Reaction of diphenacylanilines with 2-aminobenzophenone: An abnormal friedlander reaction yielding indoles

Article abstract of DOI:10.1080/00397911.2011.627524

This article describes an abnormal Friedlander reaction between diphenacylaniline and 2-aminobenzophenone in the presence of a catalytic amount of (±)-camphorsulfonic acid yielding 2-aroyl-3-arylindoles in quantitative yield. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.627524

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Reaction of Diphenacylanilines with
2-Aminobenzophenone: An Abnormal
Friedlander Reaction Yielding Indoles
Nidhin Paul a & Shanmugam Muthusubramanian a
a Department of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University, Madurai, India
Accepted author version posted online: 10 May 2012.Version of
record first published: 21 Feb 2013.
To cite this article: Nidhin Paul & Shanmugam Muthusubramanian (2013): Reaction of
Diphenacylanilines with 2-Aminobenzophenone: An Abnormal Friedlander Reaction Yielding Indoles,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:8, 1200-1209
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Synthetic Communications1, 43: 1200–1209, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.627524
REACTION OF DIPHENACYLANILINES WITH
2-AMINOBENZOPHENONE: AN ABNORMAL
FRIEDLANDER REACTION YIELDING INDOLES
Nidhin Paul and Shanmugam Muthusubramanian
Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University, Madurai, India
GRAPHICAL ABSTRACT
Abstract This article describes an abnormal Friedlander reaction between diphenacylaniline
and 2-aminobenzophenone in the presence of a catalytic amount of (ꢀ)-camphorsulfonic
acid yielding 2-aroyl-3-arylindoles in quantitative yield.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Abnormal Friedlander reaction; 2-aroyl-3-arylindole; (ꢀ)-camphorsulfonic
acid; diphenacylaniline
INTRODUCTION
Many of the bioactive alkaloids from the plants of marine or terrestrial domain
are based on the indole moiety.[1] The indole framework has vast application in
material sciences,[2] agrochemicals,[3] and pharmaceuticals. Indoles and their deriva-
tives are known to exhibit antibacterial,[4] antifungal,[4b] antiviral,[5] antitubercular,[6]
anticancer,[7] anti–Alzheimer’s disease,[8] anti-HIV,[9] gonadotropine-releasing
hormone antagonist,[10] and h5-HT2A receptor antagonist[11] properties. Melatonin
1 (Fig. 1), an important hormone that regulates biological rhythms and acts as a
receptor-independent free-radical scavenger,[12,7b] and the natural product martefra-
gin A 2, which is an inhibitor of lipid peroxidation,[13] have indole in their molecular
makeup. 3-(1H-Indol-3-yl)propanoic acid 3, which is extracted from the root
nodules of the pea plant (Pisum sativum), is a potent neuroprotective agent.[14]
Received July 1, 2011.
Address correspondence to Shanmugam Muthusubramanian, Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India. E-mail: muthumanian2001@
yahoo.com
1200

ABNORMAL FRIEDLANDER REACTION
1201
Figure 1. Structures of indole drugs and alkaloids. (Figure is provided in color online.)
Fluvastatin 4[15] is a synthetic member of the statin class containing the indole
moiety. Indolodioxane (U86192A) 5 is active in antihypertension[16] and MDL
103371 6 is a kind of glycine receptor antagonist[17] for the treatment of strokes.
Tryptophan derivatives possess inhibitory activity against the IDO enzyme.[18]
Well-documented strategies for the synthesis of indoles include the Fisher indole syn-
thesis,[19] the Bischler indole synthesis,[20] and the Madlung cyclization.[21] Despite
many creative approaches,[22] general and efficient syntheses that control the intro-
duction of substituents at C-2 and C-3[23] of the indole are still lacking.
In continuation of our interest in the construction of novel organic mole-
cules,[24] herein we report the abnormal Friedlander reaction of 2-aminobenzophe-
none with diphenacylaniline, resulting in indole derivatives.
RESULTS AND DISCUSSION
Different diphenacylanilines were prepared by a reported procedure[25] from
substituted phenacyl bromide and aniline. With the expectation of generating bisqui-
nolines 9 through a double-Friedlander reaction, diphenacylaniline 8 is allowed to
react with 2 mol of 2-aminobenzophenone 7 (Scheme 1) with different acid catalysts.
Scheme 1. Synthesis of 2-aroyl-3-arylindole 11. (Figure is provided in color online.)

