A novel synthesis of N1-(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones

Abstract

A new synthesis of N 1 -(substituted)-pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones, which are analogues of the natural product toxoflavin, is reported. Condensation of preformed alkyl or aryl hydrazones with 6-chloro-3-methyl-5-nitrouracil efficiently provides pyrimidotriazinediones in a three-step process that broadens the scope of R 1 substituents. KeywordsPyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones; Toxoflavin; Hydrazones; Cyclizations; Zinc Toxoflavin (1; Fig. 1), which was originally isolated from Pseudomonas cocovenenans, was first synthesized in 1961.1 Since then, a number of analogues have been prepared in order to explore the potent antibiotic and pharmacological properties of the pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-dione class represented by this natural product.2 Many of these analogues have the same methyl substituent found at the N 1 position of toxoflavin, partially due to the ease with which a methyl group can be incorporated via the use of methylhydrazine early in the synthesis.3 Other analogues have either a proton at N 1 or a variety of alkyl and benzyl groups. Conspicuously absent, however, are pyrimido [5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones with an aryl substituent at the N 1 position. This can be attributed to the classical route that has been utilized, which requires that nucleophilic attack of 6-chloro-3-methyluracil proceed via the secondary nitrogen of the mono-substituted hydrazine. However, for mono-aryl hydrazines, such attack typically proceeds via the primary nitrogen. Herein, we report a novel and efficient route to pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones that allows for incorporation of aryl and alkyl substituents at N 1 of this ring system, thus broadening the scope of accessible analogues.Our strategy is shown in Scheme 1 and is exemplified with phenylhydrazine. First, phenylhydrazine (2) was treated with p-anisaldehyde (3a) under reflux conditions to form hydrazone 4a, which readily precipitated out of ethanol upon cooling. The resulting hydrazone (4a) was then treated with 6-chloro-3-methyl-5-nitrouracil (5), derived from nitration of commercially-available 6-chloro-3-methyluracil by the published method.4 The resultant 6-(2-(4-methoxybenzylidene)-1-phenyl)hydrazinyl-3-methyl-5-nitrouracil (6a) was cyclized to 3-(4-methoxyphenyl)-6-methyl-1-phenylpyrimido[5,4-e][1,2,4]triazine-5,7(1H, 6H)-dione (7a) upon treatment with zinc (4 equiv) and ammonium chloride (2 equiv) while exposed to air and with vigorous stirring in refluxing 50% aq ethanol. The N 1 -phenylpyrimidotriazinedione was isolated cleanly by treating the suspension with 1 N aq HCl to dissolve residual zinc and then washing the precipitate with 1 N aq HCl while filtering.5 The zinc-mediated cyclization was also tried in pure water or ethanol as the solvent, but the yields were considerably diminished. While hydrogenation over Pd/C has been shown to yield pyrimidotriazinediones previously from intermediates analogous to 6a, the reported yields are deplorable, usually only 2-5%.6 In star...

Investigation of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5,7-diones as small molecule antagonists of β-catenin/TCF transcription

“…(i) 4-substituted benzaldehyde, EtOH, reflux (31–87% yield); (ii) NaNO 2 , aq. AcOH, 0 °C – 25 °C (~80% yield); (iii) DTT, EtOH (47 – 87% yield); (iv) see reference 20; (v) for 10b , BBr 3 , DCM (63% yield); (vi) BrCH 2 CH 2 Br, Cs 2 CO 3, DMF (47% yield); (vii) NHMe 2 , ACN, 80 °C (33% yield). See Supplemental Materials for experimental details.…”

“…In earlier work, we reported on a novel and efficient route to 3-aryl derivatives of 3 that allows for incorporation of aryl and more elaborate alkyl substituents at the N 1 position, thus broadening the scope of accessible analogues. 20 We also reported on the generation of compounds within the isomeric fervenulin series ( 4 , Figure 1). 21 …”

“…Additional target derivatives 10a,b and 11c were derived from 6-chloro-3-methyl-5-nitrouracil ( 9 ) by our recently published methodology to make compounds with more elaborate N 1 substituents. 20 The synthesis of N 8 -substituted pyrimidotriazinedione derivatives (fervenulin series) was achieved by two reaction pathways and is shown in Scheme 2. Heating compound 8a or the 7a / 8a mixture in DMF led to a well precedented N 1 demethylation reaction to give 12 .…”

A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones and Facile Extension to 5,7(6H,8H) Isomers

“…2 We recently have reported on a novel synthesis of compounds related to 1, including hitherto inaccessible N 1 -phenyl analogues 3. 3 In this paper, we report on the further application of this synthesis to a variety of N 1 -alkyl and N 1 -aryl compounds, and an efficient process for extending this synthesis to the generation of compounds within the isomeric fervenulin series.The strategy and range of analogues synthesized within the pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-dione (toxoflavine) series is shown in Table 1. First, monosubstituted hydrazines 5, either as the free base or hydrochloride salt, were condensed under reflux with aromatic aldehydes 6 in ethanol or tetrahydrofuran to form hydrazones 7, which usually precipitated out of solution upon cooling.…”

“…2 We recently have reported on a novel synthesis of compounds related to 1, including hitherto inaccessible N 1 -phenyl analogues 3. 3 In this paper, we report on the further application of this synthesis to a variety of N 1 -alkyl and N 1 -aryl compounds, and an efficient process for extending this synthesis to the generation of compounds within the isomeric fervenulin series.…”