AmberChrom/brine as a Green Catalytic System for Synthesis of Pyrrolin-2-ones

A literature survey shows that the preparation of pyrrolinone derivatives has been of considerable synthetic interest, 1 – 7 and this may be attributed to the biological activity of the moiety in a number of natural products and drugs. Among these we may note Cotinine (the major metabolite of nicotine), 8 Doxapram hydrochloride (a respiratory stimulant), 9 Ethosuximide (an anticonvulsant), 10 Rolipram (an inhibitor of cardiac cyclic AMP phosphodiesterase), 11 ( (cid:1) )-Azaspirene (an angiogenesis inhibitor), 12 Lactacystin (formed by bacteria of the genus Streptomyces bacteria), 13 Salinosporamide A (synthe-sized by the organism Salinispora tropica ), 14 HDPOs (HIV integrases), 15 and several pesticides 16 (Figure 1). These compounds are useful intermediates for performing intramolecular 17 and intermolecular 18 [2 þ 2] photocycloaddition reactions and as syn-thons for highly substituted pyrroles. 19 The synthesis of 2-pyrrolinone derivatives by the one-pot three-component reaction among aromatic aldehydes, arylamines, and acetylenedicarboxylate derivatives has been studied by several methods: a) in water-ethanol without catalyst, 20 b) in the presence of p -toluensulfonic acid, 21 c) under ultrasound 22 or microwave 23 irradiation, d) using admicellar catalysis (nano-TiO 224 ), e) in the presence of ionic liquids, 25 – 27 f) by such nano-magnetic particles as Fe 3 O 4 @ SiO 2 @ Propyl – ANDSA 28 and Fe 3 O 4 @ PEG-400@oxalic acid, 29 and under visible light (

Encouraged by these results, we turned our attention to a new method for the synthesis of the title compounds from aldehydes, anilines, and dimethylacetylenedicarboxylate (DMAD) catalyzed by the environmentally friendly, inexpensive and reusable catalyst AmberChrom50WX4 as shown in Scheme 1.
AmberChrom50WX4 (formerly DOWEX) is a copolymer of styrene and divinylbenzene (DVB) with fine meshes. This microporous copolymer has maximum resistance to reduction, oxidation, mechanical wear, and breakage. This material is also insoluble in common solvents (H 2 O, MeOH, EtOH, CH 3 CN, Et 2 O, THF, CH 2 Cl 2 ). AmberChrom50WX4 (as a strong acid cation exchange resin) can provide a convenient acidic surface for the intended multicomponent reaction because of the presence of sulfonic acid groups within the matrix of styrene and divinylbenzene. 40 In order to optimize reaction conditions, several experiments were carried out ( Table 1, entries 1-12). The best results were obtained by using AmberChrom50WX4 (1 g) in ethanol (5 mL) for the model reaction of aniline (1 mmol), benzaldehyde (1 mmol), and DMAD (1 mmol) (entry 4, Table 1) in the preparation of the corresponding 2-pyrrolidinone (1a, Ar ¼ Ph, Ar' ¼ Ph). The mixture of aniline, aldehyde, and AmberChrom50WX4 was stirred at room temperature for 30 minutes. Then DMAD was added to the reaction mixture, and the reaction was completed after 24 hours to give methyl 4-hydroxy-5oxo-1,2-diphenyl-2,5-dihydro-1H-pyrrole-3-carboxylate in 90% yield. It is notable that a greater amount of catalyst did not decrease reaction time (entries 5-6, Table 1). In addition, different solvents (entries 7-12, Table 1) were examined under the optimized reaction conditions, and ethanol was determined to be both convenient and comparatively green.
These were promising results, but the lengthy reaction time remained a challenge. To address this issue, a new catalytic combination system was designed; that is, AmberChrom50WX4 was used in the presence of a few drops of brine. A series of experiments provided optimization (Table 1, entries [14][15][16][17][18][19][20]. The results demonstrated that AmberChrom50WX4 (1 g)/brine (0.1-0.2 mL) (entries 16-17, Table 1) significantly reduced the reaction time and still gave an excellent yield of the product (6 hours, 95%). Significantly, the reaction was slowed down or even quenched by more aqueous media (entries 18-20, Table 1).
To examine the scope of the procedure, more reactions were carried out using a variety of aromatic aldehydes and arylamines as shown in Table 2. All the reactions were complete within 6-8 hours (column 2, Table 2) in excellent isolated yields (90-95%) (column 3, Table 2), using the combination catalyst. The FT-IR, 1 H NMR, 13 C NMR and elemental analysis data all supported the proposed structures (see Experimental section). In addition, the melting points of known compounds matched the literature values in the citations provided in Table 1. [20][21][22][23][24][25][26][27][28][29][30] The reusability of the catalyst was examined (see Experimental section). The second run of the recovered catalyst without regeneration was not satisfactory, because the reactions led to longer reaction times and poor yields, typically 48 hours and 35%, respectively. By way of contrast, the regenerated AmberChrom50WX4 was as efficient as in the first run.
The efficiency of AmberChrom50WX4 for the synthesis of the title compounds has been compared with the other protocols in the literature 20-30 as shown in Table 3. Using all the parameters of comparison, AmberChrom50WX4 is highly effective for the preparation of pyrrolin-2-one derivatives and represents a good balance among Scheme 1. The synthesis of pyrrolin-2-one derivatives in the presence of brine, AmberChrom50WX4 and AmberChrom50WX4/brine in EtOH. The yields were referred to isolated pure product.   suitability for a variety of substrates, green characteristics, ready availability and the use of conventional energy sources. In conclusion, it was shown that AmberChrom50WX4/brine can be used as a suitable catalytic system for the synthesis of pyrrolin-2-ones. The products were synthesized by using a range of aromatic aldehydes and anilines in the one-pot three-component reaction with dimethyl acetylenedicarboxylate. Excellent yields (90-95%) of the products were achieved within 6-8 hours at room temperature. Easy work-up, high yields and low cost are valuable characteristics of this new method, making it a useful choice for the synthesis of these unique heterocyclic compounds.

