1,2,4,5-Tetrazine hydrolysis

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... 

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 synthesis of pyrrolo[2,3- 7 pyridazines can be achieved by starting either with pyridazine, a tetrazine, or a pyrrole. Pyridazinone 80 reacts with bromomethyl derivatives to give poor yields of 81 <1996H(43)1863> (Equation 34), while 5-acetyl-2-methyl-4-nitro-6-phenyl-3(2//)-pyridazinone, after treatment with sarcosine ethyl ester for a brief time at room temperature, followed by acid hydrolysis afforded a good yield of 82 (70%) <1994S669>. 

Most 1,2,4,5-tetrazines are unstable both to acids and bases. Acidic hydrolysis affords nitrogen and/or hydrazine and either carboxylic acids or aldehydes. It seems that the products formed during hydrolysis have not in all cases been detected (78HC(33)1075, p. 1093). 

Dihydro-1,2,4,5-tetrazines, formulated as the 1,2-dihydro tautomers (40), rearrange under the influence of acids to 4-amino-1,2,4-triazoles (70) (78HC(33)1075, p. 1151). Further acidic hydrolysis of (70) resulted in the formation of various products, such as diacylhy-drazines, hydrazine, carboxylic acids and 1,3,4-oxadiazoles (71) (78HC(33)1075, p. 1151). 

Basic hydrolysis of 3-phenyl-l,2,4,5-tetrazine (81) led to the isolation of benzalazine (82) in 80% yield (71KGS708). In most other cases studied the isolated product was an aldehyde acylhydrazone (83), indicating that during the basic hydrolysis one carbon atom of the tetrazine ring is reduced from the acid oxidation level to an aldehyde level (78HC<33)1075, p. 1094). A mechanism for the reaction has been proposed by Libmann and Slack (56JCS2253). Benzalazine (82) was also isolated when 3-azido-6-phenyl-l,2,4,5-tetrazine (84) was hydrolyzed by base (71KGS711). 

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). 

Treatment of 3-phenyl-l,6-dihydro-l,2,4,5-tetrazin-6-one (94) with base led to the isolation of benzalazine (82) (69KGS566). Alkaline hydrolysis of hexahydro-1,2,4,5-tetrazines (74) gave an aldehyde hydrazone or an aldehyde and hydrazine as with the acidic hydrolysis <78HC(33)1075, p. 1213). 

In the first step the formation of 5-phenyl-2-TMS-l, 2,3,4,-tetrazole (374) occurs which can either be hydrolyzed to 5-phenyl-l,2,3,4-tetrazole (375) or pyrolysed to give a N-TMS-benzaldehydehydrazonium compound (376). 376 can furthermore either dimerize to form 3,6-diphenyl-l,2,5-bis(TMS)-2,5-dihydro-l,2,4,5-tetrazine (377) and after subsequent hydrolysis and oxidation 3,6-diphenyl-l,2,4,5-tetrazine (3 79) or on the other hand react with a further equivalent 373 yielding in the last step 3,5-diphenyl-l, 2,4-triazole (381)214 (Scheme 55). 

The preparation of 3-aryl-6-azido-l,2,4,5-tetrazines 12 by treatment of 3-aryl-6-bromo-l,2,4,5-tetrazines 11 with aqueous solutions of sodium azide in 6M hydrochloric acid has been reported.28 1 This means that 11 and 12 are stable against hydrolysis in aqueous acid. 

Nitrogen and/or hydrazine and carboxylic acids or aldehydes are formed on acid hydrolysis of 1,2,4,5-tetrazines, but no detailed study on the acid hydrolysis of 1,2,4,5-tetrazines has been reported. 

Alkaline hydrolysis of 3-phenyl-l,2,4,5-tetrazine affords benzalazinc in 80% yield,285 while action of sodium carbonate on 3,6-bis(4-pyridyl)-l,2,4,5-tetrazine (1) affords the acyl-hydrazone 2 in 56 % yield.286 A mechanism for the alkaline hydrolysis of 1,2,4,5-tetrazines has been suggested.286... 

Neunhoeffer s contribution on the reactions of 1,2,4,5-tetrazines in CHEC-I broadly covered most of the principal reactions instability to acids and bases, acidic hydrolysis, basic hydrolysis, thermal rearrangements, attack of various nucleophiles at the 3- or 6-position, oxidation, and reduction reactions by various reagents, thermolysis and photolysis <84CHEC-I(3)531>. There is little progress to be reported in these fields. A brief survey is presented in Sections 6.21.6 and 6.21.9. Still rapidly growing is the field of (4-1-2) cycloaddition reactions of 1,2,4,5-tetrazines, upon which we shall concentrate in Sections 6.21.5.4 and 6.21.5.5. 

The fully conjugated tetrazine nucleus in principle cannot undergo rearrangement reactions. Ring transformations of dihydro, tetrahydro, and hexahydro 1,2,4,5-tetrazines under acidic and basic conditions (partial hydrolysis) are well known and were competently and extensively treated by NeunhoefiFer <84CHEC-I(3)53i>. Short surveys can be found in Sections 6.21.6 and 6.21.9. No new aspects seem to be worthy of discussion here. 

Under anhydrous conditions 3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine isomerizes to the 4-amino-1,2,4-triazole derivative (326). Hydrolysis under the influence of acids or bases transforms the 1,4-dihydro-1,2,4,5-tetrazine system to diacylhydrazines (329), carboxylic acids (330), and hydrazine, 1,3,4-oxadiazoles (328), or 1,2,4-triazoles (327) depending on the reaction conditions <78HC(33)1077>. 

Temozolomide (12) <93CC1177> and related compounds <87JMC357) were also found to react with nucleophiles in a similar manner i.e., with ring opening of the tetrazine part of the molecule. Thus, hydrolysis afforded the triazene compound (18), and alcoholysis (84JMC196> yielded an aminoimidazole carboxylic ester (19) (Scheme 2). 

Displacement of Sulphur. The Wittig reaction of resonance-stabilized phosphorus ylides with thioacyl-urethanes gives acylated enamines, e.g. (84), from which )ff-keto-esters are obtained by hydrolysis. Hydrazine displaces sulphur in thioanilides, giving amidrazones, but with two equivalents of arylselenoamides it gives 2,5-diaryl-1,3,4-selenadiazoles. Selenoamides react with an excess of hydrazine to give 1,2,4,5-tetrazines (see also Chap. 6, p. 294). l,2-Bis(thio-benzamido)ethane, when treated with NEt, and HgO, cyclizes to 2-phenyl-... 

In 1980, Sauer et al. synthesized 3,7-dicyanosemibullvalene 4-4 (Scheme 4.4). Cycloaddition of 1,2,4,5-tetrazines with 3,3 -bicyclopropenyl in a cycloaddition-cycloelimination sequence followed by hydrolysis, amination, and dehydration gave 3,7-dicyanosemibullvalene 4-4. The author also determined the activation barrier of Cope arrangement of 4-4 at -158 °C as 5.7 kcal/mol, slightly higher than the value 5.4 kcal/mol of unsubstituted SBV at the same temperature. This result indicates that electro-deficient cyano group at 3,7-position has little effect on the stabilization of delocalized structure [32]. 

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