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Synlett 2009(9): 1480-1484  
DOI: 10.1055/s-0029-1216742
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

3-Aroylindoles via Copper-Catalyzed Cyclization of N-(2-Iodoaryl)enaminones

Roberta Berninia, Sandro Cacchi*b, Giancarlo Fabrizib, Eleonora Filistib, Alessio Sferrazzaa
a Dipartimento A.B.A.C., Università della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’, Via S. Camillo De Lellis, 01100 Viterbo, Italy
b Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Fax: +39(06)49912780; e-Mail: sandro.cacchi@uniroma1.it;
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Publication History

Received 20 January 2009
Publication Date:
04 May 2009 (online)

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Abstract

3-Aroylindoles have been prepared via copper-catalyzed cyclization of N-(2-iodoaryl)enaminones, readily available from 2-iodoanilines and α,β-ynones. The reaction tolerates a variety of useful functionalities including ether, keto, cyano, bromo, and chloro substituents. This indole synthesis can also be carried out from 2-iodoanilines and α,β-ynones through a sequential process that omits the isolation of enaminone intermediates.

Key words

indoles - enaminones - cyclization - copper - catalysis

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Typical Procedure for the Cyclization of N -(2-Iodoaryl)-enaminones 1 to 3-Acylindoles 2 To a stirred solution of 1d (118.2 mg, 0.25 mmol) in DMF (2.5 mL), CuI (2.4 mg, 0.0125 mmol), 1,10-phenanthroline (2.3 mg, 0.0125 mmol), and K2CO3 (69.0 mg, 0.50 mmol) were added at r.t. The reaction mixture was warmed at 100 ˚C and stirred for 10 h. After cooling, the reaction mixture was diluted with Et2O, washed with 1 N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 [n-hexane-EtOAc, 70:30] to afford 82.8 mg (96% yield) of 2d: white solid; mp 184-185 ˚C. IR (KBr): 3423, 2927, 1601, 1562, 1435, 1223 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 12.22 (br s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.60-7.57 (m, 2 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.27 (t, J = 7.9 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 2 H), 7.04-6.92 (m, 4 H), 6.85 (d, J = 7.6 Hz, 1 H), 3.67 (s, 1 H). ¹³C NMR (100.6 MHz, DMSO-d 6): δ = 191.2, 164.3 (d, J CF = 251 Hz), 159.3, 144.4, 137.1 (d, J CF = 22 Hz), 136.3, 133.2, 132.2 (d, J CF = 9 Hz), 129.7, 128.7, 123.5, 122.5, 122.0, 121.1, 115.4, 115.3, 115.1 (d, J CF = 4 Hz), 112.6, 112.4, 55.6. ¹9F NMR (376 MHz, DMSO-d 6): δ = -108.6. Anal. Calcd for C22H16FNO2: C, 76.51; H, 4.67. Found: C, 76.40; H, 4.58.

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Compounds 2a and 3 were isolated in 30% and 60% yield, respectively, when the reaction was carried out in DMA at 120 ˚C (3 h).

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Typical Procedure for the Preparation of 3-Acylindoles 2 Omitting the Isolation of Enaminone Intermediates To a stirred solution of 2-iodoaniline (109.5 mg, 0.5 mmol) in MeOH (1.0 mL), 1,3-diphenylprop-2-yn-1-one (154.5 mg, 0.75 mmol) was added at r.t. The reaction mixture was warmed at 120 ˚C and stirred for 48 h. After that period the volatile materials were evaporated at reduced pressure, and CuI (4.8 mg, 0.025 mmol), 1,10-phenanthroline (4.5 mg, 0.025 mmol), K2CO3 (138.0 mg, 1.0 mmol), and DMF (4 mL) were added. The reaction mixture was warmed at 100 ˚C and stirred for 2.5 h. After cooling, the reaction mixture was diluted with Et2O, washed with1 N HCl and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 [n-hexane-EtOAc, 75:25] to afford 106 mg (76% yield) of 2a: white solid; mp 223-224 ˚C. IR (KBr): 3055, 1593, 1564, 1450, 1421 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 12.19 (br s, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.54-7.51 (m, 3 H), 7.40-7.35 (m, 3 H), 7.26-7.10 (m, 7 H). ¹³C NMR (100.6 MHz, DMSO-d 6): δ = 192.6, 144.6, 140.3, 136.3, 132.1, 131.8, 130.1, 129.6, 129.0, 128.7, 128.5, 128.3, 123.4, 121.9, 121.1, 112.7, 112.4. Anal. Calcd for C21H15NO: C, 84.82; H, 5.08. Found: C, 84.71; H, 5.19.