Oxidative S N H-alkoxylation of 1,3,7-triazapyrenes

Abstract

The classic strategies for synthesizing alkoxy derivatives of nitrogen heterocycles are based on the nucleophilic substitution of good leaving groups. Among these are also nonoxidative methods occurring via a tele-mechanism. Hence heteroarenes with di-or trichloromethyl substituents react with alkoxide anions to give products of substitution of hydrogen in the ring by an alkoxy group [1][2][3][4].In the case of electron-deficient aza aromatic substrates a better alternative can be a direct oxidative nucleophilic substitution of hydrogen (ONSH [5]) by an alkoxy group since it does not need the preliminary introduction of good nucleofuges into the molecule. However, in the literature there are only individual examples of the successful alkoxylation of heterocycles via the ONSH process [6,7].In studying the reactivity of 1,3,7-triazapyrenes [8] relative to nucleophiles we unexpectedly found that they very readily undergo a double alkoxylation under unusual conditions. Reaction of 1,3,7-triazapyrene (1a) and its 2-methyl-substituted 1b with excess KOH and K 3 Fe(CN) 6 in aqueous methanol solution occurs at room temperature to give a high yield of the previously unknown 6,8-dimethoxy derivatives of this heterocycle (2a and 2b respectively). A similar reaction with 1a and ethyl or propyl alcohols gave the 6,8-diethoxy-(2c) and 6,8-dipropoxy-1,3,7-triazapyrene (2d). N N N R N N N R OR 1 1a,b R 1 OH, H 2 O KOH, K 3 Fe(CN) 6 2a-d R 1 O 2 a R = H, R 1 = Me (98%), b R = R 1 = Me (89%), c R = H, R 1 = Et (91%), d R = H, R 1 = Pr (69%)

Synthesis and cleavage of 1,3,7-triazapyrene ethers

“…Against this background, our previous observations of the easy ONSH alkoxylation [8,9], amination [10], and alkylamination [11] of 1,3,7-triazapyrenes is of great interest. Thus, the oxidative alkoxylation of 1,3,7-triazapyrene (1a) and its 2-methyl derivative 1b occurs at room temperature in the corresponding aqueous alcoholic solutions with an excess of KOH and K 3 Fe(CN) 6 [8], whereas compounds 1a and 1b remain unchanged in the conditions mentioned above [6].…”

“…6,8-Dioxo-1,6,7,8-tetrahydro-1,3,7-triazapyrene (8). A solution of one of the compounds 2a,c or 7 (0.5 mmol) in 60% H 2 SO 4 (10 ml) was refluxed for 24 h. After cooling, the mixture was diluted with H 2 O (40 ml) and neutralized with ammonia solution to pH 7.…”

“…Thus, the reaction of 1,3-dimethyllumazine with N-bromosuccinamide in the corresponding primary alcohol led to 6-alkoxy-and 6,7-dialkoxy derivatives of 1,3-dimethyllumazine [6]. Methoxylation of 2-nitro-5,10,15,20-tetraphenylporphyrin copper complex with sodium methoxide in DMF is reported in paper [7].Against this background, our previous observations of the easy ONSH alkoxylation [8,9], amination [10], and alkylamination [11] of 1,3,7-triazapyrenes is of great interest. Thus, the oxidative alkoxylation of 1,3,7-triazapyrene (1a) and its 2-methyl derivative 1b occurs at room temperature in the corresponding aqueous alcoholic solutions with an excess of KOH and K 3 Fe(CN) 6 [8], whereas compounds 1a and 1b remain unchanged in the conditions mentioned above [6].…”

“…The starting 1,3,7-triazapyrenes 1a,b [19] and 1c [20], and the standards of alkoxy derivatives 2a-d [8] were synthesized by the indicated methods.…”

Oxidative amination and hydroxylation of 1,3,7-triazapyrenes in aqueous medium

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We have already reported the unusual capacity of 1,3,7-triazapyrenes 1a and 1b [1] and 7-alkyl-1,3,7-triazapyrenium salts [2][3][4][5] to react readily in aqueous solution with O-nucleophilic reagents to give mono-and disubstitution products. This is the result clearly not only of the -electron deficiency of these compounds but also the specific peri-fusion structure of this heterocyclic system.

The oxidative amination of the most electrophilic heterocycles such as naphthyridines [6] or 1,2,4-triazine [7] is carried out by action of a solution of KMnO 4 in liquid ammonia.

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