2(3 H )-Furanones as synthons for polyamides of 1,3-diazines and 1,3,5-triazines

2(3 H )-Furanones 3a-d having an exocyclic double bond and an N-acetylisation nucleus were converted into novel polyamides of pyrimidine derivatives via reaction with nitrogen nucleophiles. NMR, GC/MS and chemical evidence confirmed all proposed structures.


Introduction
The rapid assembly of "drug-like" core templates is fundamental to the discovery phase of many medicinal chemistry programs.If the syntheses of these core templates will allow for their ready functionalization, a meaningful SAR study can be efficiently conducted.In addition to ready assembly and core functionalization, the core template should have relatively low molecular weight and log P. [1,2] This will allow room for the molecule to grow as functionalization is incorporated, thus allowing the targeting of the many essential criteria of drug candidates including selectivity, potency, and efficacy.We identified compounds 5a-d, 6a-d, 8a-d, and 10ad as attractive molecular scaffolds for our medicinal chemistry program since both platforms are relatively novel in the patent literature, compatible with our pharmacophore model and have relatively low starting molecular weights and calculated log P values.Over the past two decades, 2(3H)-furanones have attracted strong interest from our group [3][4][5][6][7][8], because of possible applications of the corresponding biologically active compounds [9,10].Nitrogen heterocycles constitute an important class of natural and non-natural products many of which exhibit useful biological activity [11][12][13][14].Isatin 1, and a number of its derivatives, possess a reactive ketocarbonyl group that readily undergoes condensation reactions under mild conditions [15a].It was
We are pleased to report herein a facile method for the synthesis of mono and diamides of biologically important pyrimidines 5a-d and 6a-d via reaction with one and two mole equivalents of 2(3H)-furanones 3a-d and with one mole equivalent of trimethoprime 2 in ethanol in good to excellent yields (64-80%).There have not been reports of the synthesis of the ring systems 5a-d and 6a-d in the chemical literature.The reaction of 2(3H)-furanones 3a-d with trimethoprime 4 in 1:1 mole ratio, refluxing in ethanol over 12 h, afforded monoamido 1,3diazines 3a-d in 64-80% yield (Scheme 1).In contrast, the 1,3-diazines 3a-d were isolated in very low yield (10-15%) when the reaction took place in a non-protic solvent.However, reaction of 2(3H)-furanones 3a-d with trimethoprime 4 in a 2:1 mole ratio provided the diamido 1,3-diazines 6a-d in 53-62% yields.The latter, 6a-d, remain under our investigation and have anticipated biological activity.The 2(3H)-furanones 3a-d were treated neat with a molar equivalent of melamine 7 (1:1 mole ratio) and heating above the melting point over 2-3 h afforded monoamides 8a-d in low yield (22-35%).These products 8a-d were isolated in similar or even better yields (36-50 %) when the reaction took place in a protic solvent (EtOH) by ring opening (Scheme 1).However, when the reaction was repeated by adding two mole equivalents of 3a-d and one mole equivalent of melamine 7 (2:1 mole ratio) the corresponding melamides 9a-d were obtained, which were formed also by refluxing 8a-d with one mole of 3a-d for 6-12 hours.Since 9a-d are the penultimate intermediates, it follows that the utility of this reaction will depend on their ease of preparation.The route described has some limitations in that it requires multiple steps as well as pure starting materials or reaction conditions that limit the ultimate utility of the reaction.Similar reaction conditions were repeated carefully by adding three mole equivalents of 3a-d into one mole equivalent of melamine 7

Biological activity
Compounds 5a-d, 6a-d, 8a-d, and 10a-d remain under our investigation and show promising biological activities against Neurodegenerative disorders (Alzheimer disease), Cardiovascular diseases (atherosclerosis) and Viral diseases (AIDS).The findings from these latter studies will be published elsewhere.

Experimental Section
General Procedures.Melting points were determined on a Boetius hot-stage apparatus and are uncorrected.Chromatographic separations were performed using silica gel (Merck, 70-230 mesh).Thin-layer chromatography was carried out on Macherey-Nagel precoated silica plates (0.25 mm layer thickness). 1 H NMR and 13 C NMR spectra were recorded with a Gemini 200 spectrometer in CDCl 3 solution unless otherwise specified (internal standard TMS).Mass spectra were taken on a VG Trio-2 and Gc/Ms-QPL000EX (EI, 70 eV) apparatus.IR spectra were recorded with a Perkin-Elmer 1430 instrument in KBr disks.M-H-W Laboratories (Phoenix Az) and the Microanalytical center of Cairo and Ain Shams Universities performed elemental analyses.
General procedure for 3a-d.2-(3H)-Furanones (3a-d) were prepared following the literature method [24,27], via condensation of isatin 1 (1.47 gm, 0.01 mol) with 3-aroylpropionic acids 2 (0.01 mole) in acetic anhydride (10 mL) and fused sodium acetate (0.03 mol) under Perkin conditions.The corresponding E-isomers were obtained as the sole products, with no detectable amount of the Z-isomers being identified by TLC and 1 H NMR. The reddish green precipitate was collected by filtration and recrystalized from acetic acid to give 3a-d.General procedure for 5a-d.To a suspension of 3a-d (0.1 mol) in ethanol (30 mL), was added trimethoprime 4 (0.1 mol) and the reaction mixture was refluxed for 6-12 hours.After cooling, the reddish brown precipitate was collected by filtration and recrystalized from toluene to give 5a-d.General procedure for 6a-d.To a suspension of 3a-d (0.2 mol) in ethanol (30 mL), was added trimethoprime 2 (0.1 mol) and the reaction mixture was refluxed for 6-12 hours.After cooling, the reddish brown precipitate was collected by filtration and recrystalized from toluene to give 6a-d.7)), 8.12-6.77(m, 18H, -Ar-H), 6

General procedure for 8a-d
To a suspension of 3a-d (0.1 mol) in ethanol (30 mL), was added melamine 5 (0.1 mol) and the reaction mixture was refluxed for 6-12 hours.Afetr cooling, the semi-solid precipitate was collected by filteration and titurated with pet.ether.The solid product obtained was recrystalized from ethanol to give 8a-d.

General procedure for 10a-d
To a suspension of 3a-d (0.3 mol) in ethanol (30 mL), was added melamine 7 (0.1 mol) and the reaction mixture was refluxed for 6-12 hours.After cooling.the semi-solid precipitate was collected by filtration and triturated with pet.ether.The solid product obtained was recrystalized from ethanol to give 10a-d.