1.3.5- Triazines reaction with dienophiles

The tautomerism of 1,3,5-triazines has been reviewed previously (B-76MI22000, pp.138,152,168). NMR and IR studies have shown that cyanuric acid exists mainly in the oxo form. Although the cyanurates and isocyanurates are the two major derivatives, there is no doubt that compounds with both types of functional group present in the same molecule are possible (e.g. Scheme 36). Trithiocyanuric acid exists predominantly in the thioamido form. In contrast, melamine exists in the amino form. /S-Oxoalkyl-1,3,5-triazines exist mainly in the enol form, and thus they undergo ene type reactions with dienophiles. 

A special method, with only two examples, starts from 1,2,4-triazines.20 21 Diels-Alder reaction with the strained dienophile dimethyl tricyclo[4.2.2.02,5]deca-3,7,9-triene-7,8-dicarboxylate (14) is followed by an elimination of nitrogen via a retro-Diels-Alder process. The formed product, however, cannot be isolated, but reacts via another retro-Diels-Alder reaction and an electro-cyclic reaction to provide the azocine derivative 15. The sequence order of the reactions is not clear, but both pathways lead to the same product. 

Sauer and Heldmann [97] recently reported an interesting application of ethynyltributyltin as an electron-rich dienophile in an inverse electron-demand Diels-Alder reaction with the electron-deficient triazine derivative 94. This method is interesting because the reaction is highly regioselective and the trialkylstannyl group is easily replaced by several groups under mild conditions, leading to substituted pyridines 95 (Scheme 2.41). 

Derivatives of the pyrimido[4,5-e][l,2,4]triazines at the 7-position were prepared (75JOC2329) by displacement of the respective chloro derivatives. Reaction of pyrimidotriazines 291 or 294 (R = S02Me) with acetylenic alcohols or amines gave azalumazines 292 or azapterins 295, respectively, with dienophilic side chains (88JOC800). Compounds 292 or 295 underwent intramolecular Diels-Alder reaction to give 6,7-annulated 5-deazapteridines 293 and 296, respectively (88JOC3568). 

Triazines usually react with dienophiles in Diels-Alder reactions to afford pyrimidine derivatives (Equation 7). 

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/retro-Diels-Alder-type reactions, of di- and especially poly-azines with electron-rich dienophiles, interconvert six-membered rings. 1,2,4-Triazines react with enamines and enol ethers to give pyridines (Scheme 76) (CHEC-n(5)242). 

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. 

Another well-studied cycloaddition of 1,2,4-triazines is the reaction with ynamines (423). In this the dienophile often attacks the 1,2,4-triazines across the 2- and 5- rather than the 3- and 6-positions. This can perhaps be due to the transition state of the cycloaddition with ynamines being more polar than that in the cycloaddition with alkenes, and a partial negative charge in the 1,2,4-triazine ring is better stabilized at a nitrogen (N-2) than at a carbon (C-6). The products isolated from these reactions are pyrimidines (424). It was shown by using lsN-labelled 3-methyl-l,2,4-triazine that the reaction is in fact a [4 + 2] cycloaddition to N-2 and C-5 and not a [2 + 2] cycloaddition to the N(4)—C(5) bond (72LA(758)125). 

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). 

A few cases of [4 + 2] cycloaddition reactions of 1,2,4-triazines with C=N double bonds have been reported. Reaction of 1,2,4-triazines (441) with benzamidine (442) in boiling toluene led to the isolation of the 1,3,5-triazines (443). It may be supposed that here the dienophile adds to the 2- and 5-positions of the 1,2,4-triazine, as in the reaction with ynamines, then a nitrile (R6CN) is eliminated and aromatization follows by loss of ammonia. In one case, the initially formed 1,3,5-triazine (443) reacted with a second molecule of benzamidine by [4 + 2] cycloaddition and elimination of R3CN and ammonia, resulting finally in triphenyl-1,3,5-triazine (444). This is a known reaction in the 1,3,5-triazine series (see Chapter 2.20) (81TL1393). 

Triazine and its derivatives react with dienophiles by a [4 + 2] cycloaddition reaction (equation 4) (75CB3877). The l,2-dihydro-l,3,5-triazines (35) can also undergo Diels-Alder reactions with potent dienophiles (equation 5) (77KGS122). 

The 1,2,4-substituted triazine core is a versatile scaffold to access a wide range of condensed heterocyclic ring systems via intramolecular Diels-Alder reactions with a vast array of dienophiles. The triazine ring system is also a key component of commercial dyes, herbicides, insecticides and also recently appeared in medicinal chemistry. One way to synthesise triazines is to use a three-component reaction that has been described in the literature several times, both under traditional thermal heating and under solvent-free microwave-assisted conditions42. However, the previously described methods focussed only on simple aliphatic phenyl and ester substituents. 

