Open Access Published by De Gruyter July 4, 2017

A simple one-pot synthesis of 2,4-diaryl- 9H-pyrido[2,3-b]indoles under solvent-free conditions

Mehdi Khoshneviszadeh, Aida Yahagh, Mehdi Soheilizad and Mohammad Mahdavi

Abstract

A novel, simple, one-pot synthesis of 2,4-diaryl-9H-pyrido[2,3-b]indoles is described. Heating a mixture of chalcone, oxindole and ammonium acetate in the presence of potassium tert-butoxide under solvent-free conditions afforded the title compounds in good to excellent yields.

Introduction

Pyrido[2,3-b]indoles (α-carbolines) have attracted considerable attention due to their occurrence in carcinogenic metabolites, biologically active compounds and natural products [1], [2], [3]. Some synthetic pyrido[2,3-b]indoles including 1 are γ-aminobutyric acid (GABA) modulators with potential as therapeutic agents for the treatment of anxiety disorders [4]. Recently, some of related compounds have shown activity against Alzheimer’s disease, Parkinson’s disease, cerebrovascular accidents, amyotrophic lateral sclerosis, viral infections and autoimmune diseases [5], [6]. Some compounds are antidepressant and antineoplastic agents [7], [8].

Pyrido[2,3-b]indoles can be synthesized by reaction of α-oxoketene dithioacetal with 1-methyl-2-oxoindole enolate anion and subsequent cyclization of the adduct in the presence of NH4OAc [9], reaction of 2-aminoindole with 3,3-dimethoxy-2-formyl-propionitrile sodium salt [10], reaction between 2-aminoindole and acetylenic esters [11], condensation of 2-amidinylindole-3-carbaldehyde with acetophenone [12], cyclization of 1-methyl-3-(2-carbomethoxyethyl)-2-iminoindoline [6], cross coupling of ortho-pivaloylaminophenyl-ortho′-halopyridine [13], intramolecular [4+2] cycloaddition-elimination of 3-(2-ethynylphenylamino)-2(1H)-pyrazinone [14], intramolecular hetero-Diels-Alder cycloaddition-aromatization of ortho-vinyl C=C-conjugated arylcarbodiimide [15] and pyrolysis of 1-benzylpyrazole with chloroform [16]. Several of these multi-step methods have drawbacks such as not easily accessible starting materials, low overall yields, harsh reaction conditions, long reaction times and use of toxic and hazardous starting materials, reagents and/or solvents.

As part of our ongoing program to develop new facile methods for the preparation of biologically active heterocyclic compounds from readily available building blocks [17], [18], [19], [20], we report herein a simple one-pot synthesis of 2,4-diaryl-9H-pyrido[2,3-b]indoles.

Results and discussion

Heating a mixture of oxindole 2, chalcone 3 and ammonium acetate in the presence of a catalytic amount of potassium tert-butoxide under solvent-free conditions produced the 2,4-diaryl-9H-pyrido[2,3-b]indole 4a–h in 82–90% yield (Scheme 1). The reaction was carried out by mixing the oxindole and the chalcone, then adding a catalytic amount of t-BuOK, stirring the mixture at 150°C for 5 min to form an oily mixture, followed by treatment with an excess of NH4OAc and stirring at 200°C for an additional 30 min. TLC and 1H NMR analyses of the resultant yellowish liquid clearly indicated formation of pyrido[2,3-b]indole 4a–h.

Scheme 1

Scheme 1

A possible reaction pathway for the formation of 2,4-diaryl-9H-pyrido[2,3-b]indole 4 is suggested in Scheme 2. The initial Michael addition reaction of the oxindole 2 with chalcone 3 [21], [22], [23], [24], [25], leads to the formation of the intermediate product 5. Then, condensation of ammonium acetate with this intermediate compound followed by tautomerization generates the enamine 7. Finally, intramolecular cyclization of 7 followed by tautomerization and oxidation of 8 affords the product 4.

Scheme 2

Scheme 2

Conclusion

A solvent-free reaction between oxindole 2, chalcone 3, and ammonium acetate in the presence of potassium tert-butoxide provides a simple one-pot approach to the synthesis of a substituted pyrido[2,3-b]indole. Use of simple starting materials, good atom economy, short reaction time and good yield of the product are the main advantages of this method.

Experimental

Oxindoles and potassium tert-butoxide were obtained from Merck (Germany) and Sigma-Aldrich (USA). Chalcones were prepared according to the literature procedure [26]. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H and N were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on an Agilent Technologies HP 5973 mass spectrometer operating at an ionization potential of 20 eV. 1H NMR (250.1 MHz) and 13C NMR (62.9) spectra were measured with a Bruker DPX-250 spectrometer in CDCl3 with TMS as an internal standard. IR spectra were recorded in KBr pellets on a Shimadzu IR-460 spectrometer.

