Direct Synthesis of 4-Acetyl-1-alkyl-1H-pyrrol-2(5H)-ones from Difunctionalized Allyl Bromide

Abstract We describe a simple and efficient protocol for accessing some unsaturated heterocyclic compounds in a direct evaluation of allyl bromide as Z-ethyl 3-bromomethyl-4-oxopent-2-enoate. The latter reacts with primary amines via two successive nucleophilic substitutions followed by a 5-exo-trig cyclization to produce selectively 4-acetyl-1-alkyl-1H-pyrrol-2(5H)-ones in good yields. GRAPHICAL ABSTRACT


INTRODUCTION
The c-lactam framework is an important subunit widely found in many classes of organic aza-heterocycles. They are ubiquitous structural models in various natural products and biologically active pharmaceutical compounds. A number of a,bunsaturated c-lactams have been shown to exhibit significant pharmacological activities and are considered as important synthons [1] especially for the preparation of c-amino acids, [2] various alkaloids, [3] and natural products. [4] It is also known that some of these five-membered ring compounds develop antitumor properties, [5] as well as inhibit COX-2 [6] and HIV protease, [7] and hence their potential applications have stimulated much interest in the construction of these kinds of molecules. [8] Some general methods have been developed to access these five-membered heterocycles through the condensation of dimethoxydihydrofuran derivatives with primary amines; [9] the cyclization reaction of c-stannylated allylic aminoester; [10] the addition of primary amines to difunctionalized symmetrical 1,3-dienes [11] or to dimethyl a-(bromomethyl) fumarate; [12] acidic treatments of b-methoxy-b-aminoesters; [13] heating methanosulfonyl c-lactam derivatives; [14] the Horner-Wadsworth-Emmons (HWE) reaction of phosphono-c-lactams; [15] the one-pot, three-component condensation of acylpyruvates, aromatic aldehydes, and ethylenediamine; [16] and reaction of rhodium(I) carbenes with alkynes and alkenes. [17] Here, we report a recent synthetic approach to 4-acetylpyrrol-2(5H)-ones 5 from a new 3-bromomethyl-4-oxopent-2-enoic ethyl ester 4 which, to our knowledge, has not been previously described.

RESULTS AND DISCUSSION
According to the procedure developed earlier by our group, [18] commercial acetylacetone was successfully converted into ethyl 3-acetyl-4-oxopentanoate 1 using NaH in dry tetrahydrofuran (THF) and ethyl bromoacetate at reflux. The second step consisted of the deacylation of 2-alkylated-2,4-diketone using 30% aqueous formaldehyde and concentrated (6-10 M) solution of potassium carbonate, which afforded the vinyl ketone 2 (Scheme 1).
a-Bromomethylated substrates are recognized as being of great importance. During recent years, reports have shown the value of allyl bromides as powerful reagents in the synthesis of b-functional a-methylene-c-butyrolactones, [19] retinoic acids, [20] and cyclic ketones; [21] in the substitution reaction with enamines [22] and sulfite salts; [23] in oxidation with dimethylsulfoxide (DMSO); [24] and in the cycloaddition reaction of the corresponding pyridinium ylides. [25] For these reasons, a great deal of effort has been devoted to the development of methods for the preparation of compounds bearing a-bromomethyl moieties. However, only one method has been reported [26] for the preparation of the a-bromomethylated ketoester 4 using N-bromosuccinimide (NBS) as the brominating agent. On the other hand, we have shown that the addition of dibromine in carbon tetrachloride at room temperature to the vinyl ketone 2 followed by an efficient regio-and stereoselective dehydrobromination [27] of the dibrominated adduct 3 using triethylamine at 0 C produced ethyl 3-bromomethyl-4-oxopent-2-enoate 4 in 74% yield. The interpretation of the nuclear Overhauser effect spectroscopy (NOESY) 1 H NMR spectra led to the assignment of its configuration. The absence of correlation between the CH 2 Br protons and the ethylenic proton CH was in favor of the Z-configuration (Scheme 2).
Because the c-lactams are very interesting compounds in terms of pharmaceutical applications, we found that allylbromide 4 readily reacted with primary amines to provide pyrrol-2(5H)-ones 5a-h arising from two consecutive bimolecular Scheme 1. Synthesis of enone 2 by hydroxymethylation followed by fragmentation.

EXPERIMENTAL
Tetrahydrofuran (THF) was distilled prior to use from a deep-blue solution of sodium-benzophenone ketyl. All other reagents and solvents were standard-grade commercial products and were used without further purification. All reactions were monitored by TLC on silica-gel plates (Fluka Kieselgel 60 F254, Merck) and the series visualized by a 254-nm ultraviolet lamp and aqueous potassium permanganate solution. Crude products were purified using column chromatography on silica gel (Fluka Kieselgel 70-230 mesh). 1 H NMR and 13 C NMR spectra were recorded on a Bruker AMX 300 spectrometer at 300 MHz for 1 H, 282 MHz for 19 F, and 75 MHz for 13 C in CDCl 3 as solvent and TMS as the internal standard. The chemical shifts (d) and coupling constants (J) are expressed in parts per million (ppm) and Hertz (Hz), respectively. All NMR spectra were acquired at room temperature. Multiplicity of peaks is indicated as s, singlet; d, doublet; t, triplet; q, quartet; qt, quintuplet; sept, septuplet; and m, multiplet. High-resolution mass spectrometry (HRMS) analyses were performed in Laberca, a laboratory at Oniris (Nantes-Atlantic National College of Veterinary Medicine, Food Science, and Engineering) on a mass spectrometer equipped with a door coupled to a linear Orbitrap (LTQ-Orbitrap of Thermo Fisher Scientific) in positive electrospray ionization.  4-ACETYL-1-ALKYL-1H-PYRROL-2(5H)-ONES 3403

Synthesis of Z-Ethyl 3-Bromomethyl-4-oxopent-2-enoate 4
According to previous works, ethyl 3-methylene-4-oxopentanoate 2 was obtained in 66% yield. To a stirred solution of 2 (32 mmol, 5 g) in CCl 4 (80 mL), 1.2 equiv. of bromine (38.4 mmol, 2 mL) was added dropwise at 0 C. The resulting mixture was left for 1 h at room temperature, washed with an aqueous solution of Na 2 S 2 O 3 , and dried over MgSO 4 to eliminate excess of bromine. Triethylamine (Et 3 N, 70.4 mmol, 9.6 mL) was added to the cold mixture (0 C) and stirring was continued for 3 h at room temperature. The mixture was filtered and then concentrated under reduced pressure to leave an oil, which was purified by chromatography on silica gel (petroleum ether=AcOEt, 9:1 General Procedure for the Synthesis of 4-Acetyl-1-alkyl-1Hpyrrol-2(5H)-ones 5a-h Primary amine (2.55 mmol, 2 equiv.) was added dropwise to a solution of ethyl 3-bromomethyl-4-oxopent-2-enoate 4 (0.3 g, 1.27 mmol) in bromobenzene (7 mL). The solution was heated for 0.5 to 2.5 h at 150 C. The solvent was concentrated under reduced pressure and the crude product was purified by chromatography on silica gel.

CONCLUSION
In summary, we have successfully developed a simple and efficient method for the synthesis of Z-ethyl 3-bromomethyl-4-oxopent-2-enoate 4, which was used directly in the production of 4-acetyl-1-alkyl-1H-pyrrol-2(5H)-ones 5a-h. The target compounds are important synthetic intermediates and may find some applications in the development of biologically active compounds.

FUNDING
This work was supported by the Higher Education and Scientific Research of Tunisia.