Tetrazines, Diels-Alder

Most of the synthetic approaches towards benzoannelated [2.2]paracyclo-phanes use the Diels-Alder reaction to build up the annelated rings [18,22,29]. [2.2]Paracyclophane-l-ene (32) and [2.2]paracyclophane-1,9-diene (42) can be considered as the simplest dienophiles for this purpose. Since the first syntheses of these compounds in 1958 by Cram et al. [32], various attempts have been made to get them to react with dienes in terms of Diels-Alder reactions. However, [2 + 4] cycloadditions were never observed [33], and could not be facilitated either by the application of high pressure, or the presence of Lewis acid catalysts Diels-Alder adducts were not even obtained with dienes such as tetrachloro-thiophene dioxide, known for its high reactivity in [2 + 4] cycloadditions with an inverse electron demand. All the more surprising was the observation that monoene 32 reacts smoothly with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate at room temperature leading to a dihydropyridazine-annelated paracyclophane 39 in high yield [34a]. As reported for other tetrazine Diels-Alder reactions... 

Recent reports have described the first examples of intramolecular alkyne 1,2,4,5-tetrazine Diels-Alder reactions."b,c... 

While enamines are poor dienophiles for Diels-Alder reactions, their addition to tetrazines has provided a route to pyridazines (595). 

Interestingly, in the inverse-electron-demand Diels-Alder reactions of oxepin with various enophiles such as cyclopentadienones and tetrazines the oxepin form, rather than the benzene oxide, undergoes the cycloaddition.234 236 Usually, the central C-C double bond acts as dienophile. Oxepin reacts with 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dienone to give the cycloadduct 6 across the 4,5-C-C double bond of the heterocycle.234 The adduct resists thermal carbon monoxide elimination but undergoes cycloreversion to oxepin and the cyclopenta-dienone.234... 

The inverse electron-demand Diels-Alder cycloaddition of ethyl l//-azepine-l-carboxylate (1) with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylatc (36) yields the C4 —C5 adduct 37.266... 

Oxidation of the 2//-4a,7-dihydro derivative 15, the inverse electron-demand [4+2] Diels-Alder cycloadduct of ethyl 1 /7-azepine-l -carboxylate and dimethyl l,2,4,5-tetrazine-3,6-dicar-boxylate, with tetrachloro-l,4-bcnzoquinone furnishes the pyridazino[4.5-r/]azepine 16.112... 

The Diels-Alder reaction of cyclopropenes with 1,2,4,5-tetrazines (see Vol.E9c, p 904), a reaction with inverse electron demand, gives isolable 3,4-diazanorcaradienes 1, which are converted into 4H-1,2-diazepines 2 on heating. The transformation involves a symmetry allowed [1,5] sigmatropic shift of one of the bonds of the three-membered ring, a so-called walk rearrangement , followed by valence isomerization.106,107... 

The inverse electron demand Diels-Alder reaction of 3-substituted indoles with 1,2,4-triazines and 1,2,4,5-tetrazines proceeds in excellent yields both inter- and intramolecularly. The cycloaddition of tryptophan 124 with a tethered 1,2,4-triazine produced a diastereomerically pure cycloadduct 125 <96TL5061>. 

The hetero-Diels-Alder reaction can also employ dienes containing heteroatoms. Cycloaddition of substituted styrenes with di-(2-pyridyl)-1,2,4,5-tetrazine was investigated by Engberts (Eq. 12.56).127 Again, the rate of the reaction increased dramatically in water-rich media. Through kinetic studies, they showed that the solvent effects on the... 

Methods have been described that involve microwave-assisted graphite-supported dry media for the cycloaddition of anthracene, 1-azadienes and 1,2,4,5-tetrazines with several C-C dienophiles and carbonyl compounds in hetero-Diels-Alder reactions [35], This technique leads to a shortening of reaction times, a situation that enables work to be undertaken at ambient pressure in an open reactor to avoid the formation of unwanted compounds by thermal decomposition of reagents or products. 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

A common method to synthesize pyridazines remains the inverse electron-demand Diels-Alder cycloaddition of 1,2,4,5-tetrazines with electron rich dienophiles. [4 + 2]-Cycloadditions of disubstituted 1,2,4,5-tetrazine 152 with butyl vinyl ether, acrylamide, phenylacetylene, and some enamines were performed to obtain fully substituted pyridazines 153 . This reaction was accelerated by electron withdrawing groups, and is slowed by electron donating groups, R1 and R2on the tetrazine. 

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. 

These authors found that the tetrazinylhydrazone derivative 46 when reacted with pyrrolidinoenamine 47 in methanol yields the cyclopenta-fused derivative of the title ring system 48 in 94% yield. A similar transformation was carried out successfully by using morpholine-enamine in somewhat poorer yield. When the transformation was tried in acetonitrile as a solvent, a totally different reaction was observed a regular Diels-Alder reaction between the tetrazine ring and the enamine double bond (of inverse electron demand) took place to yield pyridazines. 

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. ... 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

Elimination of nitrogen from Diels-Alder adducts of certain heteroaromatic rings has been useful in the synthesis of substituted aromatic compounds.224 Pyridazines, triazines, and tetrazines react with electron-rich dienophiles in inverse-electron-demand cycloadditions. The adducts then rearomatize with loss of nitrogen and the dienophile substituent.225... 

Reaction of electron-deficient diaryl-1,2,4,5-tetrazine with Cgg may also be considered as a hetero-Diels-Alder reaction (Scheme 4.11) [82-84]. The initially formed Diels-Alder product undergoes a rapid retro-Diels-Alder reaction under loss of nitrogen, which renders the cycloaddition irreversible. The obtained diaryl-dihydropyridazine monoadducts are isolable but imstable and they react readily with water under the influence of light to afford a 1,4-hydrogenated product [82]. 

Electron-deficient heteroaromatic systems such as 1,2,4-triazines and 1,2,4,5-tetrazines easily undergo inverse electron demand Diels-Alder (lEDDA) reactions. 1,2-Diazines are less reactive, but pyridazines and phthalazines with strong electron-withdrawing substituents are sufficiently reactive to react as electron-deficient diazadienes with electron-rich dienophiles. Several examples have been discussed in CHEC-II(1996) <1996CHEC-II(6)1>. This lEDDA reaction followed by a retro-Diels-Alder loss of N2 remains a very powerful tool for the synthesis of (poly)cyclic compounds. 

The stereoselective normal electron demand Diels-Alder reaction of chiral 13-diaza-13-butadienes 42, derived from acyclic carbohydrates, with diethyl azodicarboxylate 2 yields the corresponding functionalized l,23,6-tetrahydro-133,4-tetrazines 43. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1 3 - Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation <99JOC6297>. 

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

---