Radical 6-endo-trig Cyclization of β,β-Difluoro-o-isocyanostyrenes: A Facile Synthesis of 3-Fluoroquinolines and Their Application to the ­Synthesis of 11-Alkylated Cryptolepines

Abstract

o-Isocyano-substituted β,β-difluorostyrenes undergo tin-mediated radical cyclization in a 6-endo-trig fashion, followed by: (i) transformation of the C-Sn bond, and (ii) dehydrofluorination or reduction, leading to 2,4-disubstituted 3-fluoroquinolines or 3,3-difluorotetrahydroquinolines. This sequence was successfully applied to the synthesis of 11-alkylated cryptolepines.

alkenes - radical reactions - fluorine - quinolines - fused-ring systems

References and Notes

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11

4-Butyl-3-fluoro-2-phenylquinoline ( 7c)
To a solution of 1a (113 mg, 0.51 mmol) in toluene (4 mL) was added n-Bu₃SnH (0.15 mL, 0.56 mmol) and a catalytic amount of AIBN under Ar. The reaction mixture was heated at 80 °C for 1 h and removal of the solvent under reduced pressure. To a solution of the residue in DMF (3 mL) were added PhI (102 mg, 0.50 mmol), Pd(PPh₃)₄ (48 mg, 0.042 mmol), and CuI (40 mg, 0.21 mmol) at r.t. After the reaction mixture was stirred for 2 h at 80 °C, DBU (0.070 mL, 0.46 mmol) was added, and the reaction mixture was heated at 80 °C for 1 h. The reaction was quenched with phosphate buffer (pH 7), and the mixture was filtered through Celite^®. Organic materials were extracted with Et₂O three times. The combined extracts were washed with aq KF, brine, and dried over MgSO₄. After removal of the solvent under reduced pressure, the residue was purified by preparative TLC on silica gel (hexane-EtOAc, 10:1) to give 7c (100 mg, 70%) as a pale yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 0.98 (3 H, t, J = 7.6 Hz), 1.49 (2 H, tq, J = 7.6, 7.6 Hz), 1.67-1.76 (2 H, m), 3.14 (2 H, td J = 7.6 Hz, J _HF = 1.9 Hz), 7.49-7.57 (4 H, m), 7.63-7.67 (1 H, m), 7.96 (1 H, d, J = 8.2 Hz), 8.02-8.06 (2 H, m), 8.16 (1 H, d, J = 8.2 Hz). ¹³C NMR (126 MHz, CDCl₃): δ = 13.8, 22.8, 24.7 (d, J _CF = 4 Hz), 31.9, 123.3 (d, J _CF = 5 Hz), 126.8, 127.8 (d, J _CF = 3 Hz), 128.1, 128.4, 129.3, 129.4, 130.8, 132.6 (d, J _CF = 15 Hz), 136.2 (d, J _CF = 5 Hz), 145.2 (d, J _CF = 3 Hz), 148.6 (d, J _CF = 17 Hz), 152.9 (d, J _CF = 256 Hz). ¹⁹F NMR (471 MHz, CDCl₃/C₆F₆): δ = 32.4 (s). IR (neat): 2958, 2929, 2871, 1603, 1458, 1406, 1381, 1362, 1192, 760 cm^-1. HRMS-FAB: m/z calcd for C₁₉H₁₉FN: 280.1502 [M + 1]⁺; found: 280.1495.

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