A Novel Synthesis of [4-(3-Methyl-1H-Indol-2-Yl)Phenyl]Phenylmethanone

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 ring¹. The discovery of indomethacin, ethodolac and tenidap, as potent anti-inflammatory agents, has led to the exploration of the indole nucleus². A significant number of derivatives were reported to possess potent wide spectrum of biological activity especially antibacterial^3-4, antifungal⁵, anti inflammatory^6-10 and analgesic¹¹. 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^12-15. The palladium-catalyzed annulation of 2-haloanilines with alkynes, in particular, is of great importance due to the easy availability of substrates¹⁶. Indole integrated with diphenylmethanone at position 3 plays a significant role in control of larvicidal mosquitoes that cause malarial fever¹⁷. Similar compound with diphenylmethanone substituent at position 2 was synthesized from o-ethynyl aniline and trifluoro sulfonyl benzophenone via two step reaction¹⁸. 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.

Experimental

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,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 ¹H NMR and ¹³C NMR data were recorded with a Bruker 500MHz high resolution NMR Spectrophotometer and CDCl₃ 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 procedure²⁰ 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%

[4-(1-bromopropyl)phenyl](phenyl)methanone (3b)

This was prepared by the procedure²⁰ employed earlier using N-bromosuccinimide in tetra

chloro methane. Yield: 85%

1-[4-(benzoyl)phenyl]propan-1-one(4b)

This was prepared by using bis tetrabutylammonium dichromate as the oxidizing agent by the method²⁰ employed earlier.

Yellow solid; Yield:99% m.p.86-88⁰ C; IR (KBr): ν_max 1678, 1664 cm^-1; ¹H NMR (CDCl₃, ppm):  1.2 (t,3H,CH₃), 3.1 (q, 2H,CH₂), 7.4-8.1 (m, 9H,Aromatic-H); ¹³C NMR: 8.2, 32.3, 127.9, 128.5, 130.2, 133.1, 139.5, 141.2, 196.1, 200.4,Mass spectrum: m/z (%) = 238.281(M⁺, 55.6) 209.2 (100), 181.2 (10.2), 105.1 (69.1), 77.1 (61.1) ; Anal Calcd. for (C₁₆H₁₄O₂): C 80.65 H 5.92; Found C 80.65 H 5.72; HRMS: (C₁₆H₁₄O₂) M⁺ Calcd: 238.28116; Found: 238.28120

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 hrs. 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 BF₃-etherate (1 mL) was added drop wise. The solution was refluxed on a mantle for 3 hr. 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.

Yellow powder; Yield: (95%); mp:198-200 ^oC ; IR(KBr): ν_max1650 (C=O), 3343 (NH)cm^-1,

¹H NMR (500MHz; DMSO-d₆):  2.46 (s, 3H, CH₃), 7.00-8.07 (m, 13H, Aromatic-H), 11.34 (s, 1H, indole-NH);¹³CNMR(125 MHz):  10.6,109.6,111.8,119.4,119.4,122.9,127.6,129.1,129.9,130.1,130.8,132.9,133.1,137.8,195.7.

Mass m/z (%): 311.30 (M⁺, 100%), 310.27 (37.2), 209.20(46.1), 130.17(25.8), 105.1(65.6) 77.14(64); Analysis Calcd. for C₂₂H₁₇NO: C 84.86,H 5.50, N 4.50 Found: C 84.51, H 5.51, N 4.62.

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-(1-bromoethyl)phenyl](phenyl)methanone 3a

The compound was prepared by bromination of phényl(4-ethylphényl)méthanone 2a using N-bromosuccinimide in carbon tetra chloride using the procedure previously reported in our laboratory. The product was obtained as an orange syrupy liquid.Yield:82%

Preparation of (4-benzoylphenyl)ethanone (4a)

The (4-benzoylphenyl)ethanone was prepared  from [4-(1-

bromoethyl)phenyl](phenyl)methanone 3a by the reported procedure¹⁹ using bis tetra butylammonium dichromate as the oxidizing agent. The melting point and spectral data were in close agreement with that reported earlier. Light yellow solid, Yield: 74%; m.p:80-84^oC; IR(KBr):ν_max1689,1656cm^-1,¹H NMR(CDCl₃/TMS,ppm): 2.56(s, 3H, CH₃), 7.2-8(m, 9H, Ar)

Synthesis of [4-(1H-indol-2-yl)phenyl](phenyl)methanone (5a)

To a solution of 1-(4-benzoylphenyl)ethanone(5.6g, 25mmol) in ethanol (50mL) was added phenylhydrazine (3mL, 25mmol) and concentrated hydrochloric acid (0.5mL). The reaction mixture was refluxed for 3 h. Then ethanol was distilled off and the resulting hydrazone was obtained as a dark brown solid. This was dissolved in xylene (50mL) and anhydrous ZnCl₂ (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 .

