Enantioselective Synthesis of 1- and 4-Hydroxytetrahydrocarbazoles through Asymmetric Transfer Hydrogenation

Abstract

Several 1- and 4-hydroxytetrahydrocarbazoles were prepared in high yields (up to 99%) and excellent enantiomeric excesses (up to >99% ee) from the corresponding 1- and 4-oxotetrahydrocarbazoles through asymmetric transfer hydrogenation by using the commercially available Noyori–Ikariya ruthenium catalyst. The immediate use of the freshly prepared catalyst and the use of a HCO₂H–DABCO (11:6) mixture as the hydrogen source are crucial for achieving high activity and enantioselectivity. In this way, a tetrahydrocarbazole heterocycle fused to a lactone moiety was synthesized in 45% yield and 97% ee.

Key words

asymmetric synthesis - transfer hydrogenation - tetrahydrocarbazolones - hydroxytetrahydrocarbazoles - hexahydrofurocarbazolone - ruthenium catalysis

• References and Notes

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• 29 (1S)-6-(Trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazol-1-ol (3d); Typical ProcedureAn oven-dried 25 mL Schlenk tube A equipped with a magnetic stirrer bar was charged with catalyst 2 (12.7 mg, 20 μmol, 2 mol). The tube was capped with a glass stopper, evacuated for 15 min, and back-filled with N₂. The glass stopper was then replaced with a rubber septum under a positive pressure of dry N₂, and HCO₂H/TEA (5:2) azeotropic mixture (1.1 mL) was added to the tube. In a separate oven-dried 10 mL Schlenk tube B, 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazol-1-one (1d; 269 mg, 1.0 mmol) was dissolved in anhyd THF (5 mL) under N₂, and the solution was transferred into Schlenk tube A by means of a cannula. The resulting mixture was stirred at 40 °C for 24 h under N₂. THF was removed by rotary evaporation under reduced pressure, and the residue was treated with H₂O (20 mL) and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic phases were dried (Na₂SO₄), filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by flash column chromatography (silica gel) gave a pale-pink oil; yield: 271 mg (quant; 98% ee).TLC: R_f = 0.5 (silica gel; hexanes–EtOAc, 3:2). [α]_D ²³ +16 (c = 0.5, MeOH). HPLC: Chiralcel OD-H; hexane–i-PrOH (90:10), 1.0 mL/min; λ = 254 nm (UV/vis); t _R = 8.8 min (3d), 10.8 min (ent-3d). FTIR (KBr): = 3415 (s), 2934 (m), 1870 (w), 1453 (m), 1213 (s), 1057 (m), 914 (m), 820 (m), 685 (m) cm⁻¹. ¹H NMR (600 MHz, DMSO): δ = 11.06 (s, 1 H), 7.36 (d, J = 8.7 Hz, 1 H), 7.32 (s, 1 H), 6.99 (dd, J = 8.7, 0.9 Hz, 1 H), 5.21 (d, J = 6.6 Hz, 1 H), 4.85–4.65 (m, 1 H), 2.66–2.58 (m, 1 H), 2.58–2.51 (m, 1 H), 2.04–1.92 (m, 2 H), 1.79–1.68 (m, 2 H). ¹³C NMR (APT, 150 MHz, DMSO): δ = [141.32, 141.31 (C, ³J_C–F = 1.6 Hz)], 139.6 (C), 134.5 (C), 126.6 (C), [123.07, 121.38, 119.70, 118.02 (CF₃, ¹J_C–F = 253.9 Hz)], 114.2 (CH), 112.0 (CH), 110.3 (CH), 110.1 (C), 62.5 (CH), 33.3 (CH₂), 20.6 (CH₂), 20.1 (CH₂). ¹⁹F NMR (564 MHz, DMSO): δ = –56.9. HRMS (ESI): m/z [M − H₂O + H]⁺ calcd for C₁₃H₁₁F₃NO: 254.0787; found: 254.0781.