Efficient and Mild Four-component Process for the Synthesis of Highly Substituted Dihydro-2-oxopyrroles using ZrOCl2∙8H2O as an Environmental-ly Friendly Catalyst

This study investigated the catalytic ability of ZrOCl2∙8H2O as a mild, environmentally benign nature, and economical catalyst for the multi-component efficient synthesis of biologically active highly substituted dihydro-2-oxopyrrole derivatives with excellent yields and short reaction times. This procedure has several advantages, including use of mild, nontoxic, and inexpensive catalysts, one-pot synthesis, environmentally benign nature, simple operational procedure, and highly efficient conditions.

Multi-component domino reactions have recently attracted considerable interest [21][22][23][24][25][26][27] as powerful tools in the synthesis of organic compounds with biological and pharmaceutical properties because of their notable advantages, such as atom economy, environmental friendliness, low cost, one-pot, and simple work-up.
During the past decades, the use of zirconium compounds as catalysts in organic synthesis has attracted great interest because of their notable advantages, such as nontoxicity, environmental friendliness, easy to handle, high efficiency, and low cost [28]. The advantages of using ZrOCl2•8H2O as a catalyst [29][30] in the synthesis of organic compounds are mild, inexpensive, nontoxicity, environmentally benign nature, and high activity. In addition, we carried out one-pot multi-component condensations using ZrOCl2•8H2O as catalyst and obtained excellent yields in short reaction times.
On the basis of these findings, the development of a simple, clean, economical, and environmentally safe method for the synthesis of these compounds has become the major aim of our research. Results revealed that ZrOCl2•8H2O is an efficient, environmentally benign, and economical catalyst for the one-pot, fourcomponent synthesis of highly substituted dihydro-2oxopyrrole derivatives.

Materials and Methods
General. The melting points of all compounds were determined using an Electro thermal 9100 apparatus. The 1 H NMR spectra were recorded on Bruker DRX-400 Avance and Bruker DRX-300 Avance instruments with CDCl3 as solvent. All reagents and solvents purchased from Merck, Fluka, and Acros chemical companies were used without further purification.
General procedure for the preparation of highly substituted dihydro-2-oxopyrroles (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. Then, amine 3 (1.0 mmol), formaldehyde 4 (1.5 mmol), and ZrOCl2•8H2O (15 mol%) were added, and the reaction was stirred for an appropriate time. After completion of the reaction (by thin layer chromatography), the mixture was separated with filtration and the solid washed with ethanol (3×2 mL) with no column chromatographic separation to produce pure compounds (5a-t). The catalyst is solvable in ethanol and was removed from the reaction mixture. Products were characterized by comparison of spectroscopic data ( 1 H NMR). Supporting Information associated with this article can be found in the online version.

Results and Discussion
The generality of this four-condensation reaction was studied under optimized conditions, and the reaction between aniline, dimethyl acetylenedicarboxylate, and formaldehyde was investigated as a model reaction. The effect of different amounts of catalyst in MeOH as a solvent was studied in this protocol. In the absence of a catalyst, a trace amount of this product was detected after 12 h ( Both classes of aromatic or aliphatic amines containing electron-releasing and electron-withdrawing substituent gained the appropriate products in excellent yields and short reaction times. The reaction times of aromatic or aliphatic amines having electron-withdrawing groups and electron-donating groups were similar. We also applied dialkyl acetylenedicarboxylate (methyl or ethyl). In each of these substitutions, no significant difference in reaction rate and product yield was found.
The results are summarized in Table 2.
The proposed mechanism for the synthesis of highly substituted dihydro-2-oxopyrroles [17]

Conclusion
We have studied an efficient, environmentally benign nature and economical catalyst for the one-pot fourcomponent synthesis of highly substituted dihydro-2oxopyrrole derivatives. ZrOCl2•8H2O has catalyzed the synthesis of these bioactive compounds under mild reaction conditions. Notable advantages of this procedure include use of mild, nontoxic, and inexpensive catalysts, one-pot synthesis, environmentally benign nature, simple operational procedure, and highly efficient conditions.