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

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

References

• 1 Topp L. Hando J. Dillon P. Roche A. Solowij N. Drug Alcohol Dependence  1999,  55:  105 
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• 13 Davies HML. Gregg TM. Tetrahedron Lett.  2002,  43:  4951 
• 14 3-Arylindan-1-ones have been synthesized from 3-bromo-indenone and pinacol boronate esters, which have to be prepared from the corresponding boronic acids: Clark WM. Kassick AJ. Plotkin MA. Eldridge AM. Lantos I. Org. Lett.  1999,  1:  1839 
• 15 Heffner RJ. Joullié M. Synth. Commun.  1991,  21:  2231 
• 17 Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
• 19 Rylander PN. Catalytic Hydrogenation in Organic Syntheses   Academic Press; New York: 1979.  p.114 
• 20 Jourdant A. Gonzalez-Zamora E. Zhu J. J. Org. Chem.  2002,  67:  3163 

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).