General procedure for synthesis of 4a–h

A mixture of an oxindole (1.0 mmol), a chalcone (1.0 mmol) and potassium tert-butoxide (0.034 g, 0.3 mmol) was stirred at 150°C for 5 min and the resultant oily mixture was then treated with ammonium acetate (0.154 g, 2.0 mmol) over 4 min and stirred at 200°C for an additional 30 min. The resultant yellowish liquid solidified upon cooling to room temperature and was crystallized from a mixture of EtOAc/n-hexane (1:1).

2-Phenyl-4-(p-tolyl)-9H-pyrido[2,3-b]indole (4a)

Pale yellow solid; yield 90%; mp 217–218°C; IR (cm−1): 3153, 1591, 1566, 1362, 1294, 1207, 1109, 997, 870, 820, 746, 696; 1H NMR: δ 2.55 (s, 3H), 6.47 (d, J=7.8 Hz, 1H), 7.02 (dd, J=7.7, 7.4 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.50–7.60 (m, 3H), 7.62 (s, 1H), 7.71 (d, J=7.0 Hz, 2H), 7.73 (d, J=7.5 Hz, 1H), 8.28 (d, J=7.5 Hz, 2H), 12.36 (s, 1H); 13C NMR: δ 21.4, 111.4, 112.9, 114.4, 119.3, 120.6, 122.3, 126.2, 127.8, 128.6, 128.7, 129.1, 129.4, 136.3, 138.5, 139.4, 140.3, 146.3, 153.4, 154.2; MS: m/z 334 (M+). Anal. Calcd for C24H18N2: C, 86.20; H, 5.43; N, 8.38. Found: C, 86.20; H, 5.42; N, 8.35.

2-Phenyl-4-(m-tolyl)-9H-pyrido[2,3-b]indole (4b)

Pale yellow solid; yield 85%; mp 187–188°C; IR (cm−1): 3329, 1583, 1566, 1485, 1450, 1385, 1292, 1211, 771, 740, 695; 1H NMR: δ 2.53 (s, 3H), 6.52 (d, J=8.1 Hz, 1H), 7.02 (dd, J=7.6, 7.4 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.55–7.62 (m, 6H), 7.69 (d, J=7.8 Hz, 1H), 8.28 (d, J=7.5 Hz, 2H), 12.23 (s, 1H); 13C NMR: δ 21.5, 111.4, 112.9, 114.4, 119.4, 120.6, 122.3, 125.8, 126.2, 127.8, 128.6, 128.7, 129.1, 129.3, 129.4, 138.4, 139.2, 139.5, 140.2, 146.4, 153.4, 154.2; MS: m/z 334 (M+). Anal. Calcd for C24H18N2: C, 86.20; H, 5.43; N, 8.38. Found: C, 86.19; H, 5.50; N, 8.35.

4-(4-Methoxyphenyl)-2-phenyl-9H-pyrido[2,3-b]indole (4c)

Pale yellow solid; yield 92%; mp 220–221°C; IR (cm−1): 3266, 1607, 1595, 1564, 1510, 1456, 1394, 1360, 1294, 1248, 1178, 1030, 837, 773, 742, 696; 1H NMR: δ 3.97 (s, 3H), 6.94 (dd, J=7.5, 1.0 Hz), 7.06 (dd, J=7.6, 7.4 Hz), 7.15 (d, J=8.4 Hz, 2H), 7.30 (t, J=7.5 Hz, 1H), 7.47–7.59 (m, 4H), 7.74 (d, J=8.4 Hz, 2H), 7.75 (d, J=7.4 Hz, 1H), 8.20 (d, J=7.6 Hz, 2H), 10.99 (s, 1H); 13C NMR: δ 55.4, 111.3, 112.8, 114.2, 114.4, 119.4, 120.7, 122.3, 126.3, 127.7, 128.7, 129.1, 130.0, 131.5, 139.3, 140.2, 146.0, 153.3, 154.3, 160.1; MS: m/z 350 (M+). Anal. Calcd for C24H18N2O: C, 82.26; H, 5.18; N, 7.99. Found: C, 82.31; H, 5.23; N, 7.98.

4-(4-Chlorophenyl)-2-phenyl-9H-pyrido[2,3-b]indole (4d)

Pale yellow solid; yield 87%; mp 227–228°C; IR (cm−1): 3250, 1591, 1545, 1481, 1458, 1389, 1350, 1296, 1207, 1022, 773, 739, 698; 1H NMR: δ 7.05 (dd, J=8.5, 7.7 Hz, 1H), 7.41 (dd, J=8.5 Hz, J=7.1 Hz, 1H), 7.44 (d, J=7.1 Hz), 7.48–7.54 (m, 4 H), 7.66 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.5 Hz, 2H), 8.22 (dd, J=7.1, 1.4 Hz, 2H), 12.11 (s, 1H); 13C NMR: δ 111.3, 111.5, 112.9, 119.4, 119.6, 121.7, 126.6, 126.9, 128.8, 128.9, 128.9, 130.6, 133.6, 137.5, 139.2, 139.6, 143.7, 152.6, 153.1; MS: m/z 356 [M+37Cl], 354 (M+ 35Cl). Anal. Calcd for C23H15ClN2: C, 77.85; H, 4.26; N, 7.89. Found: C, 77.83; H, 4.38; N, 7.88.

