Intramolecular thermal cyclizations of methyl ( E )-3-arylamino-2- benzoylaminobut-2-enoates

Methyl 3-anilino-2-(benzoylamino)but-2-enoates 3a–h were prepared from methyl 2-benzoylamino-3-oxobutanoate 1 and anilines 2a–h . Heating of butenoates 3a–h in refuxing anisole resulted in intramolecular cyclocondensation between the arylamino and benzoyl group to give methyl 1-aryl-5-methyl-2-phenyl-1 H -imidazole-4-carboxylates 4a–h . In the case of butenoates 3g,h , 4-[1-(arylamino)ethylidene]-2-phenyl-1,3-oxazol-5(4 H )-ones 5g,h were also formed as side products.


Introduction
Imidazoles certainly belong among the most important, significant, and abundant five-membered heterocycles, which are constituents of a variety of natural and synthetic products.Therefore, it is not surprising, that many different synthetic methods for the construction of the imidazole ring have been developed.However, there has been only a limited number of syntheses described in the literature, in which acyclic precursors containing the C-N-C-C-N structural element have been used. 1 Such examples are cyclizations of α-acylaminocarboxylic acid derivatives, [2][3][4][5] Nsubstituted derivatives of α-aminocarbonitriles, 6 N-substituted 1,2-diaminoalkanes, 7 and bis amides of oxalic acid. 8lkyl 3-(dimethylamino)propenoates and related enaminones are easily available and have proven to be versatile reagents for the preparation of a variety of heterocyclic systems, 3substituted dehydroalanine esters, functionalized heterocycles, and natural product analogs. 9ecently, we reported the preparation of methyl 3-anilino-2-(benzoylamino)but-2-enoates 3a-e, available in three steps from hippuric acid via transformation into 4- [ (dimethylamino)ethylidene]-2-phenyl-5(4H)-oxazolone, followed by methanolysis and treatment with anilines. 10Heating of 3a-c in polyphosphoric acid (PPA) at 130-140 °C resulted in formation of oxazolo[4,5-c]quinolines as the main products and methyl 1-aryl-5-methyl-2phenyl-1H-imidazole-4-carboxylates 4a-c as the side products. 11Formation of imidazoles 4 prompted us to continue this research and now we report thermal cyclisations of methyl 3anilino-2-(benzoylamino)but-2-enoates 3a-h under neutral conditions into imidazoles 4a-h.

Results and Discussion
Methyl 3-anilino-2-(benzoylamino)but-2-enoates 3a-h were prepared by treatment of methyl 2benzoylamino-3-oxobutanoate 1 10 with anilines 2a-h in refluxing ethanol in the presence of catalytic amounts of p-toluenesulfonic acid (PTSA) according to a slightly modified procedure described previously in the literature. 11Heating of butenoates 3a-f in anisole under reflux afforded the corresponding methyl 1-aryl-5-methyl-2-phenyl-1H-imidazole-4-carboxylates 4a-f in 14-57% yield.On the other hand, heating of butenoates 3g,h gave imidazoles 4g,h as the major products and 4-[1-(anilino)ethylidene]-2-phenyl-1,3-oxazol-5(4H)-ones 5g,h as the minor products (Scheme 1).Formation of imidazoles 4a-h can be explained by intramolecular cyclocondensation between the arylamino group and the benzoyl group resulting in elimination of water (Path A).On the other hand, formation of oxazolones 5g,h revealed another competitive cyclocondensation reaction, which takes place between the benzoylamino group and the ester group by elimination of methanol (Path B) (Scheme 2).Structures of all novel compounds were determined by spectroscopic methods (IR, NMR) and by analyses for C, H, and N. Oxazolones 5g,h were isolated as mixtures of the major (Z)and the minor (E)-isomers.The (Z)-configuration around the exocyclic C=C double bond in the major isomer of oxazolone 5h was determined by X-Ray diffraction (Figure 1).

Experimental Section
General Procedures.Melting points were taken with a Kofler micro hot stage.The 1 H NMR spectra (300 MHz) spectra were obtained with a Bruker Avance DPX 300 (300 MHz) spectrometer with CDCl 3 as solvent and Me 4 Si as internal standard.IR spectra were recorded with a Perkin-Elmer Spectrum BX FTIR spectrophotometer (KBr discs).The microanalyses for C, H, and N were obtained with a Perkin-Elmer CHN Analyser 2400.TLC was run using Merck Alufolien Kieselgel 60 F 254, 0.2 mm.Column chromatography (CC) was performed on silica gel (Fluka, Kieselgel 60, 0.04−0.063mm).All starting materials were commercially available (in most cases from Fluka) and purified following the standard techniques.Methyl 2-benzoylamino-3-oxobutanoate 1 10 and methyl 3anilino-2-(benzoylamino)but-2-enoates 3a-d 11 were prepared according to the procedures described in the literature.

General procedure for the preparation of methyl 3-anilino-2-(benzoylamino)but-2-enoates 3e-h
These compounds were prepared according to a slightly modified procedure described in the literature. 11A mixture of aniline 2e-h (0.001 mol), 1 (0.235 g, 0.001 mol), anhydrous ethanol (4 mL), and a catalytic amount of p-toluenesulfonic acid was heated under reflux for 5-12 h.A Dean-Stark trap, filled with molecular sieves (3Å), was used to remove water formed during the reaction.Volatile components were evaporated in vacuo, the residue was triturated with diethyl ether (3 mL), and the precipitate was collected by filtration to give 3e-h.

Figure 1 .
Figure 1.ORTEP view of the major (Z)-isomer of compound 5h showing atom labels of the non-hydrogen atoms.Ellipsoids are plotted at a 50% probability level.