Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
The aforementioned crude amine [Fig 1] (1.99 g, 6.83 mmol, 1 equiv.) was dissolved in DCM [Fig 2] (68 mL). To this solution was added formic acid [Fig 3] (515 μl, 13.68 mmol, 2.0 equiv.), CDMT [Fig 4] (2.52 g, 14.34 mmol, 2.1 equiv.), NMM [Fig 5] (1.65 mL, 15.03 mmol, 2.2 equiv.) and DMAP [Fig 6] (83 mg, 0.68 mmol, 0.1 equiv.) in that order. The mixture was stirred for 1 hour then partitioned [Fig 7] between 1N HCl (25 mL) and DCM (15 mL). The aqueous layer was extracted with DCM (15 mL, 3X), and the combined organic layers washed with 1N HCl (50 mL), saturated NaHCO3 (50 mL), brine (50 mL), and dried (Na2SO4). Volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography [Fig 8] (gradient from 1:1 → 2:1 EtOAc:Hexanes → pure EtOAc) to afford the corresponding formamide (1.81 g, 81% from bromoisoxazole 7) as a white foam.
iii. The aforementioned formamide [Fig 9] (1.20 g, 3.76 mmol, 1 equiv.) was dissolved in DCM (37.6 mL) and Et3N (7.78 mL, 56.4 mmol, 15 equiv.) and cooled to – 20 °C. Phosgene [Fig 10] (20 wt% solution in toluene, 1.84 mL, 3.76 mmol, 1 equiv.) was added very slowly dropwise over 5 minutes to the cooled solution. The reaction mixture was stirred for 20 minutes at –20 °C, then quenched at this temperature by the dropwise addition of saturated aqueous NaHCO3 (25 mL). The reaction mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and DCM (50 mL), and the aqueous layer extracted with DCM (50 mL, 2X). The combined organic layers were washed with 1N HCl (50 mL, 2X), saturated aqueous NaHCO3 (50 mL), brine (50 mL) and dried (MgSO4). Volatiles were removed in vacuo [Fig 11] and the crude material purified by silica gel flash chromatography (1:1 hexanes:Et2O) to afford isonitrile (0.86 g, 76%) as a colorless solid.
To a re-sealable vial was added isonitrile [Fig 12] (1.03 g, 3.42 mmol, 1 equiv.) and AIBN [Fig 13] (1.68 g, 10.3 mmol, 3.0 equiv.) and the flask was evacuated then back-filled with argon. Degassed toluene (68.4 mL) was added followed by Bu3SnH [Fig 14] (8.88 mL, 33.51 mmol, 9.8 equiv.). The sealed vial was placed into a 100 °C oil bath for 2.5 hours. After cooling, all volatiles were removed in vacuo and the crude material purified by silica gel flash chromatography (gradient from 10:1 → 5:1 hexanes:Et2O) to afford the corresponding olefin [Fig 15] 9 (858 mg, 91%) as a colorless oil: TLC (pure CH2Cl2): Rf = 0.57; 1H NMR (600 MHz, CDCl3) δ 5.66 (s, 2 H), 2.38 – 2.33 (m, 1 H), 2.18 (bs, 1 H), 2.08 – 2.03 (m, 2 H), 1.97 – 1.92 (m, 2 H), 1.73 – 1.66 (m, 1 H), 1.57 – 1.49 (m, 4 H), 1.45 –1.29 (m, 7 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.6, 1.5 Hz, 6 H); 13C NMR (150 MHz, CDCl3) δ 129.9, 123.7, 75.3, 45.7, 42.0, 40.6, 37.3, 37.0, 35.8, 32.2, 31.6, 29.2, 25.8, 25.6, 24.0, 23.7, 22.2, 21.3, 20.7, 13.9; IR (film) νmax 3467, 2953, 1456, 1372, 1055, 1033, 1012, 958, 759 cm-1; HRMS (m/z): [M+Na]+ calcd. for C19H32NaO, 299.2345; found, 299.2349.