Synthesis of 1-aryl-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-4(5H)-ones by two steps, in a three-component reaction

Article abstract of DOI:10.4067/S0717-97072016000300021

An efficient method for the synthesis of 1-aryl-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-4(5H)-ones is achieved in two steps, using a three-component reaction of phenacyl bromide, dimedone and aniline derivatives in water-ethanol (1:1) under reflux cond

Full text of DOI:10.4067/S0717-97072016000300021

J. Chil. Chem. Soc., 61, Nº 3 (2016)
SYNTHESIS OF 1-ARYL-6,6-DIMETHYL-2-PHENYL-6,7-DIHYDRO-1H-INDOL-4(5H)-ONES BY TWO STEPS, IN
A THREE-COMPONENT REACTION
JABBAR KHALAFY*, FAHIMEH BADPARVAR, AHMAD POURSATTAR MARJANI
Department of Chemistry, Faculty of Science, Urmia University, Urmia 57154, Iran
ABSTRACT
An efficient method for the synthesis of 1-aryl-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-4(5H)-ones is achieved in two steps, using a three-component
reaction of phenacyl bromide, dimedone and aniline derivatives in water-ethanol (1:1) under reflux conditions.
Keywords: Phenacyl bromide, Dimedone, Anilines, 1H-Indol-4(5H)-ones, Three-component reaction.
INTRODUCTION
In recent years, nitrogen-containing heterocyclic compounds have been
the focus of both chemists and biochemists due to their wide range of biologi-
cal and pharmaceutical properties.1,2
Among the various classes of nitrogen-containing heterocycles, indoles
have many biological and pharmacological activities, such as GABA receptor
ligands,3 antipsychotic,4 anticancer,5 antioxidant,6 antiproliferative agents,7 an-
Scheme 2. Synthesis of 1H-indol-4(5H)-one derivatives
tirheumatoidal and anti-HIV,8,9 and as soluble guanylatecyclase inhibitors.10,11
Therefore, the synthesis and selective functionalization of indoles12-14 and using
indoles as starting materials for the synthesis of a series of alkaloids, pharma-
ceuticals and perfumes15 have been the focus of researchers. A number of these
are costly and harmful to the environment. By contrast, few synthetic methods
based on green chemistry have been reported.16-18
The improved procedure reported in this article is a simple and environ-
mentally benign in comparison with other method mentioned in the literature.
The spectral data for all products is consistent with the assigned structures.
In particular, in the 1H-NMR spectra of the products, the indole 3-H is charac-
terized by a singlet at δ = 6.79-6.93 ppm. The CH next to the carbonyl group
resonated as singlets at δ = 1.86-2.42 ppm while 2the CH2 next to the pyrrole
ring appear as singlets at δ = 2.12-2.53 ppm. Each of the two methyl groups on
the aliphatic ring appear as singlets at δ = 0.85-1.27 ppm.
None the less, the synthesis of indoles in aqueous or less toxic solvents
by reducing the stages of the synthetic routes has been reported.19 Multi-com-
ponent reactions (MCRs) are powerful methods for the synthesis of organic
compounds,20 and are defined as convergent chemical processes where three
or more reagents are combined in such a way that the final product retains
significant portions of all starting materials. They lead to the connection of
three or more starting materials in a single synthetic operation with high atom
economy and bond-forming efficiency, thereby increasing molecular diversity
and complexity in a fast and often operational simplicity.21-22
