1.2.4- Triazines, cycloaddition

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

The 27T-electrons of the carbon-nitrogen double bond of 1-azirines can participate in thermal symmetry-allowed [4 + 2] cycloadditions with a variety of substrates such as cyclo-pentadienones, isobenzofurans, triazines and tetrazines 71AHC(13)45). Cycloadditions also occur with heterocumulenes such as ketenes, ketenimines, isocyanates and carbon disulfide. It is also possible for the 27r-electrons of 1-azirines to participate in ene reactions 73HCA1351). 

Triazine, 3-methyl-cycloaddition reactions, 3, 427 mass spectra, 3, 396... 

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). 

The reaction of oxepin and 2,7-dimethyloxepin with dimethyl 3-cyano-l,2,4-triazine-5,6-dicarb-oxylate takes the same course as the cycloaddition to the tetrazine. Two different addition products 11a and 12 are obtained in the case of oxepin, whereas dimethyloxepin yields only the [4 + 2] adduct lib.235... 

The inverse electron demand Diels-Alder [4 + 2] cycloadditions of methyl 1,2,4-triazine-3-carb-oxylates 36 (cf. Section B.2.2.) with cyclopropene followed by loss of nitrogen from the unstable cycloadducts 37 provide useful access to 4//-azepine-2-carboxylates 38.83-85... 

Treatment of methyl 6-phenyl-l,2,4-triazine-3-carboxylate (41) with cyclopropene produces methyl 6-phenyl-4//-azepine-2-carboxylate (42) in equilibrium with its bicyclic valence tautomer 43, which undergoes a second cycloaddition with cyclopropene to yield the bisadduct 44.112... 

A recent variation of these reactions uses 6/f-l, 3-oxazin-6-ones as the electron-deficient heterodiene in place of the triazine.113114 With cyclopropene at — 35 C oxazinone 45 furnishes the 4//-azepine 46 in excellent yield. Likewise, with 3-methylcyclopropene the 4-methyl derivative 46 (R = Me) is formed. Cycloaddition with 1-methylcyclopropene, however, generates a mixture of 7-tert-butyl, 2-methyl 3-methyl- and 5-methyl-4//-azepine-2,7-dicarboxylate in a 2 1 ratio and a 97 % overall yield. 

As with the 1,2,4-triazines,83 temperature control during these cycloadditions is important, since additions at 0-25 C result in the formation of 2 1 cyclopropene-azepine cycloaddition products.113... 

Similarly, 4//-azepinc-2-carboxylates 16, obtained by cycloaddition of 1,2,4-triazines with cyclopropenes (see Section 3.1.1.1.2.), isomerize in practicable yields to 3//-azepines 17 in refluxing pyridine,84-85 or with sodium methoxide in refluxing methanol.28-83... 

In a sequence of cycloaddition and cycloreversion, 3-phenyl-l, 2,4-triazine 1-oxides react with benzyne, generated from 2-aminobenzoic acid (see Houben-Weyl, Vol. 5/2 b, p 622 ff), to give 2-phenyl-l, 3-benzoxazepines in moderate yield.419... 

Triazine (38) is ideal for inverse electron-demand Diels-Alder cycloadditions, for example, with azulene to give a l,4-bis(CF3)phthalazine (89CB711). A rare example of the synthesis of a five-membered heterocycle originating from [4 + 1] cycloaddition followed by [4 + 2] cycloreversion was reported using (38). The intermediate tetraazanorbomadienimine (39) is highly strained and eliminates N2 [82AG(E)284]. 

Trifluoromethyl-l,2,4-triazines and 1,2,4-triazin-5-ones are versatile precursors for azetidines and pyridines by cycloaddition reactions. Enhancement of reactivity was observed through the presence of the trifluor-omethyl group (88CPB3354). 

Pyrrolo annulated triazine 77 was prepared (88TL4415) by the [6 + 4]-cycloaddition of azoniafulvene ion 76 with azomethine imines generated from benzylidene phenylhydrazone (Scheme 19). 

Treatment of 1,2,4-triazines 91a-91e with the electron-deficient die-nophile dimethyl acetylenedicarboxylate gave products, depending on the substituents [77LA( 10) 1718]. Pyrrolo-[2, -/][ ,2,4]triazines 92 were obtained via [4 + 2]-cycloaddition [77LA(9)1413, 77LA( 10)1718] with 91, but interaction with 91b in the absence of solvent gave, in addition to 92, the pyrido[2,l-/][l,2,4]triazine 93 and [l,3]oxazino[2,3-/][l,2,4]-triazine 94. In case of 91a pyridine and benzene derivatives were also formed in addition to 92 (Scheme 23). 

Thiazolotriazines 636 (R = CO,Me) were prepared [84JCS(P1)2707] by cycloaddition of dimethyl acetylenedicarboxylate with triazine derivative 632. Derivatives of thiazolo[3,2-b][l,2,4]triazin-3,7-diones 637 have been formed (74JPR163) on reaction with aromatic aldehydes and diazonium salts to give 636 (R = Ar) and 638, respectively. Regioselective catalyzed... 

Disubstituted pyridines [86] 87 have been prepared by catalyzed cycloaddition of 4-methyl-1,2,3-triazine 85 with aldehyde enamines 86 (Equation 3.29). The best yields were obtained when ZnBr2 was used as catalyst. 

Scheme 73 General scheme for cycloaddition of triazines with enamines...

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>. 

Elimination of nitrogen from D-A adducts of certain heteroaromatic rings has been useful in syntheses of substituted aromatic compounds.315 Pyrazines, triazines, and tetrazines react with electron-rich dienophiles in inverse electron demand cycloadditions. The adducts then aromatize with loss of nitrogen and a dienophile substituent.316... 

In contrast to some analogous structures, pyrido[2,l-f][l,2,4]triazine 108 is quite stable toward atmospheric oxygen. It reacts, however, with singlet oxygen in a cycloaddition reaction, and the intermediate 109 thus formed loses nitrogen resulting in the pyridone 110 (Scheme 8) <2001JHC205>. 

The pyrido[l,2-tf][l,3,5]triazine-2,4(3//)-dione derivative 89 was obtained in a cycloaddition reaction of diphenyl-methyl isocyanate 90 with 2-pyridyl isocyanate 91 derived from the corresponding acyl azide via Curtius rearrangement <2002ARK438>. Compound 89 was also synthesized by the reaction of diphenylacetyl chloride 118 and picolinyl azide 116a in the presence of triethylamine (Scheme 11) <2002ARK438>. ... 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

The reaction of 1,2,3-triazolium-l-aminides 3 with propiolate esters led to fluorescent 2,5-dihydro-1,2,3-triazine derivatives 4 in one pot, involving a Huisgen cycloaddition followed by a sequence of rearrangements <06JOC5679 06TL1721>. These reactions can be carried out in acetone, in water, or under solvent-free conditions. 

The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A, O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S1513>. 

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