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Passerini multicomponent reaction of indane-1,2,3-trione: an efficient route for the one-pot synthesis of sterically congested 2,2-disubstituted indane-1,3-dione derivatives

The Passerini reaction of indane-1,2,3-trione, isocyanides and benzoic acid derivatives proceed at room temperature and sterically congested 2,2-disubstituted indane-1,3-dione derivatives are synthesized in excellent yields. The reaction proceeds smoothly and cleanly under mild conditions and no side reactions are observed.


Introduction
In recent years, multicomponent reactions (MCRs) have become important tools in modern preparative synthetic chemistry because these reactions increase the efficiency by combining several operational steps without isolation of intermediates or changes of the conditions. [1][2][3][4][5][6] This principle, therefore, is highly efficient in terms of time as well as resources. 7 Among the known multicomponent reactions to date, the most valuable reactions are those based on isocyanides. Isocyanide-based multicomponent reactions (abbreviated to IMCRs by Ugi and Dömling) by virtue of their synthetic potential, their inherent atom efficiency, convergent nature, ease of implementation, and the generation of molecular diversity, have attracted much attention because of the advantages that they offer to the field of combinatorial chemistry. 8 IMCRs are particularly interesting because they are more versatile and diverse than the remaining MCRs. The great potential of isocyanides for the development of multicomponent reactions lies in the diversity of available bond forming processes, their functional group tolerance, and the high levels of chemo-, regio-, and stereoselectivity often observed. The outstanding position of IMCRs can be traced back to the exceptional reactivity of the functional group of the isocyanide. No other functional group reacts with nucleophiles and electrophiles at the same atom, leading to the so-called α-adduct. Today most IMCR chemistry relates to the classical reactions of Passerini and Ugi. Indeed, the large number of different scaffolds now available mostly builds on these two IMCRs and their combination with other types of reactions. 9-18 Passerini reactions involve an oxo component, an isocyanide, and a nucleophile. [19][20][21] The Passerini reactions are beginning to find utility in the drug discovery process, and total syntheses of biologically relevant natural products. This reaction has been widely used in synthetic and medicinal chemistry. 12 For example, it has often been involved as a key step in the total synthesis of natural products due to the fact that the α-acyloxycarboxamide group is a frequently recurring motif in many pharmacologically interesting natural products. 22 The mechanism of the Passerini reaction has been investigated by Baker and Stanonis. 23 In connection with our recent interest to isocyanide chemistry, [24][25][26][27] we report the Passerini multicomponent reaction between, indane-1,2,3-trione, isocyanides and benzoic acid derivatives in this article.
The reaction proceeds smoothly and cleanly under mild conditions and no side reactions are observed. The pure products (4a-j) are stable at room temperature for several months. The structures of the products were deduced from their IR, 1 H NMR, 13

Experimental
Starting materials and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. IR spectra were measured on a Shimadzu IR-460 spectrometer. 1 H and 13 C NMR spectra were measured (CDCl 3 solution) with a BRUKER DRX-250 AVANCE spectrometer at 250.0 and 62.5 MHz, respectively. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 20 eV. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. The results agreed favorably with the calculated values.

General procedure
To a magnetically stirred solution of indane-1,2,3-trione (1) (0.2 mmol) and benzoic acid derivatives (3) (0.2 mmol) in dry CH 2 Cl 2 (5 mL) was added dropwise a solution of isocyanides (2) (0.2 mmol) in CH 2 Cl 2 (2 mL) at room temperature over 10 min. The mixture was stirred for 1 to 2 hours at room temperature. The solvent was removed under reduced pressure and pure products (4a-j) were obtained. The characterization data of the compounds are given below.

Conclusions
We believe that the reported method offers a mild, simple, efficient and one-pot synthetic method for the preparation of sterically congested 2,2-disubstituted indane-1,3-dione derivatives from Passerini multicomponent reaction of indane-1,2,3-trione. The reaction proceeds smoothly and cleanly under mild conditions and no side reactions were observed. The products were obtained in excellent yields. Their ease of work-up, high yields and mild reaction conditions make it a useful addition to modern synthetic methodologies. Other aspects of this process are under investigation.