Titanium-Catalyzed Hydroamination of Propargyl Alcohol Derivatives: Synthesis of 3-Silyloxy-2-methylindoles via Hydrohydrazination

Abstract

A general method for the one-pot synthesis of substituted 3-(tert-butyldimethylsilyloxy)indoles via hydrohydrazination of alkynes and subsequent Fischer indole synthesis has been developed. For the first time titanium-catalyzed hydroaminations of ­propargyl alcohol derivatives are shown.

Key words

alkyne - hydrazine - hydroamination - indole - titanium

References and Notes

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14

For a recent review on Markovnikov and anti-Markovnikov functionalization of olefins and alkynes, see ref. 1b.

22

Representative Procedure: Synthesis of 1-Benzyl-3-( tert -butyldimethylsilyloxy)-2-methyl-1 H -indole (4b)
In an ACE pressure tube under an argon atmosphere the ligand 2,6-di-tert-butyl-4-methylphenol (22.0 mg, 0.1 mmol) is dissolved in 3 mL dry toluene. To this solution N-benzyl-N-phenylhydrazine (257.7 mg, 1.3 mmol), tert-butyldimethylsiloxy-2-propyne (209.0 mL, 1.0 mmol) and Ti(NEt₂)₄ (18 µL, 0.05 mmol) were added. The reaction mixture was heated at 100 °C for 24 h. Then the pressure tube was opened under argon to add ZnCl₂ (410.0 mg, 3.0 mmol). The reaction mixture was heated at 100 °C for further 24 h. After cooling to r.t. the solution was decanted and the dark residue was washed with toluene and EtOAc. After removal of the combined solvents in vacuo and purification by column chromatography (eluent: hexane-EtOAc = 10:1) yielded 1-benzyl-3-(tert-butyldimethyl-silyloxy)-2-methyl-1H-indole (175.8 mg, 50%) as light yellow solid (mp 69 °C). ¹H NMR (300 MHz, CDCl₃): δ = 7.45-7.40 (m, 1 H), 7.27-7.21 (m, 3 H, m-, p-Ph), 7.10 (m, 1 H), 6.93 (m, 2 H), 6.86-6.87 (m, 2 H, o-Ph), 5.22 (s, 2 H, CH₂Ph), 2.20 (s, 3 H), 0.83 (s, 12 H), 0.15 (s, 6 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 136.4 (i-Ph), 135.6, 133.6, 128.9 (m-Ph), 128.4, 127.8 (p-Ph), 125.8 (o-Ph), 121.7, 120.6, 120.8, 120.7, 108.7, 46.9, 25.8, 18.2, 9.1, -5.3 ppm. MS (EI, 70 eV): m/z (relative intensity) = 351 (100) [M⁺], 294 (27), 260 (13), 221 (25), 204 (12), 177 (8), 115 (15), 91 (90), 73 (71), 65 (8), 43 (6). HRMS (EI): m/z calcd for C₂₂H₂₉NOSi: 351.2013; found: 351.1999.