found that 85% hydrazine hydrate still works without any difference in yield. Common recrystallization solvents are benzene or toluene. The amide hydrazones are stable to moisture, and so some amide hydrazones can be recrystallized from water, but they are sensitive to light and heat. As an example, we observed that picolinamide hydrazone (white crystals) partially turns into an orange compound, which has been identified as 3,6-picolin-(2H)-tetrazine. 

The triazolines resulting from the various reaction schemes are predominantly A2-compounds the cycloaddition reactions of azomethinimines and nitrile ylides lead to A3-triazolines. The amidrazones are unique a A3- or A2-system results, depending on the presence or absence of N-2 substitution (84KGS1415). The rare A -compounds are presumed to result from the nonregioselective addition of diazomethane to the imine double bond (72LA9) or by fluorination of 3,6-diamino-s-tetrazine (67USP3326889 70USP3515603). 

Cycloaddition reactions of the C(3)=N bond of azirines are common (Scheme 45) <71AHC(13)45, B-83MI 101-03,84CHEC-I(7)47>. Azirines can participate in [4 + 2] cycloadditions with dienes including cyclopentadienones, isobenzofurans, triazines, and tetrazines. They also participate in 1,3-dipolar cycloadditions with azomethine ylides, nitrile oxides, mesoionic compounds, and diazomethane. Cycloadditions with heterocumulenes, benzyne, and carbenes are known. Azirines also participate in other pericyclic reactions, such as ene reactions. 

Intramolecular cycloaddition of 1,2,4,5-tetrazines to a nitrile group has also been reported. Heating 3-[(2-cyanophenyl)oxy(sulfanyl)]-l,2,4,5-tetrazines in chlorobenzene affords condensed 1,2,4-triazines 14.203... 

The mass spectra of 1,2,4,5-tetrazines 1 are very simple. In most cases a fragmentation to one molecule of nitrogen and two molecules of the appropriate nitriles was observed.190,373 In dialkyl-1,2,4,5-tetrazines protonated and deprotonated nitrile structures were also observed.195 In the spectra of 3,6-diaryl-l,2,4,5-tetrazines peaks at a mass unit [M+ +2] were observed, which were explained by the formation of diaryldihydro-l,2,4,5-tetrazines in the ion source.372... 

The second (3 + 3) fragment method concerns reactions which can be explained as dimerization of nitrile imines 8. Since in most cases R2 is a substituent and not a proton, these reactions give 1,4-disubstituted 1,4-dihydro-l,2,4,5-tetrazines 9 which cannot be transformed into aromatic 1,2,4,5-tetrazines 10. These reactions will not be discussed in detail. 

Thermal or photochemical elimination of nitrogen from tetrazoles 1 affords nitrile imines 8 (see Houben-Weyl, Vol E8d, p774ff) which dimerize to give 1,4-dihydro-l,2,4,5-tetrazines 9 which are oxidized under the reaction conditions to 1,2,4,5-tetrazines 10 (when R2 = H).175-179... 

Other methods for the synthesis of l,4-dihydro-l,2,4,5-tetrazines 9 which can be explained by intermediate formation of nitrile imines 8 are the photolysis of 1,2,3-triazoles 2181 and sydnones 3,182 reaction of tetrazoles 4180 with tosyl chloride, elimination of pyridine from the pyridinium compounds 5,189-190 of hydrogen chloride from the hydrazonic acid chlorides 1 s.3-i88 or elimination 0f sulfinate from the a-sulfonyl hydrazone 7.189... 

In most cases these C,N2 fragments are prepared by reaction of activated carboxylic acid derivatives (C, fragment), such as dithiocarboxylates 2, thioesters 3. nitriles 5, imidates 6, amidines 7, thioamides 8, selenoamides 9, selenoesters 11, orthocarboxylates 14, with hydrazine (N2 fragment) and are transformed to l,4-dihydro-l,2,4,5-tetrazines 17 without isolation. Therefore, these syntheses are treated as a (2 + 1 +2+1) fragment method. 

Cycloaddition of 1,2,4,5-tetrazines with C-N double or triple bonds yields dihydro-1,2,4-tri-azines 13 or 1,2,4-triazines 14 (see Section B.2.2.1.3.). Various systems with C—N double bonds have been used imines, including dihydropyrroles and dihydroisoquinolines 341 344 hydra-zones, including dihydropyrazoles,343 348 oxime ethers,343 imidates, including dihydrooxa-zoles 345 357 thioiniidates, including dihydrothiazoles 345,349,350 357 358 amidrazones 357,358 amidines 359 and isocyanates or isothiocyanates.351 Nitriles are the examples of systems with a C-N triple bond.352 -356... 

In addition to intermolecular cycloaddition reactions of 1,2,4,5-tetrazines with various dienophiles, intramolecular cycloaddition reactions with alkene367 and acetylene 360 367 dienophiles or nitrile groups355-356 have also been reported. By this method condensed pyrid-azines 15 or 1,2,4-triazines 16 (see Section B.2.2.1.3.) are obtained. In most cases the side chain is bound to the 1,2,4,5-tetrazine ring by a heteroatom (O, S or In ). In a few cases the side chain is bound by a carbon atom or contains an additional heteroatom. The general reaction scheme is shown. 

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