One-Pot, Catalyst-Free Synthesis of Spirooxindole and 4H-Pyran Derivatives

Abstract The synthesis of biologically valuable spirooxindoles and 4H-pyrans is described under catalyst-free conditions through sequential Knoevenagel–Michael–cyclization reactions from isatin or aromatic aldehyde, malononitrile, and 1,3-dicarbonyl compounds. The reaction conditions are very simple, providing excellent yield. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT


DISCUSSION
For optimization of the conditions, the reaction of 4-fluorobenzaldehyde, malononitrile, and dimedone was considered as the model. Here all the starting materials were mixed together, and the reaction was performed in different solvents at room temperature. Initially water, the polar protic environmentally friendly solvent, was tried and the expected product 4a was obtained in 75% after 24 h (

SPIROOXINDOLE AND 4H-PYRAN DERIVATIVES
any catalyst in polar protic solvents such as water, ethanol, and isopropanol with limited success. The nonpolar solvents (cyclohexane and toluene) and borderline polar-aprotic solvents (tetrahydrofuran and methylene dichloride) were totally ineffective in this sequential reaction (Table 1, entries 3 to 6), whereas polar aprotic solvents (DMF and DMA) gave moderate yields of 4a (Table 1, entries 10 and 11). Dioxane, acetonitrile, and acetone were not successful ( Table 1). The highly polar aprotic solvent dimethylsulfoxide (DMSO) worked well in this reaction, giving quantitative yield (98%) of 4H-pyran 4a in a short reaction time ( Table 1, entry 12) and hence was identified as the solvent of choice. The mild basic character of the oxygen in DMSO facilitates the reaction efficiently and also the product was isolated in a pure form by simple filtration. DMSO is a versatile and powerful solvent for organic reactions involving displacement, elimination, condensation, and polymerization reactions, and it can facilitate a reaction without a catalyst. [5] Recently, Xue et al. [5a] have reported the uncatalyzed Knoevenagel condensation of isatin and rhodanines in DMSO,and Dash et al. [5b] have reported the aldol reaction of thiazolidinedione in DMSO medium without the use of any catalyst.
The substrate scope was then explored with different aromatic aldehydes and 1,3-dicarbonyl components, and the results are presented in Table 2. The reaction has gone smoothly in the presence of strong electron-releasing (OCH 3 ) and electron-withdrawing (NO 2 ) groups in the phenyl ring ( Table 2, entries 2 to 5). The reaction went well even with a free carboxylic acid group in the phenyl ring, requiring no protection (Table 2, entry 6). Heteroaromatic aldehydes also participated well in this reaction (Table 2, entries 7 and 8). When cyclohexan-1,3-dione and 4-hydroxycoumarin were employed instead of dimedone, the reaction took more time for completion with poor yield. When the reaction was carried out at 70 C, the reaction was completed in 3-10 h in these cases ( Table 2, entries 9 to 14).
The plausible mechanism of this uncatalyzed sequential reaction is given in Scheme 1. The mild basic nature of oxygen of DMSO may facilitate the Knoevenagel condensation and the Knoevenagel product can then undergo Michael addition with 1,3-dicarbonyl compound. The subsequent cyclization leads to the 4H-pyran skeleton 4.
The established protocol was extended to isatin, and the reaction of isatin, malononitrile, and dimedone or cyclohexan-1,3-dione was carried out in DMSO at 70 C for 1 h. The desired products 6a and 6b were obtained in 85% and 74% respectively (Scheme 2). The reaction of isatin, malononitrile, and 4-hydroxycoumarin yielded the products 7a and 7b in good yield, but required more reaction time compared to that for 6.

SUPPORTING INFORMATION
Full experimental details, analytical data, and copies of 1 H and 13 C spectra can be found via the Supplementary Content section of this article's Web page. Scheme 2. Synthesis of spirooxindole skeleton.