Tetrazines cycloaddition reactions

Tetrazines, synthesis and properties 84MI18 78HC(33,1)1. s-Tetrazines, cycloaddition reactions of 81 KGS 1462. Tetrazines, synthesis from hydrazines 84H(22)1821. Verdazyl radicals, vibrational spectra of 84UK1959. 

The use of tetrazine cycloaddition reactions is not limited only to bio-orthogonal chemistry. It also finds application in materials chemistry. It was used to allow an easy modification of a highly ordered pyrolytic 2D graphite surface under ambient conditions (14CM5058). 

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 cycloaddition reactions of the novel 3-methylsulfrnyl-6-methylthio- 37 and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl- 38 -1,2,4,5-tetrazine to afford the corresponding pyridazines 39-40 proceeded with a regioselectivity opposite to expected and complementary to that observed for the corresponding sulfides <06JOC185>. 

The inverse-electron-demand Diels-Alder reaction of 3,6-dichloro[l,2,4,5]tetrazine with alkenes and alkynes provides the synthesis of highly functionalized pyridazines. ° Also, the 4 + 2-cycloaddition reactions of the parent [l,2,4,5]tetrazine with donor-substituted alkynes, alkenes, donor-substituted and unsubstituted cycloalkenes, ketene acetals, and aminals have been investigated. ... 

Figure 13 1,2-Diazines obtained by cycloaddition reactions starting from 1,2,4,5-tetrazines.

Cycloaddition reactions of the C = N bond of azirines are common, e.g. Scheme 31 (71AHC(13)45, B-83MI 101-03, 84CHEC(7)47). Azirines can also participate in [4 + 2] cycloadditions with cyclopentadie-nones, isobenzofurans, triazines, and tetrazines. 

There are many methods known for the synthesis of 1,2,4,5-tetrazines (39) but most afford the desired compounds only in low yield. There has been great interest in these compounds by physical organic chemists on account of their physical and spectroscopic properties, while preparative organic chemists have been interested in their high reactivity as dienes in cycloaddition reactions. 

The number of 1,2,4,5-tetrazines used in these cycloaddition reactions is limited. The most frequently used are the 3,6-dicarboxylates, the 3,6-diphenyl, 3,6-dimethyl, 3,6-di(2-pyridyl) and bis(perfluoroalkyl) compounds a few others have also been used. The most reactive substances seem to be the 1,2,4,5-tetrazinedicarboxylates, possessing the extra electron-withdrawing effect of the two carboxylate groups. 

Arene oxide-oxepin systems have also been reported to undergo [2 + 4] or [4 + 6] pericyclic cycloaddition reactions with heterocyclic dienes like the tetrazine 279 and the triazine 280. 65 Thus 86 96 reacts with 279 and 280 to yield the dihydrooxepino [4,5-d] pyridazine 281 and the oxepino [4,5-c] pyridine 282, respectively, via a [2 + 4] cycloaddition as well as the phthalazine 283 and isoquinoline 284, respectively, probably via a [6 + 4] cycloaddition reaction. However, 157 gives only 285 and 286 arising from a [2 + 4] cycloaddition reaction. 

There have been three reported syntheses of 1,2-diazocines by means of ring-expansive cycloaddition reactions. In the first case, Sasaki and coworkers reacted 4,4-dimethyl-3,5-diphenylisopyrazole 25 with diphe-nylcyclopropenone to obtain diazocine 26 (73SC249). The second cycloaddition was achieved by Haddadin et al., who condensed cyclobutanone with tetrazine 27 (Ar = Ph) to afford diazocine 28 (Ar = Ph, X = O) or 29, depending on whether methanolic base or diethylamine was used as catalyst (84TL2577). A similar reaction was used to prepare a triazocine see Section IV,A,1. 

The 2,3-dihydrobenzo[l,2-7 5,4-3 ]difuran 705 can undergo a cycloaddition reaction with tetrazine 706 followed by furan ring opening and lactonizaton to afford the pyridazino-fused coumarin 707 (Scheme 174) <2005T4805>. Similarly, benzo[l,2-3 5,4-7 ]difurans 708 react with tetrazine 706 to form the pyridazino-fused coumarins 709 and 710 (Equation 283) <2005T4805>. 

Diels-Alder cycloaddition reactions with tetrazines provide a useful approach to the preparation of pyrrolo[2,3-d]pyridazines. Thus, the lactam acetal (97), which is in equilibrium with the cyclic ketene A,O-acetal (98), reacts with tetrazines (99) to give the partially reduced product (100) <86CB3600>. The methylthio analogue of the acetal (97) also reacts similarly with tetrazines (Scheme 7) <87JHC545>. 

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