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Synlett 2003(10): 1515-1517
DOI: 10.1055/s-2003-40868
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Indatraline Using a Suzuki Cross-Coupling Reaction and a
Chemoselective Hydrogenation: A Versatile Approach

Janine Cossy*, Damien Belotti, Aude Maguer
Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33(1)40794660; e-Mail: janine.cossy@espci.fr;
Further Information

Publication History

Received 16 April 2003
Publication Date:
24 July 2003 (online)

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Abstract

Indatraline and its derivatives can be obtained in five steps from indanone by using a Suzuki cross-coupling reaction and a chemoselective hydrogenation catalyzed by Wilkinson’s catalyst.

Key words

indatraline - indanone - Suzuki reaction - hydrogenation - Wilkinson’s catalyst

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16

The reaction was performed on 5-10g of indanone.

18

Typical Experiment for the Suzuki Reaction: A solution of the β-bromoindenone 3 (4.18 g, 20 mmol) and 3,4-dichlorophenyl-boronic acid (4.2 g, 22 mmol) in THF (100 mL) containing absolute EtOH (20 mL) and H2O (20 mL) was degased with argon for 20 min. Na2CO3 (6.36 g, 60 mmol) and Pd(PPh3)4 (1.16 g, 1 mmol) were added to this solution. The resulting mixture was vigourously stirred at r.t. for 1.5 d under an argon atmosphere and then diluted with CH2Cl2 (250 mL). The reaction mixture was washed with H2O (2 × 100 mL) and the aqueous layer extracted with CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (60/40 petroleum ether/CH2Cl2) to give the β-arylindenone 4 as a yellow solid (4.95 g, 90% yield): Mp 148-150 °C. IR: 1700 cm-1. 1H NMR (CDCl3): δ = 7.74 (d, J = 2.0 Hz, 1 H), 7.63-7.25 (6 H), 6.01 (s, 1 H). 13C NMR (CDCl3): δ = 121.2 (CH), 123.1 (CH), 123.9 (CH), 126.6 (CH), 129.1 (CH), 129.6 (CH), 131.1 (CH), 131.9 (C), 132.9 (C), 133.1 (CH), 133.4 (C), 134.6 (C), 143.3 (C), 160.1 (C), 196.3 (C). MS (EI): m/z
(rel. int.) = 274 (86) [M+], 239 (100), 211 (28), 176 (73).

21

Typical Experiment for the Wilkinson Hydrogenation: (PPh3)3RhCl (0.122 g, 0.132 mmol) was added to a solution of β-arylindenone 4 (0.91 g, 3.3 mmol) in THF/t-BuOH
(1/1, 24 mL) under an argon atmosphere. The resulting solution was saturated with hydrogen and stirred under one atmosphere of hydrogen overnight at r.t. The reaction mixture was filtered through a short pad of alumina and washed thoroughly with EtOAc. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (90/10 petroleum ether/EtOAc) to provide β-arylindenone 5 as a colorless solid (0.74 g, 81% yield): Mp 113-115 °C. IR: 1710 cm-1. 1H NMR (CDCl3): δ = 7.82 (d, J = 7.7 Hz, 1 H), 7.61 (td, J = 7.5, 1.2 Hz, 1 H), 7.45 (t, J = 7.4 Hz, 1 H), 7.38 (d, J = 8.3 Hz, 1 H), 7.30-7.20 (2 H), 6.96 (dd, J = 8.3, 2.1 Hz, 1 H), 4.55 (dd, J = 8.1, 3.8 Hz, 1 H), 3.23 (dd, J = 19.2, 8.1 Hz, 1 H), 2.62 (dd, J = 19.2, 3.8 Hz, 1 H). 13C NMR (CDCl3): δ = 204.8 (C), 156.4 (C), 143.9 (C), 136.7 (C), 135.3 (CH), 132.9 (C), 131.1 (C), 130.9 (CH), 129.6 (CH), 128.3 (CH), 126.9 (CH), 126.6 (CH), 123.6 (CH), 46.4 (CH2), 43.5 (CH). MS (EI): m/z (rel. int.) = 276 (100) [M+], 241 (77), 212 (25), 178 (60).

22

Separated by flash chromatography on silica gel (70/30 petroleum ether/EtOAc).

23

Compound 8a: Mp 116-118 °C. IR 1710 cm-1. 1H NMR (CDCl3): δ = 7.81 (d, J = 7.6 Hz, 1 H), 7.59 (td, J = 7.5, 1.1 Hz, 1 H), 7.43 (t, J = 7.4 Hz, 1 H), 7.25 (dd, J = 7.6, 0.8 Hz, 1 H), 7.14-6.93 (4 H), 4.57 (dd, J = 8.0, 3.8 Hz, 1 H), 3.23 (dd, J = 19.3, 8.1 Hz, 1 H), 2.64 (dd, J = 19.3, 3.9 Hz, 1 H). 13C NMR (CDCl3): δ = 205.5 (C), 161.8 (d, J = 245 Hz, CF), 157.6 (C), 139.4 (C), 136.7 (C), 135.1 (CH), 129.1 (CH), 129.0 (CH), 128.0 (CH), 126.7 (CH), 123.4 (CH), 115.9 (CH), 115.6 (CH), 46.9 (CH2), 43.7 (CH). MS (EI): m/z (rel. int.) = 226 (100) [M+], 197 (30), 183 (28).

24

Compound 8b: Mp 108-110 °C. IR: 2230, 1710 cm-1. 1H NMR (CDCl3): δ = 7.83 (d, J = 7.7 Hz, 1 H), 7.67-7.56 (3 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.30-7.20 (3 H), 4.67 (dd, J = 8.1, 3.8 Hz, 1 H), 3.27 (dd, J = 19.2, 8.2 Hz, 1 H), 2.64 (dd, J = 19.2, 3.8 Hz, 1 H). 13C NMR (CDCl3): δ = 204.5 (C), 156.2 (C), 149.1 (C), 136.7 (C), 135.3 (CH), 132.7 (2 CH), 128.4 (3 CH), 126.6 (CH), 123.7 (CH), 118.5 (C), 111.0 (C), 46.2 (CH2), 44.3 (CH). MS (EI) m/z (rel. int.) = 233 (100) [M+], 204 (30), 190 (22).