1202
N. PAUL AND S. MUTHUSUBRAMANIAN
A product has been isolated and, in order to optimize the reaction conditions, we
carried out the reaction under different time intervals and varied the solvents and
catalysts (Table 1). The course of the reaction was monitored by thin-layer chro-
matography (TLC) in each case and it was observed that the reaction yielded the best
result when refluxed in ethanol for 2 h with 15 mol% of (ꢀ)-camphorsulfonic acid
(CSA). Further increase in the catalyst concentration does not improve the yield.
Among the different solvents tried, ethanol gave maximum yield (Table 1). The
reaction has been generalized by carrying it out on a set of substrates, and the crude
product separated in each case was recrystallized from an ethanol–ethyl acetate
mixture (3:2) to provide the pure product in 76–88% yield (Table 2).
CSA (15 mol %) in 7 ml of ethanol was added to a mixture of 2-aminobenzo-
phenone 7 (2 mmol) and diphenacylaniline 8 (1 mmol). The mixture was allowed
to reflux for 2 h, and after the completion of the reaction (TLC), the reaction mixture
was poured into ice-cold water. The solid that separated was recrystallized from
3:2 alcohol–ethyl acetate mixture to give 11.
The reaction was expected to yield nitrogen-linked bisquinolines 9 by a
double-Friedlander pathway or quinolones 10 by an intermolecular phenyl ring
transfer, but the product obtained has been shown to be indoles 11 (Scheme 1).
The presence of a broad singlet at 9.72 ppm (1H, NH) in the proton NMR spectrum
of 11j and the appearance of a carbonyl peak at 188.2 ppm in its 13C NMR spectrum
Table 1. Solvent and catalyst screening for the synthesis of 11a from diphenacyl aniline
Entry
Solvent
Catalyst (mol%)
Time (h)
Yield of 11a (%)
1
2
MeOH
CH3CN
THF
(ꢀ)-CSA (20)
(ꢀ)-CSA (20)
(ꢀ)-CSA (30)
(ꢀ)-CSA (15)
(ꢀ)-CSA (30)
(ꢀ)-CSA (15)
(ꢀ)-CSA (15)
p-TSA (25)
2.5
3.5
3.0
3.5
3.0
2.0
2.0
2.5
3.5
2.0
3.5
4.0
4.5
3.5
3.0
4.5
3.0
3.0
4.5
4.5
5.0
70a
74a
b
3
—
4
Ethylene glycol
DMF
55c
36c
32c
5
6
Water
CH3Cl
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
b
—
7
8
68c
60c
82a
80a
54c
71a
63c
72a
57c
73a
70a
71a
68a
9
p-TSA (15)
10
11
12
13
14
15
16
17
18
19
20
21
(ꢀ)-CSA (15)
(ꢀ)-CSA (35)
Citric acid (20)
Citric acid (45)
HCl (20)
SnCl4 ꢁ 6H2O (15)
AlCl3 (20)
YbCl3 (15)
Yb(Otf)3 (15)
BiCl3 (25)
InCl3 (15)
d
—
KOH (20)
aRecrystallized from ethyl acetate.
bNo characteristic product.
cSeparated through column.
dReactants recovered.

ABNORMAL FRIEDLANDER REACTION
1203
Table 2. Synthesis of indole from diphenacyl aniline
Entry
X
Ph
Ar
Ar0
Compound obtained Time (h) Yield of 11 (%)a
1
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
11a
11a
11a
11a
11b
11b
11b
11c
11c
11d
11e
11e
11f
2.0
2.3
1.6
2.0
2.0
2.1
1.7
2.5
2.6
2.0
2.1
1.5
1.5
2.3
2.5
2.5
1.8
2.3
2.0
1.5
2.0
2.0
2.1
1.6
82
80
88
87
79
80
83
85
78
84
79
82
78
82
83
85
82
81
76
80
87
82
81
84
4-MeC6H4
4-ClC6H4
4-FC6H4
C6H5
3
C6H5
C6H5
4
5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
6
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
C6H5
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-OMeC6H4 C6H5
4-OMeC6H4 4-ClC6H4
2-Naphthyl
3-ClC6H4
C6H5
C6H5
C6H5
11g
11 h
11 h
11i
Cl C6H5
Cl C6H5
Cl C6H5
Cl C6H5
Cl C6H5
Cl C6H5
Cl C6H5
C6H5
4-ClC6H4
C6H5
C6H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-ClC6H4
C6H5
11j
11k
11 l
11 l
11 m
11n
11n
4-OMeC6H4 C6H5
4-OMeC6H4 4-ClC6H4
Cl 2-FC6H4 C6H5
Cl 2-FC6H4 4-ClC6H4
Cl 2-FC6H4 4-ClC6H4
C6H5
C6H5
4-ClC6H4
aAfter purification by recrystallization.
prompted us to eliminate bisquinoline as the possible product.
[(4-Chlorophenyl)(5-chloro-3-phenyl-1H-2-indolyl)methanone (11j) was isolated as
colorless solid; mp 206–207 ꢂC; 1H NMR (300 MHz, CDCl3) dH: 7.03 (d, 2H,
J ¼ 8.7 Hz, Ar-H), 7.11–7.20 (m, 5H, Ar-H), 7.35 (dd, 1H, J ¼ 8.7, 1.8 Hz, Ar-H),
7.45 (d, 3H, J ¼ 8.7 Hz, Ar-H), 7.68 (d, 1H, J ¼ 1.8 Hz, Ar-H), 9.72 (s, 1H, NH);
13C NMR (75 MHz, CDCl3) dC: 113.3, 121.2, 124.8, 126.9, 127.2, 127.3, 127.9,
128.2, 128.4, 130.7, 130.8, 131.5, 132.8, 134.8, 135.4, 138.2, 188.2. Anal. calcd. for
C21H13Cl2NO: C, 68.87; H, 3.58; N, 3.82%. Found: C, 68.82; H, 3.54; N, 3.86%].
The doublet at 7.03 ppm (J ¼ 8.7 Hz, 2H, H-30) is ascribed to meta hydrogens of
para-chloroaryl ring, which has (i) H, H-COSY (correlation spectroscopy) with
another doublet at 7.45 ppm (J ¼ 8.7 Hz, H-20), (ii) C, H-COSY with C-30 at
128.2 ppm, and (iii) HMBCs (heteronuclear multiple bond correlation) with C-10
at 135.4 ppm and C-40 at 138.2 ppm. The doublet at 7.45 ppm has C, H-COSY with
C-20 at 130.8 ppm and a decisive HMBC with the carbonyl signal at 188.2 ppm,
which is impractical in the expected quinolone system (10) and feasible only with
the indole moiety, 11. In the indole ring, the doublet at 7.68 ppm (J ¼ 1.8 Hz) is
ascribed to H-4 which has C, H-COSY relation with C-4 at 121.2 ppm and HMBCs
with C-6 at 127.3 and C-7a at 134.8 ppm. The proton signal at 7.35 ppm (dd, 1H,
J ¼ 8.7, 1.8 Hz) is due to H-6 and has a C, H-COSY connection with C-6 and
HMBCs with C-4 and C-7a. The expected doublet for H-7 hydrogen has merged
with H-20 but was identified from the H, H-COSY contour with H-6 (Fig. 2). Even

