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Journal of the Chilean Chemical Society

On-line version ISSN 0717-9707

J. Chil. Chem. Soc. vol.61 no.3 Concepción Sept. 2016

http://dx.doi.org/10.4067/S0717-97072016000300021 

 

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 MARIANI

Department of Chemistry, Faculty of Science, Urmia University, Urmia 57154, Iran
* e-mail: jkhalafi@yahoo.com; j.khalafi@urmia.ac.ir


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 biological 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-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, pharmaceuticals 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

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-component 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 reaction 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-diaryl-6,7-dihydro-1 H-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.

RESULTS AND DISCUSSION

5,5-Dimethylcyclohexane-1,3-dione (2) was alkylated with phenacyl bromide (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)

 

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.

 

Scheme 2. Synthesis of 1H-indol-4(5H)-one derivatives

 

Table 1. The yields and melting points of products (5a-g).

 

The improved procedure reported in this article is a simple and environmentally 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 characterized by a singlet at δ = 6.79-6.93 ppm. The CH2 next to the carbonyl group resonated as singlets at δ = 1.86-2.42 ppm while the 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.

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 CH2 appeared at δ 37.08 (5a), 31.74 (5b), 31.74 (5c), 36.59 (5e), 31.71 (5f), 36.38 (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.

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.

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.

6,6-Dimethyl-1,2-diphenyl-6,7-dmydro-1H-indol-4(5H)-one (5a):

White solid, yield 85%, m.p. 207 oC [Lit.29 205 oC]. 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.06 (s, 3H, Me), 1.10 (s, 3H, Me), 2.42 (s, 2H, CH2), 2.53 (s, 2H, CH2), 6.79 (s, 1H, Ar), 7.04-7.10 (m, 2H, Ar), 7.11-7.21 (m, 5H, Ar), 7.37-7.44 (m, 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 vmax 3058, 2956, 2875, 1620, 1551, 1493, 1394, 1327, 1151, 1111, 771, 698 cm-1.

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 oC [Lit.30 174-176 oC]. 1H-NMR (300 MHz, CDCl3) δ (ppm): 0.89 (s, 3H, Me), 1.05 (s, 3H, Me), 1.86 (s, 2H, CH2), 2.17 (s, 2H, CH2), 2.23 (s, 3H, Me), 6.90-7.20 (m, 7H, Ar), 7.20-7.33 (m, 3H, Ar). 13C-NMR (75.5 MHz, CDCl3) δ (ppm): 17.61, 27.59, 28.72, 31.74, 46.13, 108.32, 110.34, 112.27, 125.72, 127.01, 127.56, 128.11, 129.72, 130.09, 130.38, 131.76, 134.93, 136.55, 137.72, 139.56, 185.39. FT-IR vmax 3056, 2954, 2872, 1626, 1550, 1490, 1394, 1328, 1150, 1109, 768, 700 cm-1.

6,6-Dimethyl-2-phenyl-1-(m-tolyl)-6,7-dihydro-1H-indol-4(5H)-one (5c):

Light pink solid, yield 93%, m.p. 184 oC [Lit.30 184-185 oC]. 1H-NMR (300 MHz, CDCl3) δ (ppm): 0.89 (s, 3H, Me), 1.05 (s, 3H, Me), 2.12 (s, 2H, CH2), 2.26 (s, 5H, CH2+Me), 6.79 (d, J = 6.9 Hz, 1H, Ar), 6.80 (s, 1H, Ar), 6.92 (d, J = 7.2 Hz, 1H, Ar), 6.95-7.03 (m, 4H, Ar), 7.05-7.16 (m, 3H, Ar). 13C-NMR (75.5 MHz, CDCl3) δ (ppm): 21.08, 27.57, 28.69, 30.08, 31.74, 46.29, 110.07, 112.63, 125.75, 126.90, 127.56, 127.64, 129.37, 127.99, 130.01, 130.44, 132.02, 134.48, 138.14, 138.25, 186.44. FT-IR vmax 3056, 2953, 1610, 1548, 1487, 1398, 1340, 1242, 1031, 763, 696 cm-1.

6,6-Dimethyl-2-phenyl-1-(p-tolyl)-6,7-dihydro-1H-indol-4(5H)-one (5d):

White solid, yield 94%, m.p. 185 oC [Lit.30 184-187 oC]. 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.11 (s, 3H, Me), 1.27 (s, 3H, Me), 2.41 (s, 3H, Me), 2.43 (s, 2H, CH2), 2.52 (s, 2H, CH2), 6.79 (s, 1H, Ar), 7.02-7.05 (m, 2H, Ar), 7.08-7.10 (m, 2H, Ar), 7.17-7.23 (m, 5H, Ar). FT-IR vmax 2922, 2854, 1659, 1515, 1462, 1260, 1215, 1026, 808, 761 cm-1.