Yield: 50%; mp: 110 ^oC (decomposed); IR (KBr ): 1669 (>C=O), 3313 (NH) ) cm^-1; ¹H NMR(CDCl_3/TMS): d 6.4-7.7 (m, 13H, Aromatic), 10.9 (s, 1H, indole-NH); Mass m/z (%): 298.19 (100) 221.26 (29.5), 193.03 (43.7), 105.02 (41.9), 77.1 (90.3), 55.06 (43.7).

Preparation of bis-tetrabutyl ammonium dichromate

The above oxidizing agent was prepared by the method reported¹⁹ 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 prepared¹⁸ 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.

To synthesise indoles with diphenylmethanone unit at the second position, 1-(4-benzoylphenyl)ethanone and 1-(4-benzoylphenyl)propan-1-one were required as starting materials. They were prepared by following the procedure²⁰ employed earlier. Initially Fischer indolization of 1-(4-benzoylphenyl)ethanone with phenyl hydrazine in ethanol followed by refluxing the resulting hydrazone with anhydrous zinc chloride in xylene afforded [4-(1H-indol-2-yl)phenyl](phenyl)methanone 5a in 50% yield.

The product obtained was found to melt at 110⁰C 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 ¹H NMR spectrum showed a multiplet at ẟ 6.4-7.7 due to aromatic hydrogens and a broad singlet at d 10.9 due to indole NH. This compound has been reported¹⁸ 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.

Further, it was decided to indolise the corresponding 1-[4-(benzoyl)phenyl]propan-1-one to the corresponding indole by the Fischer indolisation of the hydrazone. 1-[4-(benzoyl)phenyl]propan-1-one was treated with phenyl hydrazine in ethanol and the resulting hydrazone was subjected to Fischer indolization using BF₃– ethyl etherate in boiling acetic acid. The [4-(3-methyl-1H-indol-2-yl)phenyl](phenyl)methanone 5b was obtained in quantitative yield and the structure has been confirmed by IR, ¹H NMR and ¹³C NMR spectra. The presence of a carbonyl group was confirmed from IR by the presence of a sharp peak at 1650cm^-1.In the ¹H NMR spectrum, peak at d 3.9 containing 3H singlet was due to indole methyl hydrogen, multiplet peak at d 6.7-8.4 for aromatic hydrogens and a highly deshielded singlet peak at d 8.5 was due to NH of indole. (Figure:1).The ¹³C NMR spectrum showed 15 peaks (for twenty two carbons-18 signals) at 10.65, 109.63, 111.78, 119.38, 119.42, 122.94, 127.59, 129.13, 129.86, 130.08, 130.83, 132.93, 133.13, 137.77, and195.72.(Figure:2).The mass spectrum showed a molecular ion peak at m/z = 311.30 (Figure:3).The scheme shown below represents the various steps involved in the synthesis.

Scheme 1: Synthesis of diphenylmethanone integrated indoles  Click here to View scheme

 

Figure 1: 1H NMR spectrum of 4-(3-methylindol-2-yl) benzophenone  Click here to View figure

 

Figure 2: 13C NMR spectrum of 4-(3-methylindol-2-yl) benzophenone  Click here to View figure

 

Figure 3: Mass spectrum of 4-(3-methylindol-2-yl) benzophenone  Click here to View figure

 

Figure 4: 1H NMR spectrum of 4-propionyl benzophenone  Click here to View figure

 

Figure 5: 13C NMR Spectrum of 4-propionyl benzophenone  Click here to View figure

 

Figure 6: Mass spectrum of 4-propionyl benzophenone  Click here to View figure

 

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.

Acknowledgement

The authors gratefully acknowledge SRM University for the funds released under “The Faculty Selective Excellence Initiative” to carry out the work .We also thank University of Madras, Guindy Campus for providing the NMR and Mass Spectra.

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