Diels-Alder reactions of tetrazines

The other known benzologue (156) was obtained by Diels-Alder reaction of tetrazines (155) with 3,4-dihydroisoquinoline (154) followed by elimination of N2 (Equation (29)) <82AP(315)428>. 

Inverse demand Diels-Alder reactions of tetrazines 1 to psoralenes 267 were reported to furnish tetracyclic pyridazine dicarboxylates 268, which were used as the key intermediates in the synthesis of nitrogenated isosteres of potent DNA inhibitors <2003T8171>. In some cases, cycloaddition was followed by opening of the furan ring to give pyridazinyl-substituted coumarins 271 (Scheme 66) <2000JHC907, 2003SL2225>. 

The Diels-Alder reaction of tetrazine 14.3 with Ceo followed by intramolecular cycloaddition and loss of N2 results in the insertion of a C2-unit into the Cgo cage. In structure 14.3, the two carbon atoms marked with the pink dots are those that are eventually incorporated into the 52 cage. Figure 14.9 shows the structure of the product, C62(C6H4-4-Me)2, and confirms the presence of a 4-membered ring surrounded by four 6-membered rings. 

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 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. 

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. ... 

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>. 

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>. 

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). 

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... 

Soviet chemists have used the Diels-Alder reaction of acetone azine (309) with azotrifluoromethane (310) for the preparation of 3,3,6,6-tetramethyl-l,2-bis(trifluoromethyl)-l,2,3,6-tetrahydro-l,2,4,5-tetrazine (311) (62DOK(i42)354>. 

Pyridazines and their partially saturated analogs have been prepared on insoluble supports by Diels-Alder reaction of electron-rich alkenes or alkynes with 1,2,4,5-tetrazines (Entries 1-3, Table 15.27). The mechanism of this reaction is outlined in Figure 15.15. An additional approach, also based on the Diels-Alder reaction, is the cycloaddition of azo compounds to 1,3-dienes (Entries 4 and 5, Table 15.27). The resulting tetrahydropyridazines (Entry 4) have been used as constrained 3-strand mimetics for the discovery of new protease inhibitors [323], An example of the N-alkylation of hexahydropyridazines on solid phase is given in Section 10.3. 

Avalos et al. has reported the microwave-assisted synthesis of tetrazine derivatives by a hetero Diels-Alder reaction of homochiral 1,2-diaza-l,3-butadienes with diethyl azodicarboxylate (Scheme 3.40)65. Under conventional conditions, reactions could be performed in benzene solution at room temperature. However, under microwave heating conditions, the reaction was significantly accelerated (by a factor of 1000) when carried out solvent free. The observed stereoselectivity was identical for the hetero Diels-Alder reaction under both microwave-heated and conventional conditions. 

Preparation and Diels-Alder Reaction of a Reactive, Electron-Deficient Heterocyclic Azadiene Dimethyl 1,2,4,5-Tetrazine-3,S-Dicarboxylate. 1,2-Diazine and Pyrrole Introduction. 

Tetradehydrodianthracene undergoes 4 + 2-cycloaddition with electron-deficient dienes such as 1,2,4,5-tetrazines.263 The Diels-Alder reactions of [3.3 ortho-anthracenophanes witli A-(p-nitro, chloro, or methoxy-substituted phenyl)malehnides yield approximately equal quantities of inside and outside adducts.264 The photooxidation of bulky water-soluble 1,4-disubstituted naphthalenes with singlet oxygen yields both the expected 1,4- and the unexpected 5,8-endoperoxides.265... 

A novel formal inverse-electron-demand hetero-Diels-Alder reaction between 2-aryl-a,/3-unsaturated aldehydes and ketones produces dihydropyran derivatives stereo-specifically.161 The inverse-electron-demand Diels-Alder reaction of 3,4-r-butylthio-phene 1-oxide with electron-rich dienophiles shows vyn-jr-face and endo selectivity.162 (g) The inverse-electron-demand Diels-Alder reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163... 

The formation of pyridazines from 1,2-diaza-1,3-butadienes and electron-rich dienophiles has been reported [308] on the other hand, tetrazine and triazole derivatives have been prepared from these heterodienes and azo esters [309]. Aza Diels-Alder reactions of 1,4-diaza-1,3-butadienes have been employed for the synthesis of unsymmetrical pyrazine derivatives by Heathcock et al. [310]. 

The synthesis of pyrrole and indole [330] derivatives by aza Diels-Alder reactions of appropriate 1,2,4,5-tetrazines is another valuable synthetical option... 

Regiospecific inverse electron demand Diels-Alder reactions of enamines with 1,3-diazines or 1,2,3- and 1,2,4-triazines (see Section III.D.l), which on elimination of HCN or N2, respectively, produce a pyridine ring, can be used with 1,3,5-triazines and 1,2,4,5-tetrazines as a useful method for the synthesis of pyrimidines214-216 (1,3-diazines) and pyridazines217-219 (1,2-diazines). Examples of the use of this methodology are the preparation of the pyrimidine substituted benzomorphane 356 (equation 77)219 and the pyridazine 359 (equation 78), intermediate in the total synthesis of cis- and trans-trikentrin A216. 

Acetylenic ester 460, when heated, undergoes an intramolecular Diels-Alder reaction to produce tricyclic compound 461. Further Diels-Alder reaction of 461 with tetrazine 462 generates the intermediate 463, which affords the dihydrothiophene 464 (Scheme 75) <1995AJC593>. 

Since the initial demonstrations of the participation of substituted l,2,4,S-tetrazines ° and oxa-zoles ° ° in [4 + 2] cycloaddition reactions with alkene and alkyne dienophiles, the investigation and application of the Diels-Alder reactions of heteroaromatic systems possessing reactive azadienes have been pursued extensively. A number of general reviewshave treated the spectrum of heteroaromatic azadienes that participate in [4 + 2] cycloaddition reactions and many of the individual heteroaromatic systems have been reviewed separatcly. ° ° An extensive account was published recently and should be consulted for descriptions of the [4 + 2] cycloaddition reactions of the common heteroaromatic azadienes that have been observed to date. 

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