Indole reaction with 1,2,4-triazines

Phenylsulfonyl)indole 330 was converted to a ketone by a set of standard reactions followed by the selenium dioxide oxidation of the resulting acetyl goup to the ketoaldehyde 332 (Scheme 101). Methylthiosemicarbazide hydroiodide reacted with 332 to the triazine 333 in 83% yield. As Diels-Alder reactions with 1 -pyrrolidinocyclohexene failed, 333 was first oxidized... 

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). 

Deprotection of triazines 1099 followed by reaction of triazines 1103 with the unstable indolylimidazolylurea 1104, generated in situ from GDI and indole Grignard salt, gave the desired urea-tethered triazine 1105 albeit in poor yield (38%, Scheme 215) <1995TL6591>. Heating the urea 1105 in TIPB produced cycloadduct 1106 in 65% yield. The... 

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%). 

Intermediate 50 was subsequently heated under reflux in triisopropylbenzene (232 °C) for 1.5 to 20 h to provide the basic canthine skeleton 51. Recently, Lindsley et al. reported a rapid MW-mediated procedure for synthesis of 51 [95]. This reaction, performed in a monomode MW reactor at 180 °C, required a reaction time of only 5 min. Even more interesting, treatment of the acryl hydrazide-tethered indole input, with benzil in the presence of 10 equiv. NH4OAC delivered not only the expected triazine 50 but also, directly, the 1,2-diphenyl canthine derivative 51 (Scheme 17.37, reaction path b). The products were formed in a 9 1 ratio of 50 and 51, respectively. In the one-pot reaction, the indole underwent a three-component condensation to generate 50 followed by an intramolecular inverse-electron-demand Diels-Alder reaction and subsequent chelotropic expulsion of N2 to generate the 1,2-diphenyl canthine 51. 

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>. 

These authors found that nucleophilic additions to the unsubstituted ring system 1 can be carried out to yield a number of 7-substituted dihydro products or, in some cases, where an oxidation can follow this addition, also 7-substituted heteroaromatic derivatives (Scheme 6). Thus, reaction of 1 with indole under acidic conditions (in trifluoroacetic acid) yields 7-(177-indol-3-yl)-7,8-dihydrotetrazolo[l,5- ][l,2,4]triazine 24 <1998ZOR450>. Reaction of 1 with 3,4-difluoroacetophenone in the presence of potassium /frt-butoxide in tetrahydrofuran followed by... 

The inverse electron demand Diels-Alder (IDA) reactions of 3-substituted indoles as 2rt-components with 1,2,4-triazines and 1,2,4,5-tetrazines proceeded in excellent yields both inter- and intramolecularly <1996TL5061>. The reaction of iT-BOC-tryptamine (1110, R = BOCNH(CH2)2) and indole 1110 (R =Me) with dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 1111 in refluxing dioxane (3h) provided cycloadducts 1112 (R2 = B0C) and 1113, respectively, in excellent yields (80% and 82%, Scheme 217). Deprotection of compound 1112 produced derivative 1112 (R = H, >99%). 

Another example of interaction between A7/-triazinium salts and C-nucleophiles is the reaction of 3-substituted 1,2,4-triazines with indoles in the presence of trifluoroacetic acid (Scheme 17) (87MI2 88MI1). 

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