Figure 10: Synthesis of tetrahydroquinolones.

Synthesis of 2-methyl-5,6,7,8-tetrahydroquinolin-4-one (6) Platinum oxide (100 mg, 10 mol%) was added to a solution of 4-hydroxy-2-methylquinoline (5, 1.00 g, 6.28 mmol, 1.00 eq) in glacial acetic acid (10.0 ml). The heterogeneous mixture was catalytically hydrogenated under a balloon of hydrogen. After 22 hrs, TLC (10% MeOH–DCM) confirmed complete reaction. The mixture was filtered through celite under vacuum, washing thoroughly with EtOAc. The filtrate was concentrated and the resulting residue purified by column chromatography (10% MeOH–DCM) to give the desired product as a pale yellow oil (917 mg, 5.65 mmol, 89%); R_f 0.14 (10% MeOH–DCM); δ_H (300 MHz, CDCl₃) 1.74–1.76 (4H, m, CH₂), 2.29 (3H, s, Me), 2.49–2.52 (2H, m, CH₂), 2.67–2.70 (2H, m, CH₂), 6.16 (1H, s, Ar-H); δ_C (125 MHz, CDCl₃) 19.0 (Me), 21.8 (CH₂), 22.1 (CH₂), 27.1 (CH₂), 112.5 (CH), 122.4 (_Cq), 146.4 (Cq), 147.0 (Cq), 178.3 (Cq); Spectroscopic data consistent with literature values (JMC, 1993, 36, 1245–54). Synthesis of 2-methyl-3-iodo-5,6,7,8-tetrahydroquinolin-4-one (7) Butylamine (6.20 ml, 62.8 mmol, 10.0 eq) was added to a suspension of 2-methyl-5,6,7,8-tetrahydroquinolin-4-one (6, 1.02 g, 6.28 mmol, 1.00 eq) in DMF (10.0 ml). To this heterogeneous mixture was added I₂ (1.60 g, 6.28 mmol, 1.00 eq) in a saturated solution of KI (6.00 ml). After 20 hrs stirring at R.T., a precipitate formed in the orange solution, Excess iodine was quenched with 0.1 M sodium thiosulfate solution. The precipitate was filtered by vacuum filtration, washed with distilled H₂O and dried (Na₂SO₄) to give the desired product as a colourless solid (1.76 g, 6.09 mmol, quantative yield); δ_H (300 MHz, DMSO- d₆) 1.61–1.70 (4H, m, CH₂), 2.29 (2H, t, J 6.0, CH₂), 2.43 (2H, s, C_H2), CH₃ under DMSO peak. Synthesis of 2-methyl-3-iodo-4-ethoxy-5,6,7,8-tetrahydroquinoline (8) Potassium carbonate (1.53 g, 11.1 mmol, 2.00 eq) was added to a heterogeneous mixture of 2-methyl-3-iodo-5,6,7,8-tetrahydroquinolin-4-one (7, 1.60 g, 5.56 mmol, 1.00 eq) in DMF (15.0 ml), and the reaction heated to 50 °C for 30 mins. The R.B. flask was removed from the heating mantle and ethyl iodide was added dropwise. The reaction was then heated at 50 °C for 18 hrs. The reaction was cooled to R.T., quenched with water (40 ml). The resulting emulsion formed which was extracted with EtOAc (50 ml). EtOAc layer were washed with water (3 × 30 ml), brine (3 × 30 ml), dried (Na₂SO₄) and concentrated to give a pale yellow oil (1.09 g, 3.44 mmol, 61%); R_f 0.88 (1:1 Pet–EtOAc); HPLC (RT = 1.67 mins); LCMS (Method A), (RT = 1.6 min, m/z (ES) Found MH⁺ 318.0); δ_H (500 MHz, CDCl₃) 1.49 (3H, t, J 7.0, ethoxy CH₃), 1.73–1.78 (2H, m, CH₂) 1.84–1.88 (2_H, m, CH₂), 2.78–2.69 (5H, m, CH₂ & CH₃), 2.84 (2H, t, J 6.5, CH₂), 3.97 (2H, q, J 7.0, OCH₂); δ_C (125 MHz, CDCl₃) 15.6 (CH₃), 22.3 (CH₂), 22.8 (CH₂), ₂3.6 (CH₂), 29.3 (CH₃), 3₂.0 (_CH₂), 68.4 (OCH₂), 90.9 (Cq), 124.5 (Cq), 158.3 (Cq), 158.9 (Cq), 163.9 (Cq). Synthesis of 2-methyl-3-(4-phenoxyphenyl)-4-ethoxy-5,6,7,8-tetrahydroquinoline (10) 2-Methyl-3-iodo-4-ethoxy-5,6,7,8-tetrahydroquinoline (8, 0.266 g, 0.839 mmol, 1.00 eq), Pd(PPh₃)₄ (0.048 mg, 0.0419 mmol, 5 mol%) and 4-phenoxyphenylboronic acid (9, 0.270 mg, 1.26 mmol, 1.50 eq) were charged to a R.B. flask under N₂(g)⁴⁹. Degassed DMF (10.0 ml) was added to the flask followed by 2M K₂CO₃ (1.60 ml). The flask was heated to 85 °C under N₂(g). After 15 mins, TLC (4:1 Pet–EtOAc) confirmed reaction was complete. The reaction was cooled and diluted with EtOAc (15 ml), filtered through celite and partitioned between EtOAc (10 ml) and H₂O (25 ml). Combined organics were washed with H₂O (3 × 30 ml), then brine (3 × 30 ml), dried (Na₂SO₄) and concentrated to give a red oil which was purified by column chromatography (3:1 Pet–EtOAc), to give the desired product as a pale yellow oil (0.235 mg, 0.655 mmol, 78%); R_f 0.31 (3:1 Pet–EtOAc); HPLC (RT = 3.08 mins); δ_H (300 MHz, CDCl₃) 1.04 (3H, t, J 7.0, ethoxy CH₃), 1.76–1.93 (4H, m, 2xCH₂), 2.32 (3_H, s, CH₃) 2.72 (2H, t, J 6.0, CH₂), 2.91 (2H, t, J 6.5, CH₂), 3.50 (2H, q, J 7.0, OCH₂), 7.05–7.16 (5H, m, Ar-H), 7.20–7.29 (2H, m, Ar-H), 7.31–7.43 (2H, m, Ar-H); δ_C (125 MHz, CDCl₃) 15.7 (CH₃), 22.5 (CH₂), 23.0 (CH₃), 23.3 (CH₂), 23.4 (CH₂), 32.7 (_CH₂), 68.2 (OCH₂), 118.6 (CH), 118.9 (CH), 123.4 (CH), 126.8 (Cq), 129.8 (CH), 131.5 (CH), 154.9 (Cq), 156.5 (Cq), 157.1 (Cq), 157.3 (Cq); m/z ( ES ) (Found: MH⁺, 360.1973. C₂₄H₂₆NO₂ requires MH, 360.1964). Synthesis of 2-methyl-3-(4-phenoxyphenyl)-4-ethoxy-5,6,7,8-tetrahydroquinoline (MJM170, 4)⁴⁹ Aqueous hydrobromic acid (>48%) (1.00 ml) was added to a solution of 2-methyl-3-(4-phenoxyphenyl)-4-ethoxy-5,6,7,8-tetrahydroquinoline (10, 0.226 mg, 0.630 mmol, 1.00 eq) in glacial acetic acid (2 ml). The reaction was stirred at 90 °C for 5 days, monitoring by LMCS. The reaction was cooled to R.T. and the pH adjusted to pH5 with 2M NaOH. The precipitate was collected by vacuum filtration and recrystallized from MeOH:H₂O to give the desired product as an off-white solid (0.155 g, 0.467 mmol, 74%); HPLC (RT = 2.56 mins); δ_H (500 MHz, DMSO- d₆) 1.66–1.72 (4H, m, 2xCH₂), 2.08 (3H, s, CH₃) 2.31 (2H, t, J 6.0, CH₂), 2.56 (2_H, t, J 6.0, CH₂), 6.99 (2H, d, J 8.5, Ar-H), 7.06 (2H, d, J 7.5, Ar-H), 7.14–7.18 (3H, m, Ar-H), 7.40–7.43 (2H, m, Ar-H), 11.0 (1H, s, NH); δ_C (125 MHz, DMSO- d₆) 17.7 (CH₃), 21.5 (CH₂), 21.8 (CH₂), 21.9 (CH₂), 26.2 (CH₂), 117.8 (CH), 118.6 (CH), 121.2 (Cq), 123.3 (CH), 123.7 (Cq), 130.0 (CH), 131.4 (Cq), 132.3 (CH), 142.3 (Cq), 143.2 (Cq), 155.0 (Cq), 156.8 (Cq), 175.4 (Cq); m/z ( ES ) (Found: MH⁺, 332.1654. C₂₂H₂₂NO₂ requires MH, 332.1645).