To a solution of cortistatinone (22) (200 mg, 0.56 mmol) in absolute EtOH (9.3 mL, 0.06 M) were added hydrazine monohydrate (0.28 mL, 5.6 mmol, 10 equiv) and Et3N (0.78 mL, 5.6 mmol, 10 equiv). The reaction was immersed in a preheated oil bath at 50 °C for 6 h, after which the reaction was allowed to cool and the solvent removed in vacuo. The residue so obtained was dissolved in THF (9.3 mL, 0.06 M), and Et3N (0.23 mL, 1.68 mmol, 3 equiv) was added. A stock solution of I2 (283 mg, 1.12 mmol, 2 equiv) in THF (2.83 mL) was prepared and added dropwise to the reaction mixture; addition was halted when the iodine was not decolorized after 30 sec.
The reaction was then diluted with EtOAc (50 mL) and washed with sat. aq. Na2S2O3 (50 mL). The aqueous layer was extracted four times with EtOAc (4 × 50 mL). The combined organic portions were washed with sat. aq. NaCl (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to furnish vinyl iodide which was carried forward directly without purification. The residue from the previous reaction (yield assumed to be quantitative) was dissolved in DMSO (9.3 mL, 0.06 M). To this solution was added 7-trimethylstannylisoquinoline (164 mg, 0.56 mmol, 1 equiv), CuCl (554 mg, 5.6 mmol, 10 equiv), LiCl (235 mg, 5.6 mmol, 10 equiv) and Pd(PPh3)4 (323 mg, 0.28 mmol, 0.5 equiv). The reaction was degassed by bubbling argon through the solution for 10 min.
It was then immersed in a preheated oil bath at 60°C for 1 h. The reaction was then diluted with EtOAc (25 mL) and washed with 5% aq. NH4OH. The aqueous layer was extracted four times (4 × 25 ml) with EtOAc. The combined organic portions were washed with sat. aq. NaCl (25 mL), dried over MgSO4, filtered, and concentrated in vacuo.
The residue so obtained was purified (silica, NH3 deactivation; 10% MeOH : SI-18 CH2Cl2) furnishing vinylisoquinoline 101 (145 mg, 55% from cortistatinone 22) as a yellow foam. 1H NMR (CDCl3, 600 MHz): 9.22 (bs, 1 H), 8.48 (bs, 1 H), 7.92 (s, 1 H), 7.79 (dd, J = 8.6, 1.6 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.61 (d, J = 5.5 Hz, 1 H), 6.29 (d, J = 1.9 Hz, 1 H), 6.24 (as, 1 H), 5.57 – 5.52 (m, 1 H), 4.13 (d, J = 9.0 Hz, 1 H), 3.37 (at, J = 3.37, 1 H), 2.75 (dd, J = 11.2, 6.9 Hz, 1 H), 2.61 (dd, J = 9.0 Hz, 5.8 Hz, 1 H), 2.56 – 2.48 (m, 3 H), 2.47 – 2.38 (m, 2 H), 2.35 (s, 6 H), 2.23 (t, J = 10.1 Hz, 1 H), 2.05 – 1.96 (m, 2 H), 1.96 – 1.87 (m, 1 H), 1.76 – 1.68 (m, 1 H), 1.15 (s, 3 H); 13C NMR (150 MHz, CDCl3) δ 152.5, 150.4, 142.8, 140.0, 139.4, 135.3, 134.8, 134.3, 130.0, 128.4, 126.4, 123.9, 121.8, 120.2, 119.4, 81.2, 79.3, 74.1, 73.5, 62.3, 53.3, 47.7, 40.0 (2 C), 39.6, 38.2, 31.0, 29.3, 28.6, 19.3; HRMS (ESI-TOF) calcd for SI-16 C30H34N2O3 [M+H]+: 471.2642; found: 471.2656.
