SYNTHESIS OF A SERIES OF 2-INDOLYLMETHYLENE-LINKED COMPOUNDS BY THERMAL KNOEVENAGEL CONDENSATION UNDER CATALYST-AND SOLVENT-FREE CONDITIONS

Indole derivatives are well-known for their versatile biological activities. This has made the synthesis of compounds containing indole moiety an interesting target for synthetic organic chemists. The Knoevenagel condensation of substituted aromatic aldehydes with active methylene compounds is an important and widely employed method for carbon-carbon bond formation in organic synthesis with numerous applications in the construction of different types of organic molecules of biological significance. The reactions are usually catalyzed by bases such as aliphatic amines, ethylenediamine and piperidine or their corresponding ammonium salts, ammonia or sodium ethoxide in organic solvents. Lewis acids, zeolites, surfactants, different types of nanoparticles have also been employed to catalyze the reactions. Moreover, the uses of ionic liquids, microwave and ultrasound are found in the recent literature to effect this condensation under ecofriendly conditions.


Introduction
Indole derivatives are well-known for their versatile biological activities [1][2][3] .This has made the synthesis of compounds containing indole moiety an interesting target for synthetic organic chemists.The Knoevenagel condensation 4 of substituted aromatic aldehydes with active methylene compounds is an important and widely employed method for carbon-carbon bond formation in organic synthesis with numerous applications in the construction of different types of organic molecules of biological significance.The reactions are usually catalyzed by bases 5 such as aliphatic amines, ethylenediamine and piperidine or their corresponding ammonium salts, ammonia or sodium ethoxide in organic solvents.Lewis acids [6][7][8][9] , zeolites 10 , surfactants 11 , different types of nanoparticles 12,13 have also been employed to catalyze the reactions.Moreover, the uses of ionic liquids 14 , microwave 15,16 and ultrasound 17 are found in the recent literature to effect this condensation under ecofriendly conditions.Organic reactions under solvent-free and catalyst-free [18][19][20][21][22][23] conditions have increasingly attracted interest of chemists, particularly from the viewpoint of green chemistry.Though a number of solvent-free methodologies are known for effecting Knoevenagel condensation 13,15,16,24 , only a few catalyst-free reaction conditions are reported 25,26 .Considering the importance of synthesis of new compounds containing an indole moiety and effecting Knoevenagel condensation under catalyst-and solvent-free conditions, we undertook the present work where 3-methylindole-2carboxaldehyde (1) (readily available from a well-known indole compound skatole) 27 , with different active methylene compounds under the influence of heat only.
The interesting results obtained in this study are presented herein.Scheme 1. Synthesis of 2-indolyl-methylene-linked compounds.

Experimentals
Melting points were recorded on a Köfler block.IR spectra were recorded on a Perkin Elmer FT-IR spectrophotometer (Spectrum BX II) in KBr pellets. 1   This compound was prepared by a known procedure. 26A solution of 3-methylindole (1.64 g, 12.5 mmol) in DMF (1 mL) was added drop wise to a complex obtained from POCl3 (2.3 g, 15 mmol) and DMF (7.76 g, 105 mmol).The reaction mixture was heated at 100 o C for 3h.The crude product so obtained was cooled and subjected to column chromatography over silica gel (Spectrochem Pvt. Ltd., India, 100-200 mesh) using a mixture of petroleum ether and ether (19:1) as eluent gave first 3-methylindole-1carboxaldehyde as a colourless oil.Further elution of the column with a mixture of petroleum ether and ether (17:3) gave 1 (0.42 g, 21 %) which was crystallised from petroleum ether as colourless needles, m.p. 138-140 °C (lit. 26
In the condensation reaction of 1 with each of CAM-7 and CAM-8, a mixture of two products were obtained in approx.4:1 ratio, which were found to be inseparable by column chromatography.When the results of the reactions of 1 with cyclic 1,3-diones were analyzed, it was observed that Knoevenagel condensation products were formed in better yields from the 5-membered 1,3-diones as compared to the six-membered 1,3-diones.From the reaction mixture using CAM-3 some amount of the new xanthene-1,8(2H)-dione derivative 10 could be isolated in low yield (16%, based on amount of 1 taken), which indicated the occurrence of a facile Michael reaction on 4a under the applied reaction conditions (Scheme 2).It may, therefore, be expected that development of a method for synthesis of 10 or its analogs may be possible by use of 1 and cyclohexan-1,3-diones in 1:2 mole ratio.Furthermore, we wish to report here that attempted reaction of 1 with the acyclic 1,3-dione acetylacetone (pKa = 13.3) 30(120 o C, 3 h) did not afford any Knoevenagel condensation product.The pKa values of the active methylene compounds as quoted above indicate that the acidity of these compounds possibly plays an important role on the ease of their The formatiom of 2-9 is expected to follow a path typical for acid-catalyzed Knoevenagel condensation.Possibly, the enol forms of the cyclic active methylene compounds are acting as acid catalysts.

Conclusions
We have developed a simple and efficient method for synthesis of a series of new 2-indolylmethylene-linked compounds by Knoevenagel condensation of 3methylindole-2-carboxaldehyde and cyclic active methylene compounds under catalyst-and solvent-free conditions.Yields of the products were found to be moderate to very good in majority of cases.