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

Article abstract of DOI:10.13005/ojc/330668

We have developed a simple route for the synthesis of [4-(3-methyl-1H-indol-2-yl)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.

Full text of DOI:10.13005/ojc/330668

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No.(6):
Pg. 3211-3217
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
A Novel Synthesis of [4-(3-methyl-1H-indol-2-yl) phenyl]
(phenyl)methanone
HARINDRAN SUHANA* and S.RAJESWARI
Department of Chemistry, SRM University, Kattankulathur-603203, Tamil nadu, India.
*Corresponding author E-mail: suhana.h@ktr.srmuniv.ac.in
http://dx.doi.org/10.13005/ojc/330668
(Received: October 11, 2017; Accepted: October 27, 2017)
ABSTRACT
We have developed a simple route for the synthesis of [4-(3-methyl-1H-indol-2-
yl)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.
Keywords: Fischer indole synthesis, 1, 4-diacylbenzene, Friedel-Craft’s benzoylation,
Allylic bromination.
inflammatory6-10 and analgesic11. Due to high
INTRODUCTION
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 years12-15. 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
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 antibacterial3-4, antifungal5, anti

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SUHANA et al., Orient. J. Chem., Vol. 33(6), 3211-3217 (2017)
Yellow solid; Yield:99% m.p.86-880 C; IR (KBr): νmax
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.
1
1678, 1664 cm-1; H 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)
EXPERIMENTAL
To a solution of 1-[4-(benzoyl)phenyl]
Material and Methods
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 BF3-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.
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 1H NMR and 13C NMR
data were recorded with a Bruker 500 MHz 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
Yellow powder; Yield: (95%); m.p. :198-200oC
; IR(KBr): νmax1650 (C=O), 3343 (NH)cm-1,1H NMR
(500 MHz; DMSO-d6): 2.46 (s, 3H, CH3), 7.00-8.07
102/DA-6000 mass spectrometer/data system. (m, 13H, Aromatic-H),11.34(s, 1H, indole-NH);
Elemental analysis results were found to be in good 13CNMR(125 MHz): 10.6,1 09.6, 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.
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%
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%
[4-(1-bromopropyl)phenyl](phenyl)methanone
(3b)
This was prepared by the procedure20
employed earlier using N-bromosuccinimide in
tetrachloro methane. Yield: 85%
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%
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.

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Preparation of (4-benzoylphenyl)ethanone (4a)
The (4-benzoylphenyl)ethanone was
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 .
prepared from [4-(1-bromoethyl) phenyl] (phenyl)
methanone 3a by the reported procedure19 using
bistetra 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:80-84oC;
IR(KBr):νmax1689,1656cm-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)
Yield: 50%; m.p.: 110oC (decomposed); IR
(KBr ): 1669 (>C=O), 3313 (NH) ) cm-1; 1H
NMR(CDCl3/TMS): δ 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).
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
Scheme 1: Synthesis of diphenylmethanone integrated indoles

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Preparation of bis-tetrabutyl ammonium ethanol followed by refluxing the resulting
dichromate hydrazone with anhydrous zinc chloride in xylene
The above oxidizing agent was prepared afforded [4-(1H-indol-2-yl)phenyl](phenyl) methanone
by the method reported19 in the literature, from tetra 5a in 50% yield.
butyl ammonium bromide and potassium
dichromate.
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
RESULTS AND DISCUSSION
1669 cm-1 due to carbonyl group. The H NMR
1
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.
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
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
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 phenylhydrazine in
Fig.1. 1H NMR spectrum of 4-(3-methylindol-2-yl) benzophenone

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Fig. 2. 13C NMR spectrum of 4-(3-methylindol-2-yl) benzophenone
Fig. 3. Mass spectrum of 4-(3-methylindol-2-yl) benzophenone
Fig. 4. 1H NMR spectrum of 4-propionyl benzophenone

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Fig. 5. 13C NMR Spectrum of 4-propionyl benzophenone
Fig. 6. Mass spectrum of 4-propionyl benzophenone
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 peakat1650cm-1.In the
1H 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. Fig. 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, and 195.72. Fig. 2. The mass spectrum
showed a molecular ion peak at m/z = 311.30 Fig. 3.
The scheme shown below represents the various
steps involved in the synthesis.
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 diphenyl-
methanone 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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