A De Novo Synthetic Route to 1,2,3,4-Tetrahydroisoquinoline Derivatives

Abstract

A novel synthetic approach was developed for the construction of the 1,2,3,4-tetrahydroisoquinoline framework possessing varied functions. The synthetic strategy was based on oxidative ring opening of some indene derivatives through their C=C bond, followed by double reductive amination of the dicarbonyl intermediates with various primary alkyl- or fluoroalkylamines.

Key words

tetrahydroisoquinolines - ring opening - ring closure - reduction - amination - fluorination

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• 8 1,2,3,4-Tetrahydroquinolines 3–9, 12, and 13: General ProcedureNaIO₄ (1.5 equiv) was added to a stirred solution of the dihydroxy compound 2 or 11 (4 mmol) in THF–H₂O (25 mL + 2 mL), and the mixture was stirred for 1 h at 20 °C under argon. H₂O (40 mL) was added to dissolve the precipitate, and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The extracts were then combined and dried (Na₂SO₄). The crude diformyl product was immediately used in the reductive cyclization without purification. The appropriate fluorinated amine (1 equiv) and NaHCO₃ (2 equiv) were added to the solution of the diformyl intermediate in EtOH (20 mL), and the mixture was stirred at 20 °C for 10 min. NaCNBH₃ (1 equiv) and AcOH (2 drops) were added, and the mixture was stirred for a further 4 h at 20 °C. The mixture was then diluted with H₂O (20 mL) and extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, hexane–EtOAc).2-(2,2-Difluoroethyl)-1,2,3,4-tetrahydroisoquinoline(3)Brown oil; yield: 247.3 mg (31%); R_f  = 0.17 (hexane–EtOAc, 20:1). ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.77–2.84 (m, 4 H, H-3, H-4) 2.83–2.95 (td, ¹ J = 15.6, ² J = 4.3 Hz, 2 H, CH₂CHF₂), 3.71 (s, 2 H, H-1), 6.02 –6.39 (tt, ¹J = 55.8, ² J = 4.3 Hz, 1 H, CHF₂), 6.98–7.18 (m, 4 H, Ar-H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 29.2, 51.8, 56.6, 59.5 and 59.8 and 60.02 (t, ² J _C,F= 28 Hz, CCHF₂), 114.5 and 116.9 and 119.3 (t, ¹ J _C,F= 237.5 Hz, CHF₂), 126.4, 126.9, 127.1, 129.3, 134.6, 135.3. ¹⁹F NMR (376 MHz, DMSO): δ = –115.2. MS: (ESI) m/z = 198.2 [M + 1]; Anal. Calcd for C ₁₁H₁₃F₂N: C, 66.99; H, 6.64; F, 19.27; N, 7.10. Found: C, 66.96; H, 6.63; F, 19.26; N, 7.10. For details of the other synthesized compounds, see the Supporting Information.
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