Diels-Alder reactions of 1,2,4-triazines

C. Sulfur as an Auxilliary in the Diels-Alder Reaction of Triazines. 55... 

When the 5-methoxy derivative 107 was reacted with enamine in refluxing chloroform, pyridine 108 was obtained (Scheme 45) [28], Diels-Alder reaction of triazine 5 with norbomadiene leads to formation of pyridine 109 (Scheme 45). Low yield of 109 clearly shows that this Diels-Alder reaction proceeds in an inverse electron demand manner [28]. 

A Diels-Alder reaction of arynes with 1,2,4-triazines 102 allows the preparation of isoquinolines substituted with electron-withdrawing groups in the nitrogen-containing ring. The isoquinoline-1-carboxylic esters bearing additional substituents are of particular interest because they are not readily available by the usual routes [100,101] (Scheme 2.42). 

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>. 

Pyridine synthesis via hetero-Diels-Alder reaction of 1,2,4-triazines and dieno-philes (e.g. enamine) followed by extrusion of N2. 

PREPARATION AND INVERSE ELECTRON DEMAND DIELS-ALDER REACTION OF AN ELECTRON-DEFICIENT HETEROCYCLIC AZAOIENE TRIETHYL 1.2,4-TRIAZINE-3,5,6-TRICARBOXYLATE (l,2,4-Triazine-3,5,6-tricarbo orl 1c acid, triethyl ester)... 

DIELS-ALDER REACTION OF TRIETHYL 1,2,4-TRIAZINE-3,5,6-TRICARBOXYLATE... 

Diels-Alder reaction of triethyl l,2,4-triazine-3,5,6-tricarboxylate, 66, 150 Diels-/ lder reactions, 66, 40 Diethyl amine, 66, 145... 

An unprecedented nitrogen elimination reaction of 4-amino-7-benzylpyrrolo [23- f][133]triazine-5-caibonitrile (72) to give the pyrrole derivative 74 has been described. The following mechanism, presumably via a a retro Diels-Alder reaction of the imino tautomer 73, has been proposed <990L537>. 

The reaction of 8-chlorotheophyllines with nitrilium imides to give [l,2,4]triazolo[3,4y]purines may be described as a [3+2] cycloaddition process <2001JOC4055> see Section 10.11.5.1. The purine bicycle has been prepared through the Diels-Alder-retro-Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-amino-l-benzylimida-zole <1999JA5833> see Section 10.11.10.3. 

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]

Intramolecular Diels-Alder reactions of 1,2,4-triazines provide convenient access to condensed pyridine heterocycles. On this basis, thermolysis of propynylthiophenylamino-1,2,4-triazines (111) in refluxing bromo-benzene over a period of 2-5 days afforded 5,ll-dihydropyrido[3,2-c][l,5]benzothiazepines (112), but in yields that were consistently less than 5% (89JOC1456). The major reaction products were pyridobenzothia-zines 113 and benzothiopyranes 114 the formation of these products, involving a six-membered transition state, is preferred to the formation of the Diels-Alder product 112, which proceeds through an entropically less favorable seven-membered transition state (Scheme 34). 

The Diels-Alder reaction of 5-acetyl-3-methylthio-l,2,4-triazine with cyclic enam-ines produces 3-acetyl-l-methylthiocycloalka[c]pyridines, which are synthons for the preparation of sempervirine and its analogues.126 Cycloadditions of aryl-substituted 1,2,4-triazines (117) with 2-cyclopropylidene-l,3-dimethylimidazolidine (118) yield Diels-Alder adducts (120) that eliminate N2 to form dispiropyridines (121), which rearrange to pyrrolo[3,2-c]pyridines (122). At low temperatures, zwitterions (119) formed by nucleophilic attack of (118) on the triazines could be detected spectroscopically and, in some reactions, isolated (Scheme 34).127... 

Scheme 35 Inverse electron-demand Diels-Alder reaction of enamines and 1,2,4-triazines...

Deoxygenative v.s vicarious nucleophilic substitution of hydrogen in reactions of 1,2,4-triazine-4-oxides with a-halocarbanions has been described <02EJO1412>. Tandem vicarious nucleophilic substitution of hydrogen/intramolecular Diels-Alder reaction of 1,2,4-triazine (19) into functionalized cycloalkenopyridines 21 has been reported <02CPB463>. 

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. 

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. 

The inverse electron demand Diels-Alder reactions of 5-amino-177-pyrrole-3-carbonitriles 1121 with various 1,3,5-triazines 1122 are suitable for one-pot syntheses of highly substituted and highly functionalized 7/7-pyrrolo[2,3- -pyrimidine-5-carbonitriles 1123 (Scheme 220) <2002JOC8703>. These are the central heterocyclic nuclei of various nucleoside natural products such as Toyocamycin, Sangivamycin, and Tubercidin (Figure 5). 

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