HETEROCYCLES, Vol. 93, No. 2, 2016
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8. General Procedure for N-Demethylation of Diacetyl Oxymorphone:
To a stirred mixture of 3,14-diacetyl oxymorphone 11 (1.0 eq), and FeCl2 (0.125 eq) in MeCN (1 mL)
was added t-BuOOH (70% in water) (1.0 eq) followed by pyridine (0.5 eq). The mixture was degassed
and heated to 85 °C for 1.5 h. The reaction mixture was allowed to cool to room temperature, diluted
with CH2Cl2 (3 mL) and then washed with 0.1 M HCl (2 x 1 mL). The aqueous layer was further
extracted with CH2Cl2 (2 x 5 mL). The combined organic extracts were dried with anhydrous MgSO4,
filtered and concentrated via rotary evaporation to afford a crude residue that was chromatographed on
silica gel using EtOAc/MeOH (9:1) as eluent to afford the desired product as a white solid. NMR
analysis showed two amide rotamers. 3,17-Diacetyl noroxymorphone: mp >233 °C (EtOAc/hexanes)
1
lit.5 mp > 235 °C (EtOH); Major rotamer: H NMR (300 MHz, CDCl3) δ 6.90 (d, J=8.2 Hz, 1H), 6.72
(d, J=8.2 Hz, 1H), 5.07 (d, J=5.9 Hz, 1H), 4.73 (s, 1H), 4.35 (s, 1H), 3.66 (dd, J=14.0, 4.8 Hz, 1H),
3.15-3.04 (m, 3H), 2.88 (m, 1H), 2.63 (m, 1H), 2.33 (s, 3H), 2.30 (m, 1H), 2.16 (s, 3H), 2.02 (m, 1H),
13
1.70 (ddd, J=14.0, 14.0, 3.4 Hz, 1H), 1.58 (dd, J=12.6, 3.0 Hz, 1H); C (75 MHz, CDCl3) δ 207.3,
171.2, 168.5, 147.9, 132.9, 129.5, 129.2, 123.6, 119.9, 90.2, 70.7, 53.3, 50.4, 39.9, 35.7, 31.8, 31.7,
28.9, 22.1, 20.8; Minor rotamer: 1H NMR (300 MHz, CDCl3) δ 6.90 (d, J=8.2 Hz, 1H), 6.72 (d, J=8.2
Hz, 1H), 5.10 (d, J=5.9 Hz, 1H), 4.73 (s, 1H), 4.48 (dd, J=14.3, 4.9 Hz, 1H), 4.35 (s, 1H), 4.11 (d,
J=5.6 Hz, 1H), 3.71 (m, 1H), 3.20 (dd, J=18.6, 5.9 Hz, 1H), 3.11 (m, 1H), 3.01 (d, J=18.4 Hz, 1H),
13
2.55 (m, 1H), 2.38 (m, 1H), 2.25 (s, 3H), 1.97 (m, 1H), 1.71-1.66 (m, 2H); C (75 MHz, CDCl3) δ
206.9, 170.9, 168.4, 147.9, 133.1, 129.3, 128.7, 123.7, 119.8, 90.1, 70.8, 59.7, 50.4, 39.9, 34.4, 32.4,
31.1, 28.8, 22.3, 20.8.
9. A. Ninan and M. Sainsbury, Tetrahedron, 1992, 48, 6709.
10. Hydrolysis of diacetyl noroxymorphone to noroxymorphone: A solution of diacetyl noroxymorphone
12 (50 mg, 0.13 mmol) in 25% aq. H2SO4 (2 mL) was heated to 100 °C for 2 h. The reaction mixture
was cooled to 0 °C and basified to pH 9 using concentrated ammonium hydroxide solution. The
brown precipitate that formed was collected by centrifugation. It was washed by suspending in water
followed by centrifugation (twice). The precipitate was dried by evaporation of the azeotropic
mixture with benzene and drying in vacuo to afford noroxymorphone as a light brown solid (31 mg,
80%). Noroxymorphone: mp > 300 °C (water) lit11 mp > 300 °C; 1H NMR (300 MHz, D2O,
hydrochloride salt) δ 6.75-6.82 (m, 2H), 3.87 (m, 1H), 3.20-3.32 (m, 3H), 2.99 (td, J=14.8 Hz, 5.0
Hz, 1H), 2.85 (td, J=13.2 Hz, 4.3 Hz, 1H), 2.63 (td, J=13.4 Hz, 4.6 Hz, 1H), 2.28 (m, 1H), 2.02 (m,
1H), 1.74 (m, 1H), 1.65 (dd, J=14.5 Hz, 4.5 Hz).The hydrochloride salt was prepared by dissolving
noroxymorphone (5 mg, 0.017 mmol) in 3 M HCl (3 drops). The excess hydrochloric acid and water