4-(Furan-2-yl)-2-phenyl-9H-pyrido[2,3-b]indole (4e)

Pale yellow solid; yield 85%; mp 174–175°C; IR (cm−1): 3172, 1591, 1543, 1481, 1456, 1389, 1348, 1294, 1209, 1022, 771, 741, 694; 1H NMR: δ 6.59 (d, J=7.9 Hz, 1H), 6.72 (d, J=1.0 Hz, 1H), 7.15–7.29 (m, 3H), 7.52–7.62 (m, 3H), 7.82 (s, 2H), 8.22 (d, J=7.0 Hz, 2H), 8.49 (d, J=7.9 Hz, 1H), 11.75 (s, 1H); 13C NMR: δ 110.9, 111.0, 111.1, 111.3, 112.2, 120.1, 120.5, 123.7, 126.8, 127.5, 129.0, 129.1, 133.8, 139.3, 139.4, 143.6, 146.3, 152.3, 153.7; MS: m/z 310 (M+). Anal. Calcd for C21H14N2O: C, 81.27; H, 4.55; N, 9.03. Found: C, 81.19; H, 4.60; N, 8.99.

6-Bromo-2-phenyl-4-(p-tolyl)-9H-pyrido[2,3-b]indole (4f)

Pale yellow solid; yield 88%; mp 226–228°C; IR (cm−1): 3239, 1587, 1564, 1510, 1447, 1352, 1292, 1209, 872, 820, 770, 692; 1H NMR: δ 2.55 (s, 3H), 6.51 (d, J =8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.53–7.59 (m, 4H), 7.65 (d, J=7.5 Hz, 2H), 7.84 (s, 1H), 8.19 (d, J=7.5 Hz, 2H), 11.84 (s, 1H); 13C NMR: δ 21.5, 112.0, 112.3, 112.8, 114.9, 122.3, 124.8, 127.9, 128.5, 129.0, 129.1, 129.2, 129.6, 135.7, 137.9, 139.1, 140.0, 146.9, 153.5, 155.0; MS: m/z 414 (M+ 81Br), 412 (M+ 79Br). Anal. Calcd for C24H17BrN2: C, 69.74; H, 4.15; N, 6.78. Found: C, 69.81; H, 4.18; N, 6.79.

6-Bromo-2-phenyl-4-(m-tolyl)-9H-pyrido[2,3-b]indole (4g)

Pale yellow solid; yield 82%; mp 216–217°C; IR (cm−1): 3220, 1582, 1560, 1481, 1446, 1381, 1352, 1292, 1211, 866, 800, 770, 696; 1H NMR: δ 2.53 (s, 3H), 6.30 (d, J=8.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.41 (d, J=6.5Hz, 1H), 7.49–7.60 (m, 8H), 7.80 (s, 1H), 8.21 (d, J=6.7 Hz, 2H), 12.37 (s, 1H); 13C NMR: δ 21.5, 111.9, 112.3, 112.7, 114.8, 122.4, 125.0, 125.6, 127.8, 128.8, 129.0, 129.1, 129.2, 129.3, 129.8, 137.8, 138.5, 138.7, 139.9, 146.9, 153.3, 155.1; MS: m/z 414 (M+ 81Br), 412 (M+ 79Br). Anal. Calcd for C24H17BrN2: C, 69.74; H, 4.15; N, 6.78. Found: C, 69.68; H, 4.19; N, 6.80.

6-Bromo-4-(4-chlorophenyl)-2-phenyl-9H-pyrido[2,3-b]indole (4h)

Pale yellow solid; yield 84%; mp 264–266°C; IR (cm−1): 3240, 1586, 1559, 1517, 1483, 1452, 1350, 1290, 1205, 870, 815, 768, 695; 1H NMR: δ 6.86 (d, J=8.5 Hz, 1H), 7.47 (dd, J=8.5, 7.4 Hz, 1H), 7.55–7.59 (m, 4H), 7.64 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.77 (s, 1H), 8.16 (d, J=7.1 Hz, 2H), 11.22 (s, 1H); 13C NMR: δ 112.6, 112.8, 114.7, 122.1, 124.7, 127.7, 129.1, 129.2, 129.3, 129.4, 129.9, 130.6, 135.2, 137.0, 137.8, 139.7, 145.3, 153.2, 155.3; MS: m/z 436 (M+ 81Br37Cl), 434 (M+ 79Br37Cl, M+ 81Br35Cl), 432 (M+ 79Br35Cl). Anal. Calcd for C23H14BrClN2: C, 63.69; H, 3.25; N, 6.46. Found: C, 63.58; H, 3.38; N, 6.38.

Acknowledgments

This study was supported by the research council of Tehran University of Medical Sciences (TUMS) and Iran National Science Foundation (INSF).

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Received: 2016-11-28
Accepted: 2017-5-9
Published Online: 2017-7-4
Published in Print: 2017-8-28

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