Synthesis of 3-Chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and Its Derivatives

Abstract

Synthesis of novel 3-chloro-4-fluoro-7,8-dihydro-6H-isoquinolin-5-one and its derivatives using sequential ortho-formylation/ortho-allylation reactions of 2-chloro-3-fluoropyridine and ring-closing metathesis is described.

ortho-lithiation - ring-closing metathesis - fluoro pyridine - isoquinolinone - fused-ring system

References and Notes

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17

Preparation of compound 15: t-BuLi (1.7 m in heptane, 14.1 mL, 24 mmol) was added within 15 min to a solution of 2-chloro-3-fluoropyridine (3 g, 22.8 mmol) in anhydrous THF (70 mL) at -78 ˚C. After stirring for 1 h at -78 ˚C, N-formyl-l-N,N′,N′-trimethylethylene-1,2-diamine (3.21 g, 24 mmol) was added slowly and the reaction mixture was left to warm to -40 ˚C, followed by addition of n-BuLi (1.6 m in hexane, 21.4 mL, 34.2 mmol). The red-brown solution was stirred for 3 h at -30 ˚C before CuBr (4.25 g, 29.6 mmol) was added. The reaction mixture was then allowed to reach 0 ˚C and was stirred at this temperature for 1 h. After cooling back to -30 ˚C, a solution of allylbromide (3.1 mL, 36.5 mmol) in anhydrous THF (50 mL) was added. After stirring for 1 h at -10 ˚C, the mixture was quenched by addition of sat. aq NH₄Cl, filtered over Hyflo® and rinsed with diethyl ether. The organic layer was then washed with sat. aq NH₄Cl and brine. After drying over Na₂SO₄ and filtration, the mixture was concentrated under vacuum. The crude mixture was further purified by gradient MPLC (ethyl acetate-cyclohexane, 5→15%), followed by a second MPLC (diethyl ether-cyclohexane, 10→15%) to provide the product 15 (1.85 g, 41%) as a yellow oil. Spectral data for compound 15: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 10.31 (s, 1 H), 8.32 (s, 1 H), 5.97 (m, 1 H), 5.07 (dd, J = 10.2, 1.5 Hz, 1 H), 5.00 (dd, J = 17.2, 1.6 Hz, 1 H), 3.72 (d, J = 6.3 Hz, 2 H); ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 187.6, 153.0 (d, J _C,F = 268 Hz), 146.3 (d, J _C,F = 7 Hz), 136.4 (d, J _C,F = 20 Hz), 135.2, 128.8 (d, J _C,F = 6 Hz), 116.6, 32.2; ESI-HRMS: m/z [M + H]⁺ calcd for C₉H₈ClFNO: 200.0278; found: 200.0274.

18

Grubbs’ catalysts I and II and Grignard reagents were purchased from Aldrich Co. and used as obtained

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20

Characterization of final compounds. 5a: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.40 (s, 1 H), 2.97 (t, J = 6.1 Hz, 2 H), 2.66 (t, J = 6.3 Hz, 2 H), 2.06 (m, 2 H); ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 193.6, 150.5 (d, J _C,F = 273 Hz), 145.1 (d, J _C,F = 8 Hz), 139.5, 135.8 (d, J _C,F = 20 Hz), 126.9, 39.3, 25.0, 21.5; ESI-HRMS: m/z [M + H]⁺ calcd for C₉H₈ClFNO: 200.0278; found: 200.0274; 5b: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.38 (s, 1 H), 3.03 (m, 2 H), 2.77 (m, 1 H), 2.14 (m, 1 H), 1.84 (m, 2 H), 1.12 (d, J = 6.6 Hz, 3 H); ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 197.1, 151.2 (d, J _C,F = 274 Hz), 145.9 (d, J _C,F = 8 Hz), 140.0, 136.4 (d, J _C,F = 20 Hz), 127.5, 42.9, 29.8, 24.7, 14.8; ESI-HRMS: m/z [M + H]⁺ calcd for C₁₀H₉ClFNO: 214.0430; found: 214.0431; 5c: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.26 (s, 1 H), 2.86 (m, 2 H), 2.75 (m, 2 H), 1.79 (m, 4 H); ^¹³C NMR (125 MHz, DMSO-d ₆): δ = 201.6, 149.4 (d, J _C,F = 264 Hz), 145.1, 136.3 (d, J _C,F = 20 Hz), 135.9 (d, J _C,F = 11 Hz), 135.1, 41.5, 28.3, 24.7, 22.3; ESI-HRMS: m/z [M + H]⁺ calcd for C₁₀H₁₀ClFNO: 214.0430; found: 214.0430; 5d: ^¹H NMR (500 MHz, DMSO-d ₆): δ = 8.26 (s, 1 H), 2.91 (m, 1 H), 2.83 (m, 1 H), 2.71 (m, 1 H), 2.65 (m, 1 H), 2.02 (m, 1 H), 1.90 (m, 1 H), 1.48 (m, 1 H), 0.98 (d, J = 6.7 Hz, 3 H); ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 198.9, 148.5 (d, J _C,F = 263 Hz), 144.5 (d, J _C,F = 6 Hz), 135.6, 135.5, 135.1, 49.2, 33.1, 30.1, 27.5, 21.3; ESI-HRMS: m/z [M + H]⁺ calcd for C₁₁H₁₂ClFNO: 228.0586; found: 228.0586