A New Route to the Synthesis of 2‐Amino‐6‐(methoxycarbonyl)amino‐4‐(tetrahydropyridyl)pyrimidine 1‐Oxide

Müller, Jean-Claude; Ramuz, Henri; Wagner, Hans-Peter

doi:10.1002/hlca.19830660313

Cited by 12 publications

(1 citation statement)

References 4 publications

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“…With the exception of 6e all used ketene N,Oacetals 6 were prepared by the Pinner methodology. 3,[9][10][11][12][13] When tetrazine 5 was treated at 25°C in dichloromethane with ketene N,O-acetal 6a, the deep magenta color of 5 disappeared and an evolution of gas started. After 20 minutes, the reaction was complete giving a yellow-orange…”

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[4+2] Cycloaddition of Dimethyl 1,2,4,5-Tetrazine-3,6-dicarboxylate with EWG-Substituted Primary Ketene N,O-Acetals : Synthesis of Tetrafunctional Pyridazines and Pyrroles

Müller¹,

Troschütz²

2006

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A series of EWG-substituted primary ketene N,O-acetals were reacted with tetrazine-3,6-dicarboxylate yielding, by [4+2] cycloaddition, tetrafunctionalized pyridazines, which possess an EWG group, a primary amino function and two ester moieties. Reductive ring contraction of pyridazines gave aminopyrrole derivatives. Treatment of cyanamide with tetrazine-3,6-dicarboxylate led to a 5-amino-1,2,4-triazine derivative, which was rearranged to 4-aminoimidazole-2,5-dicarboxylic acid dimethyl ester. Diprimary ketene N,N-acetals 1, substituted with an EWG group serve as valuable building blocks for the synthesis of medicinally interesting N-heterocycles especially purine and pteridine analogues. 3,3-Diaminoacrylamide (1f, EWG = CONH 2 ) represents the main substructure in guanine and pterin. In previous studies we have performed several ring-closure reactions with 1. With 1,3-biselectrophiles, i.e. b-aminovinyl ketones or ketonic Mannich bases, we obtained 2-aminonicotinonitriles 1 or 2-amino-3-nitropyridines. 2 Treatment of 1a (EWG = CO 2 Et) with 1,4-benzoquinone gave 2-amino-5-hydroxyindole-3-carboxylates, 3 which are of medicinal interest as inhibitors of human 5-lipoxygenase. In order to find new cyclization reactions with 1 we were interested in [4+2] cycloadditions leading to functional pyridines 3 or 4, valuable educts for the synthesis of new pteridine analogues.It is well documented 4 that the Diels-Alder reaction of electron-deficient 1,3-oxazin-6-ones 5 and 1,2,4-triazines with ketene N,N-acetals 6 or ketene N,O-acetals 7 gives Ndisubstituted pyridineamines. Therefore we planned to react our EWG-substituted ketene N,N-acetals 1 with 2-azadiene systems [2] to generate primary pyridineamines substituted with an ortho EWG function. These compounds could serve as starting substances for new pteridine analogues, i.e. pyrido[4,3-d]pyrimidine derivatives (Scheme 1).Stirring or boiling of 2-trifluoromethyl-4-methyl-1,3-oxazine-6-one and congeners with ketene N,N-acetal 1a (EWG = CO 2 Et) in dichloromethane, toluene or dioxane gave no product. The unsuccessful reaction with 1,3-oxazin-6-ones forced us to use another 2-azabutadiene system, which is incorporated in 1,2,4-triazinecarboxylates. In order to avoid formation of regioisomeric pyridines when using 1,2,4-triazinecarboxylates, we selected the symmetric dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (5), 8 which incorporates an s-cis-fixed 2,3-diazabutadiene system [5].Treatment of ketene N,N-acetal 1a (EWG = CO 2 Et) with tetrazine-3,6-dicarboxylate 5 at low or elevated temperatures in different solvents, i.e. dichloromethane, toluene or dioxane gave no product which could be characterized. So we turned our attention to the precursor of 1a (EWG = CO 2 Et), the ketene N,O-acetal 6a (Scheme 2).A convenient access to EWG-substituted ketene N,O-acetals 6 is the Pinner reaction of corresponding EWG-substituted acetonitriles, giving imidate hydrochlorides, from which the free imidate is liberated by base. As an imidate with a EWG group, it will tautomerize partially or t...

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confidence: 99%