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Synlett 2011(8): 1125-1128  
DOI: 10.1055/s-0030-1259932
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Catalytic Enantioselective Friedel-Crafts Alkylation of Indoles with β,γ-Unsaturated α-Keto Phosphonates in the Presence of Chiral Palladium Complexes

Young Ku Kang, Ki Hyung Suh, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax: +82(41)5301247; e-Mail: dyoung@sch.ac.kr;
Further Information

Publication History

Received 18 February 2011
Publication Date:
30 March 2011 (online)

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Abstract

The catalytic enantioselective Friedel-Crafts alkylation reaction promoted by chiral palladium complexes is described. The treatment of indoles with β,γ-unsaturated α-keto phosphonates under the mild reaction conditions afforded the corresponding Friedel-Crafts alkylation adducts with excellent enantioselectivities (up to 99% ee).

Key words

Friedel-Crafts reaction - asymmetric catalysis - chiral palladium catalysts - indoles - β,γ-unsaturated α-keto phosphonates

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Typical Procedure
To a stirred solution of (E)-diethyl 1-oxobut-2-enylphos-phonate (2a, 20.6 mg, 0.1 mmol), Pd catalyst 1c (5.4 mg, 0.005 mmol) in CH2Cl2 (1 mL) was added indole (3a, 14.0 mg, 0.12 mmol) at r.t. The reaction mixture was stirred for 2 h at r.t. Then MeOH (0.15 mL), followed by DBU (0.03 mL), was added directly to the reaction mixture. The reaction was allowed to stir for 2 h at r.t. The reaction was diluted with EtOAc (10 mL), then washed with sat. NH4Cl. The organic layer was dried over anhyd MgSO4, filtered, concentrated, and purified by flash column chromatography (EtOAc-hexane, 1:5) to afford (S)-methyl 3-(1H-indol-3-yl)butanoate (4a, 70%, 15.2 mg). [α]D ²8 7.3 (c 0.7, CHCl3, 93% ee). ¹H NMR (200 MHz, CDCl3): δ = 7.99 (br s, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.23-7.05 (m, 2 H), 6.90 (d, J = 2.5 Hz, 1 H), 3.65-3.47 (m, 1 H), 3.62 (s, 3 H), 2.82 (dd, J = 14.8, 6.0 Hz, 1 H), 2.56 (dd, J = 14.7, 8.7 Hz, 1 H), 1.39 (d, J = 6.9 Hz, 3 H). ¹³C NMR (50 MHz, CDCl3): δ = 173.0, 136.1, 125.9, 121.5, 120.2, 119.7, 118.8, 118.7, 110.9, 51.1, 41.9, 27.6, 20.6. ESI-MS: m/z = 217.9 [M + H]+, 117.0, 120.9, 123.0 147.0, 176.9. HPLC (hexane-i-PrOH = 90:10, 220 nm, 0.8 mL/min) Chiralcel OD-H column, t R = 9.0 min(minor), t R = 13.8 (major).

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The two-site-binding interaction between substrate and palladium catalyst is crucial to guarantee reactivity as well as stereocontrol. In fact, when the monodentate ethyl (E)-but-2-enoate was reacted with indole under the same reaction conditions, no reaction occurred.