Dienes 1,2,4-triazines

Certain trifluoromethyl-substituted 1,2,4,5 tetrazines [260, 26i] and 1,2,4 triazines [i06] can be used as cyclic hetero-1,3-dienes and provide efficient preparative routes to partially fluorinated heterocycles (equations 55 and 56)... 

Applieation of this theory to the Boger pyridine synthesis reveals that it is a LUMOdiene-controlled Diels-Alder reaetion. Sinee the 1,2,4-triazine is eleetron defieient as a result of the ring nitrogen atoms, one must pair this diene with eleetron rieh dienophiles to allow optimal HOMO-LUMO pairing for this reaetion to beeome faeile. 

The cycloaddition reaction of 1,2,4-tiiazines 7V-oxides proceeds differently from the reaction of the corresponding 1,2,4-tiiazines. Thus the 1,2,4-triazine 4-oxide 55 acts only as a diene in the reaction with 1 -diethylaminopropyne to afford 2-methyl-4-(dimethylamino)pyrimidines 111. At the same time the 1,2,4-triazine 4-oxides 55 react with l-(dimethylamino)-l-ethoxyethylene by 1,3-dipolar cycloaddition to give 5-methyl-1,2,4-tiiazines 112 (78CB240). 

Another type of special diene, the polyaza benzene heterocyclics, such as triazines and tetrazines, is discussed in Section 6.6.2. 

Diazabicyclo[2.2.2]octa-2,5-diene N-oxide, 2374 5,6-Diphenyl-l,2,4-triazine-3-diazonium tetrafluoroborate 2-oxide, 3677... 

Vapor-phase flash pyrolysis of 4-phenyl-1,2,3-benzotriazine (8, R = Ph) at 420°-450° gives a mixture of biphenylene, 9-phenylacridine, unchanged triazine, and the 2-phenylbenzazete (158). Compound 158, which is stable at -80°, dimerizes when warmed to room temperature and reacts readily with nucleophiles and 1,3-dienes. The thermally more... 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

The reaction of the pyrido-fused pyridazino[3,4-< ][l,2,4]triazinium compound 105 with secondary amines results in the ring-opening of the pyridine moiety to yield dienyl-substituted pyridazino[3,4-< ][l,2,4]triazines of which the pyrrolidine compound 106, shown in Scheme 15, is typical <2003ARK62, 1998AC0285, 1995JOC4919>. Compound 106 has been the subject of a detailed study and has been shown to react as a diene in the presence of fumaronitrile and A -phenylmaleinimide to give the Diels-Alder adducts 107 and 108, respectively <2003ARK62>,... 

Sheldrake and co-workers devised an elegant approach to interesting cage compounds based on an intramolecular hetero Diels-Alder reaction (88CC1482) (Scheme 51). The [4 + 2] cycloaddition of triazines 223 to 1,5-cyclooctadiene at M0°C resulted in the formation of 7-azatetracyclo[7.3.0.02 6.05 lo]dodec-7-ene derivatives 225 in 44-66% yield. The initial formation of 224 followed by the intramolecular cycloaddition of the electron-poor 2-azadiene moiety to the second carbon—carbon double bond of the cyclooctadiene system accounts well for the process. The dienophile unit can be placed just over the diene system favoring... 

Triazines are generally more reactive in [2 + 4] cycloaddition in comparison with 1,2,3-tria-zines. The wide variety of dienophiles can be employed enamines, enaminones, vinyl silyl ethers, vinyl thioethers, cyclic ketene jV,O-acetals, /V-phenylmaleimide, 6-dimethylaminopentafulvene, 2-alkylidene-imidazolidines (cychc ketene aminals), cyclic vinyl ethers, arynes, benzocyclopropene, acetylenes, and alkenes like ethylene, (Z)-but-2-ene, cyclopentene, cyclooctene and bicyclo[2.2.1]hept-2-ene, hexa-1,5-diene, cycloocta-1,5-diene, diallyl ether, cyclododeca-l,5,9-triene,... 

Triazines are reactive electron-deficient dienes in Diels-Alder reactions with inverse electron demand. They react with alkenes, strained double bonds, electron-rich and electron-deficient alkynes and C=N double bonds. In most cases it is found that the dienophile addition occurs across the 3- and 6-positions of the triazine ring, but ynamines can also add across the 2- and 5-positions. The reactions are still under active theoretical and practical investigation. 

At this point the relative orientations of the dienophile and the diene must be considered. Since both the 1,2,4-triazines and the enamines are unsymmetrical, two orientations in the transition state have to be discussed, A and B of Scheme 13. 

Neunhoeffer and Lehmann have shown that it is possible to reverse the diene character of the 1,2,4-triazine ring by introducing alkoxy or dialkylamino groups into the ring. Alkoxy-, dialkoxy- and dialkylamino-1,2,4-triazines are therefore less reactive toward ynamines but they still react with these dienophiles. Bis(dialkylamino)-, trialkoxy- and tris(dialkylamino)-l,2,4-triazines (425) behave as electron-rich dienes and give cycloaddition reactions with acetylenedicarboxylate (426) but not with ynamines. Compounds (425) and (426) afford the 2,4-bis(dialkylamino)pyrimidine-5,6-dicarboxylates (427) (77LA1413). 

Tetrazines (624) are reactive dienes in Diels-Alder reactions with inverse electron demand. They react with both C—C and C—N multiple bonds. Cycloaddition of (624) with imidates thus affords 1,2,4-triazines (625) which are formed via the bicyclic intermediates (626) and the dihydro-1,2,4-triazines (627) (69JHC497). Further studies have been made on the limitations of this reaction. 

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. 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

It is also possible to generate the same triazine in situ as part of a one-pot reaction starting from ethyl thioamido oxalate followed by generation of the hydrazone and then addition of an a,/3-diketone ester and either norbornadiene or 2,3-dihydrofuran. The former diene yields the pyridine skeleton in 59-87% yield, while the latter gives fused pyridolactones in 39—44% yield (Scheme 56) <2004T8893>. 

Cyclic, electron-deficient diaza-1,3-butadienes, e. g. pyrimidines, pyridazines, triazines and tetrazines have proved to be an extremely versatile synthetical tool. Extensive studies aimed at the use of these dienes in the synthesis of natural products stem from Boger s group [11]. 

Further recent work on cycloaddition chemistry of nitrogen heterocycles deals with 1,2,4-triazines. These cyclic dienes undergo a cycloaddition-cycloreversion series as well in this case, nitrogen is evolved and thus a pyridine derivative is generated as final product. Snyder et al. efficiently constructed the canthine skeleton by heating the indolyl-tethered 1,2,4-triazine 3-85 which yielded the tetracyclic product 3-86 (Fig. 3-25) [325,326]. 

An investigation concerning intramolecular aza Diels-Alder reactions of 3-(co-alkynyl)-l,2,4-triazines has been published by Taylor et al. [327] and trichloro-1,2,4-triazine has been introduced as novel triazine diene recently [328]. 1,2,4-Triazines are a useful alternative of 1,4-diaza-l,3-butadienes with regard to the aforementioned synthesis of pyrazines since Taylor s group has found them to undergo cycloadditions with nitriles followed by extrusion of nitrogen [329]. This reaction is noteworthy since it is a Diels-Alder reaction of both electron-deficient diene and dienophile. 

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