1-(2,3-Dimethylphenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-4(5H)-one (5e):

White solid, yield 89%, m.p. 147 oC (dec.). 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.09 (s, 3H, Me), 1.12 (s, 3H, Me), 1.76 (s, 3H, Me), 2.19 (d, J = 17.1 Hz, 1H), 2.28 (s, 3H, Me), 2.33 (d, J = 16.2 Hz, 1H), 2.46 (d, J = 16.2 Hz, 1H), 2.47 (d, J = 17.1 Hz, 1H), 6.84 (s, 1H, Ar), 7.27-7.07 (m, 8H, Ar). 13C-NMR (75.5 MHz, CDCl3) δ (ppm): 13.96, 20.33, 27.99, 29.22, 35.58, 36.59, 52.20, 104.87, 119.66, 126.21, 126.84, 127.46, 127.69, 128.15, 130.52, 132.12, 134.76, 136.65, 136.84, 138.63, 145.06, 193.93. FT-IR vmax 2924, 2856, 1658, 1468, 1283, 1219, 1084, 771, 701 cm-1. Anal. Calc. for C24H25NO: C, 83.93; H, 7.34; N, 4.08. Found: C, 83.88; H, 7.41; N, 7.28%.

1-(3-Chloro-2-methylphenyl)-6,6-dimethyl-2-phenyl-6,7-dihydro-1H-indol-4(5H)-one (5f):

Light pink solid, yield 77%, m.p. 164 oC. 1H-NMR (300 MHz, CDCl3) δ (ppm): 0.86 (s, 3H, Me), 1.05 (s, 3H, Me), 1.87 (s, 2H, CH2), 2.21 (s, 3H, Me), 2.30 (s, 2H, CH2), 6.97 (t, J = 8.1 Hz, 1H, Ar), 7.00-7.15 (m, 6H, Ar ), 7.17 (d, J = 8.1 Hz, 1H, Ar), 7.25 (d, J = 8.7 Hz, 1H, Ar). 13C-NMR (75.5 MHz, CDCl3) δ (ppm): 15.34, 27.46, 28.76, 29.70, 31.71, 46.37, 110.00, 112.70, 125.91, 127.27, 127.68, 128.14, 128.86, 128.97, 129.77, 131.55, 134.85, 135.12, 135.43, 139.02, 186.23. FT-IR vmax 3064, 2956, 2873, 1618, 1467, 1398, 1297, 1151, 1110, 1016, 767, 700 cm-1 Anal. Calc. for C23H22ClNO: C, 75.92; H, 6.09; N, 3.85. Found: C, 76.12; H, 5.91; N, 3.73%.

6,6-Dimethyl-1-(naphthalene-1-yl)-2-phenyl-6,7-dihydro-1H-indol-4(5H)-one (5g):

White solid, yield 73%, m.p. 189 oC. 1H-NMR (300 MHz, CDCl3) δ (ppm): 1.05 (s, 3H, Me), 1.06 (s, 3H, Me), 2.17 (d, J = 16.5 Hz, 1H, CH2), 2.37 (d, J = 16.5 Hz, 1H, CH2), 2.45 (s, 2H, CH2), 6.93 (s, 1H, Ar), 7.04 (br s, 5H, Ar), 7.38 (t, J = 6.6 Hz, 2H, Ar), 7.51 (t, J = 7.2 Hz, 2H, Ar), 7.56 (t, J = 6.9 Hz, 1H, Ar), 7.95 (d, J = 7.8 Hz, 2H, Ar). 13C-NMR (75.5 MHz, CDCl3) δ (ppm): 28.06, 28.89, 35.54, 36.38, 52.21, 105.21, 119.88, 122.63, 125.28, 126.55, 126.92, 127.54, 127.78, 128.07, 128.42, 128.75, 129.41, 130.94, 131.89, 134.09, 134.32, 137.59, 146.16, 194.07. FT-IR vmax 3056, 2955, 2871, 1660, 1600, 1554, 1464, 1412, 1218, 1148, 758, 695 cm-1 Anal. Calc. for CH NO: C, 85.45; H, 6.34; N, 3.83. Found: C, 85.33; H, 6.45; N, 3.72%.

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.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the financial assistance from Urmia University.

 

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