Diels-Alder reactions 1,2,4-triazines. The electron-deficient azadiene system present in 1 can undergo Diels-Alder reactions with electron-rich dienophiles to give an adduct that loses nitrogen to provide 1,2-diazines. Reactions with imidates (>C=NH) substituted with an active leaving group such as SCH, proceed at moderate temperatures to afford 1,2,4-triazines in high yield (equation I). 

Neunhoeffer and Wiley (78HC226) discovered that 1,2,4-triazine served as a reactive, electron-deficient diene in inverse electron demand Diels-Alder reactions with electron-rich or strained olefins. Cycloaddition occurs exclusively across C-3/C-6 of the triazine nucleus and there is a strong preference for the nucleophilic carbon of the dienophile to be attached to C-3... 

It is well known that introduction of electron-withdrawing substituents increases electron deficiency in the 1,2,4-triazine substrate and enhances its reactivity in Diels-Alder reactions with electron-rich dienophiles (83T2869 86CRV781 87MI1). The reaction under consideration is the... 

Monocyclic 1,2,3-triazines 1 behave like other six-membered heterocycles as dienes in Diels-Alder reactions with inverse-electron demand. Substrates are electron-rich dienes and acetylenes. 11 103, 284-290 jn mosl caseSi the formation of the isolated products can be explained by an attack of the dienophile at N1 and C4 or N3 and C6 of 1. In a few cases, products were obtained, the formation of which had to be explained by an intermediate formation of an azacyclobutadiene (azete) or by an N2 and C5 attack.284,285... 

Over the last twenty years, the cycloaddition reactions of 1,2,4-triazines have been studied intensively. 1,2,4-Triazincs arc clcctron-dcficicnt systems and readily undergo Diels-Alder reactions with inverse electron demand with electron-rich dienophiles, such as enamines and ynamines, or with systems containing strained double bonds. Inter- and intramolecular cycloaddition reactions have been observed, giving pyridines and pyrimidines or condensed pyridines and pyrimidines. 

Tetrazines are reactive dienes in Diels-Alder reactions with inverse electron demand and react not only with C—C multiple bonds, but also with C-N triple and C—N double bonds (see Section C.5.2.5.1.). In 1969 Roffey and Verge192 reported the reaction of 1,2,4,5-tetrazines with imidates 2 (X = O) to give 1,2,4-triazines 5 via the bicyclic intermediate 3 and the dihydro-1,2,4-triazine 4. Further studies, in particular by Boger and coworkers have shown that much better yields of 1,2,4-triazines are obtained when thioimidates 2 (X = s) are used as the dienophile.193-195... 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

Triazines react with tricyclo[4.2.2.02,5]deca-3,7,9-triene-7,8-dicarboxylates in refluxing toluene to yield azocines 18 via the given intermediates400,401 (see Section E. 1.1.1.1.1.). In the absence of aryl groups in the 5- and 6-positions of the 1,2,4-triazines, polycyclic compounds are isolated, probably by reaction of the dienophile with the formed azabicyclo[4.2.0]octa-trienes,402 the valence tautomers of the azocines, or with the initially formed polycyclic intermediates. 

Indole has also been used as a dienophile in cycloaddition reactions with 1,2,4-triazines.414 Depending on the substituents bound to the heterocyclic system / - or y-carbolines (33-89% or 6-22% yield, respectively), benzo[/][l,7]naphthyridines (2-50%) or 5-(indol-3-yl)-l,2,4-tri-azines are isolated (60-64%). 

Synthesis of pyrimidines by reaction of 1,3,5-triazine with C-H active compounds or by Diels-Alder reactions of 1,3,5-triazine with dienophiles is discussed in Sections 2.3.2.1.3. and 2.3.2.3., respectively. The use of a Dimroth-type rearrangement to give pyrimidine derivatives is shown on p 781. 

Triethyl l,3,5-triazine-2,4,6-tricarboxylate and 2,4,6-tris(methylsulfanyl)-1,3,5-triazine react in an inverse electron demand Diels-Alder reaction with several electron-rich dienophiles.6 The tricarboxylate 9 (R1 = C02Et) undergoes a well-defined [4 + 2] cycloaddition reaction with ynamines and enamines. In the case of ynamines, the [4 -1- 2] cycloaddition is followed by a retro Diels - Alder reaction at 40 100 °C with direct formation of the substituted pyrimidines 11. In the case of enamines, the cycloaddition provides stable, isolable [4 + 2] adducts 12. The subsequent retro Diels-Alder reaction and the final aromatization step is catalyzed by a mixture of hydrochloric acid and dioxane, anhydrous p-toluencsulfonic acid or acetic acid. This two-step process can be reduced to a single operation by conducting the reaction in a solution of dichloromethane and acetic acid at 40-100 °C.6 Electron-deficient dienophiles like dimethyl acetylenedicarboxylate or 1,4-naphthoquinone do not react with this triazine. 

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