Experimental section
All substrates, reagents, and AmberChrom50WX4 (100-200 mesh, CAS No. 69011-20-7) were obtained from Sigma-Aldrich company. AmberChrom50WX4 has not been specially processed or cleaned (according to the manufacturer's instructions). It is suggested to do a suitable preliminary wash before using this strongly acidic cation exchange resin. FT-IR spectra were recorded on a Perkin Elmer FT-IR RXI. 1 H NMR, and 13 C NMR spectra were recorded on 250 or 400 MHz Bruker spectrometers. The mass spectra of new compounds have been recorded on an Agilent Technology Model 5973 instrument (analyzer: quadrupole; ion source: electron impact (EI) 70eV; analyzer temperature and ion source 230 C). The progress of the reactions was determined by thin layer chromatography (TLC), using silica gel 60 F254 aluminum sheets from Merck Company (eluent: ethyl acetate/n-hexane 1/1). Product purity was also monitored by 1 H-NMR.
Typical procedure using the combination catalyst (P2) A mixture of aromatic aldehyde (1 mmol), aromatic amine (1 mmol), AmberChrom50WX4 (1 g), and 0.1 mL of brine in 5 mL of EtOH was prepared in a round-bottomed flask (10 mL) and stirred at room temperature for 30 minutes on a magnetic stirrer. Then, dimethyl acetylenedicarboxylate (DMAD) (0.14 g, 1 mmol) was added to the reaction mixture. The reaction was completed (as monitored by TLC), as shown in Table 2. After completion of the reaction, the product and AmberChrom50WX4 were filtered off from the ethanol and brine. The product was recrystallized from anhydrous ethanol. To crystallize the product and separate the catalyst from the reaction mixture, a small amount of ethanol was added to the mixture and heated. In this process, the product was dissolved in hot ethanol, but the catalyst was not dissolved. The catalyst was separated from the crystallization mixture by using filter paper (or some cotton) and a glass funnel. The catalyst remained on the filter paper and was washed with a small amount of hot ethanol. The solution separated from the catalyst cooled, and the crystals of the product formed slowly. For regeneration, AmberChrom50WX4 was conveniently stirred in diluted hydrochloric acid (5-10%) for 30-60 minutes and then washed with distilled water and dried with a hot hair dryer.