1204
N. PAUL AND S. MUTHUSUBRAMANIAN
Figure 2. Selected HMBCs and 1H and 13C chemical shifts in compound 11j. (Figure is provided in color
online.)
though the mass value (for 11i, m=e 344.0848 [M ꢃ 1]; calcd. 344.0920 [M ꢃ 1]) is not
able to distinguish between quinolone 10 and indole 11, the structure of product is
unambiguously confirmed from single-crystal X-ray analysis of 11b (Fig. 3).
Crystallographic data (excluding structure factors) for compound 11b in this
article have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 824612. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: þ44 (0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
It is pertinent to note that the indole moiety obtained by the abnormal
Friedlander reaction was reported earlier from the reaction of phenacyl bromide
and 2-aminobenzophenone,[26] but the details regarding the reaction and the spectral
data were not well documented.
As phenacyl bromide has been shown to react with 2-aminobenzophenone,[26]
providing 2-aroyl-3-arylindoles, it is suspected that in the present investigation
diphenacyl aniline would have cleaved under acidic conditions, providing the
Figure 3. ORTEP diagram for 11b. (Figure is provided in color online.)

ABNORMAL FRIEDLANDER REACTION
1205
Scheme 2. Proposed mechanism for the formation of indole. (Figure is provided in color online.)
þ
reactive PhCOCH2 species and aniline, and the phenacyl cation would have then
reacted with 2-aminobenzophenone, giving the indole. The isolation of aniline as
a by-product from the reaction medium has added weight to this suspicion.
However, a blank reaction in which a mixture of diphenacylaniline and camphor-
sulfonic acid was subjected to identical reaction conditions failed to give any
aniline, and the starting material was left unchanged. This prompted us to propose
a suitable mechanism for the formation of indole (Scheme 2) in which the active meth-
ylene attacks the carbonyl carbon to form intermediate 12. The amino group then
displaces the -NArCH2COAr, whose leaving group ability could be increased by
protonation by the acid catalyst. The monophenacylaniline generated in this reaction
can undergo a similar reaction, yielding another mole of indole leaving aniline.
The feasibility of monophenacylaniline 16 undergoing this reaction was proved
independently by taking 16 as the starting material instead of 8 (Scheme 3).
It is interesting that under Friedlander conditions diphenacylaniline and mono-
phenacylaniline prefer to undergo a different reaction, yielding indole. An attempted
base-catalyzed Friedlander reaction between 7 and 8 was also not successful as the
expected products were not obtained.
Please see the Supporting Information, available online, for complete experi-
mental details.
Scheme 3. Synthesis of 2-aroyl-3-arylindole from monophenacyl aniline. (Figure is provided in color
online.)

1206
N. PAUL AND S. MUTHUSUBRAMANIAN
CONCLUSION
This article describes the reaction of diphenacylanilines with 2-aminobenzo-
phenone in the presence of (ꢀ)-CSA to give 2-aroyl-3-arylindoles by an abnormal
Friedlander reaction.
ACKNOWLEDGMENTS
The authors thank the Department of Science and Technology, New Delhi, for
funds under IRHPA program for the high-resolution NMR spectrometer and the
University Grants Commission, New Delhi, for the financial support to one of the
authors, N. P. N. Srinivasan of Thiagarajar College, Madurai, Tamil Nadu, India,
and J. C. Menendez of Departamento de Quimica Organica y Farmaceutica, Univer-
sidad Complutense, Madrid, Spain, are acknowledged for the X-ray diffraction and
mass analyses respectively.
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