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Synlett 2004(11): 1965-1969  
DOI: 10.1055/s-2004-830861
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2-Substituted Indoles via Pd/C-Catalyzed Reaction in Water [1]

Manojit Pal*, Venkataraman Subramanian, Venkateswara Rao Batchu, Indu Dager
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India
Fax: +91(40)23045438; Fax: +91(40)23045007; e-Mail: manojitpal@drreddys.com ;
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Publication History

Received 7 March 2004
Publication Date:
06 August 2004 (online)

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Abstract

A general and one-pot synthesis of 2-alkyl/aryl substituted indoles via a tandem Pd/C mediated coupling/5-endo-dig cyclization of terminal alkynes (including acetylenic carbinols) with o-iodoanilides in water is reported. The reaction is carried out using PPh3 and CuI as co-catalysts and 2-aminoethanol as a base. The reaction appears to tolerate a variety of functional groups present in the alkynes and does not require the use of any organic co-solvent.

Key words

indoles - Sonogashira coupling/5-endo-dig cyclization - palladium catalyst - water

1

DRL publication No 427.

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    General Procedure for the Preparation of 2-Substituted Indoles(4): A mixture of 1e (1.60 mmol), 10% Pd/C (51 mg, 0.05 mmol), PPh3 (50 mg, 0.19 mmol), CuI (18 mg, 0.09 mmol) and 2-aminoethanol (4.83 mmol) in H2O (8 mL) was stirred at 25 °C for 1 h under nitrogen. The acetylenic compound 2 (4.00-5.00 mmol) was added slowly to the mixture with stirring. The reaction mixture was then stirred at 80 °C for the time indicated in Table [1] . The mixture was cooled to r.t., diluted with EtOAc (120 mL) and filtered through celite. The filtrate was collected, washed with cold H2O (2 × 75 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue thus obtained was purified by column chromatography (hexane-EtOAc) to afford the desired product.
    Spectral and analytical data for 4a: light brown solid; yield 70%; mp 128-130 °C (hexane). 1H NMR (200 MHz, CDCl3): δ = 7.98 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 2.5 Hz, 1 H), 7.43-7.38 (m, 5 H), 7.19 (d, J = 8.4 Hz, 1 H), 6.65 (s, 1 H), 2.69 (s, 3 H, SO2CH3), 2.46 (s, 3 H, CH3). MS (CI): m/z = 286 (100) [M + 1]. IR (neat): 1586.1, 1462.5, 1361.1 cm-1. 13C NMR (50 MHz, CDCl3): δ = 142.08, 136.24, 134.20, 131.99, 130.55, 129.96 (2 C), 128.68, 127.60 (2 C), 126.39, 120.88, 115.50, 112.98, 38.91 (SO2CH3), 21.18 (CH3). HPLC: 97.3% [Symmetry Shield RP18 (250 × 4.6 mm), 0.01 M KH2PO4:MeCN, 1 mL/min 225 nm, retention time 13.7 min]. Elemental analysis found C, 67.39; H, 5.35; N, 4.89; C16H15NO2S requires C, 67.34; H, 5.30; N. 4.91%.
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DRL publication No 427.