1,2,4,5-Tetrazines Diels-Alder reactions

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 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. 

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. 

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]. 

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... 

The inverse electron demand Diels-Alder reaction of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 83 with dihydropyrrole 84 leads to the partially reduced structure 85 (Scheme 7) <1994H(38)1845>. 

In the area of reaction energetics. Baker, Muir, and Andzehn have compared six levels of theory for the enthalpies of forward activation and reaction for 12 organic reactions the unimolecular rearrangements vinyl alcohol -> acetaldehyde, cyclobutene -> s-trans butadiene, s-cis butadiene s-trans butadiene, and cyclopropyl radical allyl radical the unimolecular decompositions tetrazine -> 2HCN -F N2 and trifluoromethanol -> carbonyl difluoride -F HF the bimolecular condensation reactions butadiene -F ethylene -> cyclohexene (the Diels-Alder reaction), methyl radical -F ethylene -> propyl radical, and methyl radical -F formaldehyde -> ethoxyl radical and the bimolecular exchange reactions FO -F H2 FOH -F H, HO -F H2 H2O -F H, and H -F acetylene H2 -F HC2. Their results are summarized in Table 8.3 (Reaction Set 1). One feature noted by these authors is... 

The retro Diels Alder reaction has also been proved of value in a number of related cases benzo[c]indoles, isobenzofulvenes, furans, and ful-venes have been prepared by the tetrazine route, white the Wiersum-Mijs method has been used for the preparation of benzo[c]indole itself. ... 

Tetrazines react with alkenes to give bicycles (403) which lose nitrogen to give the 4,5-dihydropyridazine (404). This can either tautomerize to a 1,4-dihydropyridazine, be oxidized to the aromatic pyridazine, or undergo a second Diels-Alder reaction to give (405). Many heterocycles can act as the dienophiles in such reactions for example thiophene gives (406). The reaction is also used to trap unstable compounds, for example, 2-phenylbenzazete (407) as compound (408). 

Pyrroles, indoles and benzo[ft]thiophene act as good dienophiles in inverse electron demand Diels-Alder reactions with 1,2-diazines, 1,2,4-triazines and sy/n/n-tetrazines. This is examplified by the formation of compounds (189) in excellent yields on interaction of indoles and benzo[c]thiophene with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate (87JOC4610 90JOC3257). There are also many examples of such intramolecular reactions, e.g. (190 — 191). 

Inverse electron demand Diels-Alder reactions of 1,2,4,5-tetrazines with alkynes produce pyridazines directly with the elimination of nitrogen and retention of the substituents on the acetylene thus, tributylstannylacetylenes give pyridazines with a 4-tributylstannyl substituent (Scheme 24). 

Tetrazines (484) undergo Diels-Alder reactions with C-N multiple bonds. Imidates (69JHC497) or, that is better, thioimidates (83JOC621,83TL4511,85JA5745) thus afford 1,2,4-triazines (487) which are formed via intermediate bicycles (485) and dihydro-1,2,4-triazines (486). 

Synthesis of benzo[c]furans and isoindoles (181) is also possible by the addition of benzyne to the respective monocycles (178), followed by reduction (179 — 180) and pyrolysis. In an alternative procedure, (179) is reacted with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine, which affords (181) under far less vigorous conditions via a retro Diels-Alder reaction of the intermediate (182). 4-Phenyl-1,2,4-triazoles pyrolyze to form isoindoles (Section 3.4.3.12.2). 

Diels-Alder reaction of oxazolines and thiazolines (134) with tetrazines yield bicyclic compounds... 

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