A facile synthesis of substituted 6,7-dihydro-1H-indol-4(5H)-ones by re-
action of cyclohex-2-enone and 2-oxo-2-(substituted phenyl)acetaldehyde has
recently been reported.23 In addition, Kaladevi and co-workers reported the
reaction of 1-aryl-2-arylaminoethanones with substituted cyclohexane-1,3-
diones in acetic acid through an intramolecular cyclization to form 1,3-dia-
ryl-6,7-dihydro-1H-indol-4(5H)-ones.24 In continuation of our interest in multi-
component synthesis of nitrogen-containing heterocyclic compound,25 herein
we report the synthesis of 1-aryl-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-
4(5H)-ones by two steps, involving a three-component reaction of phenacyl
bromide, dimedone and various anilines in the presence of K2CO3 in water-
ethanol (1:1) under reflux conditions.
The 13C-NMR spectra are characterized by the indole 3C reonances at δ
105.65 (5a), 110.34 (5b), 110.07 (5c), 104.87 (5e), 110.00 (5f), 105.21 (5g)
(ppm). The CH2 next to the carbonyl group resonates at δ 52.13 (5a), 46.13
(5b), 46.29 (5c), 52.20 (5e), 46.37 (5f), 52.21 (5g) (ppm). The C-7 CH ap-
peared at δ 37.08 (5a), 31.74 (5b), 31.74 (5c), 36.59 (5e), 31.71 (5f), 36.382(5g)
(ppm). The C=O absorption in the FT-IR spectra were observed at 1610-1660
cm-1.
EXPERIMENTAL
Infrared spectra were recorded on a Thermo Nicolet Nexus 670 FT-IR
instrument using KBr discs. 1H and 13C NMR spectra were recorded on a Bruker
Avance AQS 300 MHz spectrometer at 300 and 75.5 MHz, respectively.
Chemical shifts were measured in CDCl3 relative to TMS as the internal
standard. Elemental analyses were performed by using a Leco Analyzer 932.
Melting points were measured on a Philip Harris C4954718 apparatus and are
uncorrected.
RESULTS AND DISCUSSION
Preparation of triketone (3):
Phenacyl bromide26 (1 mmol), 5,5-dimethylcyclohexane-1,3-dione (1
mmol) and anhydrous K2CO3 (0.13 mmol) were stirred together in dry CHCl3 (8
mL) for 12 h at 25 oC. The mixture was filtered and the residual potassium salt
of the product was dissolved in water (60 mL), and the solution was acidified
with HCl. The crude product (82%)28 was collected, washed with water, and
recrystallized from EtOH, m.p. 88 oC.
5,5-Dimethylcyclohexane-1,3-dione (2) was alkylated with phenacyl bro-
mide (1), prepared from acetophenone via bromination with bromine in acetic
acid at room temperature,26 in the presence of K2CO3, to give the triketone27
(3). (Scheme 1)
General Procedure for the synthesis of 1-aryl-6,6-dimethyl-2-phenyl-
6,7-dihydro-1H-indol-4(5H)-ones (5a-g):
The aniline (2 mmol) was added to a solution of triketone (3) (1 mmol)
in water-ethanol (1:1) (10 mL) and heated under reflux conditions overnight.
The reaction mixture was cooled to room temperature and the product was
then collected as a light pink precipitate which was washed with cold aqueous
ethanol and purified by recrystallization from methanol-acetone (1:1) to give
the desired products (5a-g) in 73-94% yield.
Scheme 1. Preparation of triketone (3)
The desired indoles were synthesized by adding anilines (4a-g) to triketon
(3) in water-ethanol (1:1) and refluxing the reaction mixture overnight (Scheme
2). The products (5a-g) were obtained in good yields after recrystallization
from methanol-acetone (1:1). The list of products (5a-g) along with their yields
and melting points are given in Table 1.
3112
e-mail: jkhalafi@yahoo.com; j.khalafi@urmia.ac.ir

