OH MEDIATED NEW SYNTHESIS 3-( 1 H-INDOL-3-YL ) ACRYLONITRILE DERIVATIVES

[Bmim]OH mediated new synthesis of 3-(1H-indol-3-yl)acrylonitrile derivatives 6 have been developed by the reaction of diethyl phthalate (1) with ethyl cyanoacetic acid hydrazide (2) to form 3-(1,4-dioxo-3,4-dihydrophthalazin-(1H)-yl)-3-oxopropanenitrile (3). Then compound 3 reacted with indole-3-aldehyde (4) by Knoevenagel condensation to form compound 2-(1,4-dioxo-1,2,3,4tetrahydrophthalazine-2-carbonyl)-3-(1H-indol-3-yl)acrylonitriles (5). Compounds 5 undergo alkylation with alkylating agents to form 6 with good yields. Compounds 6 could also be synthesized by alkylation of 4 followed by condensation with 3.


INTRODUCTION
Ionic liquids as catalysts 1 and /or media 2 in reactions have been widely used in organic transformations due to their advantages such as good solvating ability, negligible vapor pressure, high polarity and ease of work-up.
[Bmim]OH (1butyl-3-methylimidazolium hydroxide) is one such taskspecified ionic liquid which acts as reaction medium as well as a basic catalyst and has got various applications 3 in the field of synthetic methodology development.
Heterocycles containing the phthalazine moiety are of interest because they show some pharmacological and biological activities. [4][5] Mogilaiah et al 6  Indole derivatives continue to receive much attention in organic synthesis because of their biological activities. 8,9 Among them, 3-substituted indole is one of the 'privileged medicinal scaffold,' found in many biologically active compounds and natural products. 10,11 Through appropriate functional group modifications, these scaffolds are capable of providing ligands for a number of functionally and structurally discrete biological receptors. 3-Substituted indole scaffolds are found in a number of biologically active compounds especially with anticancer, anti-tumor, 12 hypoglycaemic, anti-inflammatory, analgesic and antipyretic activities. [13][14][15][16] Keeping in view the potential importance of the phthalazine and indole ring containing compounds, we now wish to report our studies on reactions of phthalic anhydride with hydrazide derivatives and their further modifications.

RESULTS AND DISCUSSION
At first, we have developed the condensation of diethyl phthalate (1) (1 mmol), ethyl cyanoacetic acid hydrazide 8 (2) (1 mmol) to from 3-(1,4-dioxo-3,4-dihydrophthalazin-(1H)-yl)-3-oxopropanenitrile 17 (3)  The gross structure of this product was assigned on the basis of its spectral data. Furthermore, the compound was supposed to be E-configuration on the presumption that bulky groups in a trans position would confer thermal stability on the molecule. This has been found to be the case by a careful examination of the Frame-work molecular models of both E and Z -configurations of 5a wherein it was observed that there was a minimum number of steric interactions in the Econfiguration.
The latter on alkylation of 5a with an alkylating agent, i.e. dimethylsulfate (DMS) in the presence of [Bmim]OH (5 ml) at 80 °C for 60-90 min gave the corresponding indole-NHalkylated derivatives 6a with 85 % yield. After having optimized the reaction conditions, the generality of the reaction was confirmed by carrying out the condensation of 3 with 4a-4c in the presence of [Bmim]OH at 80 °C for 30-35 min gave the corresponding compounds 5a-5c in good yields. The latter on alkylation of 5a-5c with alkylating agents in the presence of [Bmim]OH at 80 °C for 60-90 min gave the corresponding indole-NH-alkylated derivatives 6a-6f. Using this strategy, alternatively, 6a-6f were prepared by alkylation of 4a-4c with alkylating agents in the presence of [Bmim]OH at 80 °C for 60-90 min to form 7a-7f followed by Knoevenagel condensation of the initial product with 3 in the presence of [Bmim]OH at 80 °C for 30-40 min. All of the above reactions are summarized in Scheme 1.

EXPERIMENTAL SECTION
Melting points are uncorrected and were determined in open capillary tubes in a sulphuric acid bath. TLC was run on silica gel-G and visualization were done using iodine or UV light. IR spectra were recorded using Perkin-Elmer 1000 instrument in KBr pellets. 1H NMR spectra were recorded in DMSO-d6 using TMS as internal standard using 400 MHz spectrometer. Mass spectra were recorded on an Agilent-LCMS instrument. Starting materials 1 and 4a-4c were obtained from commercial sources and used as such.

Preparation of 3
A mixture of 1 (10 mmol), 2 (10 mmol) and [Bmim]OH (20 mL) was heated at 80 °C along with stirring and maintained until the completion of reaction as checked by TLC (15-20 min). To the resulting oily reaction mixture was added ethanol (30 mL) to force out the crude product from the polar ionic liquid reaction medium. The separated solid mass was collected by filtration and dried in oven to obtain crude 3. The later, were recrystallized from ethanol solvent to get the pure 3.

Preparation of 6 from 5 and alkylating agents
A mixture of 5 (10 mmol), alkylating agent (10 mmol) and [Bmim]OH (20 mL) was heated at 80 °C along with stirring and maintained until the completion of reaction as checked by TLC (60-90 min). To the resulting oily reaction mixture was added ethanol (30 ml) to force out the crude product from the polar ionic liquid reaction medium. The separated solid mass was collected by filtration and dried in oven to obtain crude 6. The later, were recrystallized from ethanol solvent to get the pure 6.

Preparation of 7a-7f from 4a-4c and alkylating agents
A mixture of 4 (10 mmol), alkylating agents (10 mmol) and [Bmim]OH (20 mL) was heated at 80 °C along with stirring and maintained until the completion of reaction as checked by TLC (60-90 min). To the resulting oily reaction mixture was added ethanol (30 mL) to force out the crude product from the polar ionic liquid reaction medium.
The separated solid mass was collected by filtration and dried in an oven to obtain crude 7. The later was recrystallized from ethanol solvent to get the pure 7.

Preparation of 6a-6f from 7a-7f & 3
A mixture of 7 (10 mmol), 3 (10 mmol) and [Bmim]OH (20 mL) was heated at 80 °C along with stirring and maintained until the completion of reaction as checked by TLC (35-40 min). To the resulting oily reaction mixture was added ethanol (30 mL) to force out the crude product from the polar ionic liquid reaction medium. The separated solid mass was collected by filtration and dried in an oven to obtain crude 6. The later was recrystallized from ethanol solvent to get the pure 6.