CAFFEINE AS A NATURALLY GREEN AND BIODEGRADABLE CATALYST PROMOTED CONVENIENT AND EXPEDIENT SYNTHETIC ROUTE FOR THE SYNTHESIS OF POLYSUBSTITUTED DIHYDRO-2-OXYPYRROLES

ABSTRACT. A green, convenient, high yielding and one-pot procedure for synthesis of high substituted dihydro-2-oxypyrroles by domino four-component condensation reaction between aromatic/aliphatic amines, dialkyl acetylenedicarboxylate and formaldehyde in the presence of a catalytic amount of caffeine as a green, natural, expedient and biodegradable catalyst under ambient temperature was studied. The salient features of this green approach are simplicity of operation and work-up procedures with no necessity of chromatographic purification steps, use of safe, non-volatile, non-corrosive and green catalyst, the availability and easy to handle of this solid catalyst, one-pot reaction, economical and clean synthesis.

The detection and measurement of caffeine (CAF) (Figure 2) or trimethylxanthine alkaloid, as a central nervous system and metabolic stimulant [20], have attracted the attention of many researchers.This compound is chemically related to the adenine and guanine bases of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).In the case of multifunctional molecules, such as caffeine, there may be several sites for protonation (Figure 3).Proton affinity (PA) is one of the most important thermodynamic quantities that link the thermochemistry of ions to that of the neutral molecules [21].The design of multi-component reactions (MCRs) [22][23][24][25][26][27][28][29][30][31][32] has received great attention from research groups in medicinal chemistry, drug discovery and materials science due to their significant advantages over conventional linear-type synthesis, including simple procedures, environmental friendliness, atom economy, and the ability to generate architecturally complex molecules in one synthetic step.
Finally, due to the above considerations and in continuation of our work on the development of useful and green synthetic methodology for the preparation of biologically active heterocyclic compounds using of caffeine as catalyst [33], we report herein, synthesis of polysubstituted dihydro-2-oxypyrroles via one-pot, four condensation domino reaction between aromatic/ aliphatic amines (1 and 3), dialkyl acetylenedicarboxylate 2 and formaldehyde 4 in the presence of caffeine as a cost effective, green, biodegradable and readily catalyst under mild conditions (Scheme 1).

EXPERIMENTAL
Melting points all compounds were determined using an Electro thermal 9100 apparatus.Also, nuclear magnetic resonance, 1 H NMR spectra were recorded on a Bruker DRX-400 Avance instrument with CDCl 3 as solvent.All reagents and solvents were purchased from Merck, Fluka and Acros chemical companies were used without further purification.

General procedure for preparation of substituted dihydro-2-oxypyrroles (5a-t)
A mixture of amine 1 (1.0 mmol) and dialkyl acetylenedicarboxylate 2 (1.0 mmol) was stirred in MeOH (3 mL) for 15 min.Next, amine 3 (1.0 mmol) and formaldehyde 4 (1.5 mmol) and caffeine (15 mol %, 0.029 g) were added and the reaction was stirred for appropriate time.After completion of the reaction (by thin layer chromatography TLC), the mixture was separated by filtration and the solid washed with ethanol (3×2 mL) with no column chromatographic separation to give pure compounds (5a-t).The products were characterized by comparison of spectroscopic data ( 1 HNMR).Spectra data some of known products are represented below.

RESULTS AND DISCUSSION
To generality of this transformation, we investigated caffeine catalyzed four-component reaction between aniline (2 mmol), dimethyl acetylenedicarboxylate (DMAD) (1 mmol) and formaldehyde (1.5 mmol) as a model reaction under mild conditions for the synthesis of dihydro-2-oxypyrroles.The amount of catalyst was studied with this method and in the absence of caffeine: a trace amount of this product was generated after 14 h (Table 1, entry 1).Good yields were obtained in the presence of a catalyst.The best amount of catalyst was 15 mol % (Table 1, entry 4).The higher amount of catalyst did not increase the yields products (  1, entry 4).The efficiency of caffeine was demonstrated by synthesizing polysubstituted dihydro-2oxypyrroles via four-component condensation using a series aromatic/aliphatic amines (1 and 3, 2 mmol), dialkyl acetylenedicarboxylate (2, 1 mmol) and formaldehyde (4, 1.5 mmol) at ambient temperature which results are shown in Table 2.  Comparison of catalytic ability some of catalysts reported in the literature for synthesis of polysubstituted dihydro-2-oxypyrroles are shown in Table 3.This study reveals that caffeine has shown its extraordinary potential to be an alternative efficient, green, biodegradable and an inexpensive catalyst for the one-pot clean synthesis of these biologically active heterocyclic compounds, in addition to good to high yields is the notable advantages this present methodology.

CONCLUSION
In summary, a mild, convenient and efficient procedure for the one-pot synthesis of polysubstituted dihydro-2-oxypyrroles by using of a catalytic amount of caffeine as a green catalyst under ambient temperature is reported.The use of a natural, biodegradable and inexpensive catalyst, along with simple work up, short reaction times and good to high yields, provides a compelling method to prepare these biologically active compounds.

Table 1 ,
entry 11)and the results are summarized in Table1.The effect of various solvents was investigated for this protocol H 2 O, CH 2 Cl 2 , CHCl 3 , EtOH, MeOH and CH 3 CN.Herein, the reaction occurred efficiently to afford the corresponding polysubstituted dihydro-2-oxypyrroles

Table 1 .
Optimization of the reaction condition in the presence of different amounts of caffeine a .
a Isolated yield.

Table 3 .
Comparison of catalytic ability some of catalysts reported in the literature for synthesis of polysubstituted dihydro-2-oxypyrroles a .Based on the four-component reaction of aniline, dimethylacetylenedicarboxylate, formaldehyde.Also, the Michael reaction between amine 1 and dialkylacetylenedicarboxylate 2 gives enamine B. Activated imine A undergoes a Mannich type reaction with enamine B to generate intermediate C, which converts to more stable tautomeric form D. The intramolecular cyclization in intermediate D that in the final step, it tautomerizes into the corresponding polysubstituted dihydro-2-oxypyrroles 5. a