J. Chil. Chem. Soc., 61, Nº 3 (2016)
Table 1. The yields and melting points of products (5a-g).
Entry
Aniline
Indole
Yield (%)
M.p. (oC)
O
NH2
1
N
85
207
4a
5a
O
NH2
2
3
N
90
93
175
184
5b
4b
O
NH2
N
5c
4c
O
NH2
NH2
NH2
N
4
94
185
5d
4d
O
5
6
N
89
77
147
164
5e
4e
O
N
Cl
5f
4f
Cl
O
NH2
N
7
73
189
4g
5g
NH2
NO2
8
N.R
-
-
4h
NH2
9
N.R
N.R
-
-
-
-
NO2
4i
NH2
10
O2N
4j
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J. Chil. Chem. Soc., 61, Nº 3 (2016)
6,6-Dimethyl-1,2-diphenyl-6,7-dihydro-1H-indol-4(5H)-one (5a):
C, 85.45; H, 6.34; N, 3.83. Found: C, 85.33; H, 6.45; N, 3.72%.
White solid, yield 85%, m.p. 207 C [Lit.29 205 C]. H-NMR (300 MHz,
CDCl3) δ (ppm): 1.06 (s, 3H, Me), 1.10 (s, 3H, Me), 2.42 (s, 2H, CH ), 2.53
(s, 2H, CH ), 6.79 (s, 1H, Ar), 7.04-7.10 (m, 2H, Ar), 7.11-7.21 (m, 52H, Ar),
7.37-7.44 (2m, 3H, Ar). 13C-NMR (75.5 MHz, CDCl3) δ (ppm): 28.64, 35.56,
37.08, 52.13, 105.65, 119.94, 126.87, 127.77, 128.14, 128.18, 128.26, 128.61,
129.34, 131.93, 136.33, 137.70, 144.71, 193.99. FT-IR νmax 3058, 2956, 2875,
1620, 1551, 1493, 1394, 1327, 1151, 1111, 771, 698 cm-1.
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1
CONCLUSIONS
In conclusion, we have successfully developed a facile, efficient procedure
for the synthesis of 1-aryl-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-
4(5H)-ones by two steps, including a three-component reaction in water-
ethanol under reflux. The advantageous features of this procedure are, high
yields, operational simplicity, availability of starting materials and the use of
water-ethanol as an environmentally friendly solvent.
6,6-Dimethyl-2-phenyl-1-(o-tolyl)-6,7-dihydro-1H-indol-4(5H)-one
(5b):
Light pink solid, yield 90%, m.p. 175 C [Lit.30 174-176 C]. H-NMR
(300 MHz, CDCl ) δ (ppm): 0.89 (s, 3H, Me), 1.05 (s, 3H, Me), 1.86 (s, 2H,
CH ), 2.17 (s, 2H,3CH2), 2.23 (s, 3H, Me), 6.90-7.20 (m, 7H, Ar), 7.20-7.33 (m,
3H,2 Ar). 13C-NMR (75.5 MHz, CDCl ) δ (ppm): 17.61, 27.59, 28.72, 31.74,
46.13, 108.32, 110.34, 112.27, 125.72,3127.01, 127.56, 128.11, 129.72, 130.09,
130.38, 131.76, 134.93, 136.55, 137.72, 139.56, 185.39. FT-IR νmax 3056, 2954,
2872, 1626, 1550, 1490, 1394, 1328, 1150, 1109, 768, 700 cm-1.
ACKNOWLEDGMENTS
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o
1
The authors gratefully acknowledge the financial assistance from Urmia
University.
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o
o
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1-(2,3-Dimethylphenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-
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White solid, yield 89%, m.p. 147 oC (dec.). 1H-NMR (300 MHz, CDCl ) δ
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1-(3-Chloro-2-methylphenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-
indol-4(5H)-one (5f):
o
1
Light pink solid, yield 77%, m.p. 164 C. H-NMR (300 MHz, CDCl3) δ
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2.30 (s, 2H, CH2), 6.97 (t, J = 8.1 Hz, 1H, Ar), 7.00-7.15 (m, 6H, Ar ), 7.17 (d,
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127.27, 127.68, 128.14, 128.86, 128.97, 129.77, 131.55, 134.85, 135.12,
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7.38 (t, J = 6.6 Hz,22H, Ar), 7.51 (t, J2= 7.2 Hz, 2H, Ar), 7.56 (t, J = 6.9 Hz,
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3115