A Novel Synthesis of [ 4-( 3-methyl-1 H-indol-2-yl ) phenyl ] ( phenyl ) methanone

We have developed a simple route for the synthesis of [4-(3-methyl-1H-indol-2yl)phenyl](phenyl)methanone from easily available starting materials. The (4-propylphenyl) phenylmethanone was prepared by Friedel Craft’s benzoylation of n-propyl benzene with benzoyl chloride in dichloromethane using aluminium chloride as the Lewis acid catalyst. Side chain bromination with N-bromo succinimide in tetra chloro methane furnished the bromo derivative which on oxidation with bis-tetra butyl ammonium dichromate gave 1, 4–diacyl benzene. The target molecule was obtained through Fischer indole cyclisation of the diacyl benzene namely 1-(4-benzoylphenyl)propan-1-one via the formation of the hydrazone, followed by cyclization in presence of boron trifluoride ethyl etherate in acetic acid. The structure of the target molecule was elucidated by IR, H1, C13 NMR, Mass spectroscopy and elemental analysis. This method proves to be an efficient route for the synthesis of [4-(3-methyl-1H-indol-2-yl)phenyl](phenyl)methanone in high yields, thereby facilitating the generation of potential biologically active compounds.


INTRODUCTION
Indole is one of the most important heterocyclic compounds found in nature.It consists of a six-membered benzene ring fused to five-membered nitrogen containing pyrrole ring 1 .The discovery of indomethacin, ethodolac and tenidap, as potent anti-inflammatory agents, has led to the exploration of the indole nucleus 2 .A significant number of derivatives were reported to possess potent wide spectrum of biological activity especially antibacterial [3][4] , antifungal 5 , anti inflammatory [6][7][8][9][10] and analgesic 11 .Due to high electron density at position 3, indole undergoes electrophilic substitutions at position 2 and 3, respectively.A variety of synthetic methods for the indole ring system have been developed for the past hundred years [12][13][14][15] .The palladium-catalyzed annulation of 2-haloanilines with alkynes, in particular, is of great importance due to the easy availability of substrates 16 .Indole integrated with diphenylmethanone at position 3 plays a significant role in control of larvicidal mosquitoes that cause malarial fever 17 .Similar compound with diphenylmethanone substituent at position 2 was synthesized from o-ethynyl aniline and trifluoro sulfonyl benzophenone via two step reaction 18 .This reaction was catalyzed by palladium in variable oxidation state and high temperature had been used throughout the process.In this study, a novel 2-aryl indole has been synthesized with methyl substituent in position 3, using simple starting materials and novelty in the synthetic strategy.

Material and Methods
All commercially available reagents and solvents were obtained from Sigma Aldrich Chemicals and SD Fine Chemicals.TLC was performed on pre-coated alumina sheets and visualized under UV light.Chromatographic separations were carried out on silica gel 60 Merck, & Co. Darmstadt, Germany).Melting points were obtained using open capillary tubes and uncorrected.Infra-red spectra were recorded on a Jasco Model 5300 FT-IR spectrometer in KBr over a range of 4000-200 cm -1 .The 1 H NMR and 13 C NMR data were recorded with a Bruker 500 MHz high resolution NMR Spectrophotometer and CDCl 3 was used as a solvent.Chemical shifts are reported in ppm and tetramethylsilane was taken as internal standard.Mass spectra were recorded on JEOL SX 102/DA-6000 mass spectrometer/data system.Elemental analysis results were found to be in good agreement (±0.4%) with the calculated values.

General procedure Phényl(4-propylphényl)méthanone (2b)
This was prepared by the procedure 20 employed earlier by the Friedel-Crafts benzoylation of n-propyl benzene with benzoyl chloride.The product was obtained as an orange syrupy liquid.Yield: 75%

Synthesis of [4-(3-methyl-1H-indol-2-yl)phenyl] (phenyl)methanone (5b)
To a solution of 1-[4-(benzoyl)phenyl] propan-1-one (4.76 g, 20 mmol) in ethanol (50 mL) phenyl hydrazine (2.2 mL, 20 mmol) was added.The solution was refluxed for 3 hours.The ethanol was distilled off and the resulting hydrazone was obtained as a dark brown solid.This was dissolved in acetic acid (50 mL) and BF 3 -etherate (1 mL) was added drop wise.The solution was refluxed on a mantle for 3 hours.Finally the reaction mixture was cooled and poured over crushed ice.The precipitated bright yellow compound was filtered, washed with water and dried over anhydrous calcium chloride.

Phényl(4-ethylphényl)méthanone 2a
This was prepared by the earlier reported procedure by the Friedel-Craft's reaction of ethyl benzene with benzoyl chloride.Yield:78%

Synthesis of [4-(1H-indol-2-yl)phenyl] (phenyl) methanone (5a)
To a solution of 1-(4-benzoylphenyl) ethanone (5.6 g, 25 mmol) in ethanol (50 mL) was added phenylhydrazine (3 mL, 25 mmol) and concentrated hydrochloric acid (0.5 mL).The reaction mixture was refluxed for 3 hours.Then ethanol was distilled off and the resulting hydrazone was obtained as a dark brown solid.This was dissolved in xylene (50mL) and anhydrous ZnCl 2 (6.8g, 50 mmol) was added.The reaction mixture was refluxed in an oil bath for 3 h and the progress of the reaction monitored by TLC.Then xylene was distilled off and the pot residue obtained was digested with water on a water bath for 0.5 h.A yellow glassy solid which separated out, was filtered and dried.It was purified by chromatography over silica gel using hexane / ethyl acetate (1:1) as the eluent .

Preparation of bis-tetrabutyl ammonium dichromate
The above oxidizing agent was prepared by the method reported 19 in the literature, from tetra butyl ammonium bromide and potassium dichromate.

RESULTS AND DISCUSSION
In this research work, the target molecule containing a diphenyl methanone moiety and methyl group at positions 2 and 3 respectively was synthesized.The product was obtained in good yield whereas the yield of the 2-substituted product namely [4-(1H-indol-2-yl)phenyl](phenyl) methanone which was prepared 18 by the palladium catalysed coupling of diphenylmethanone triflate with 2-ethynyl aniline was only 39%.Moreover, the use of expensive and toxic starting materials was replaced with simple, inexpensive and less toxic starting materials.The product obtained was found to melt at 110 0 C and the structure has been confirmed by IR and NMR spectra.The IR spectrum showed peaks at 3313 cm -1 due to indole NH and at 1669 cm -1 due to carbonyl group.The 1 H NMR spectrum showed a multiplet at 6.4-7.7 due to aromatic hydrogens and a broad singlet at • 10.9 due to indole NH.This compound has been reported 18 by the palladium catalyzed coupling of 4-benzophenone triflate with 2-ethynylaniline.The structure was confirmed by its IR and NMR data which was in agreement with that reported in the literature.confirmed by IR, 1 H NMR and 13 C NMR spectra.The presence of a carbonyl group was confirmed from IR by the presence of a sharp peak at 1650 cm -1 .In the 1 H NMR spectrum, peak at δ 3.9 containing 3H singlet was due to indole methyl hydrogen, multiplet peak at δ 6.7-8.4 for aromatic hydrogens and a highly deshielded singlet peak at δ 8.5 was due to NH of indole.

CONCLUSION
In the present work, we have developed a simple but highly efficient method for the synthesis of a novel diphenylmethanone integrated indole, which is also supported by the IR and NMR spectral data.Further structural optimization of diphenylmethanone based indoles is well under way with the aim of evaluating their biological activity.