ACCEPTED MANUSCRIPT
European Journal of Medicinal Chemistry
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7.27 (5H, m), 6.40 (1H, br s), 3.52 (1H, dd, J = 15.0, 6.0),
3.20 (1H, dd, J = 15.0, 6.0), 3.00-2.72 (3H, m), 2.34 (1H,
br d, J = 12.0), 1.28 (3H, s), 1.23-1.20 (6H, m), 1.09 (3H,
s); 13C NMR (75 MHz) C 199.3 (s), 168.0 (s), 153.4 (s),
146.8 (s), 134.6 (s), 132.7 (d), 131.4 (d), 130.1 (s), 128.5 x
2 (d), 126.9 x 2 (d), 125.0 (d), 123.6 (d), 49.6 (t), 44.7 (d),
37.9 (s), 37.8 (s), 37.4 (t), 36.0 (t), 35.9 (t), 33.5 (d), 23.9
(q), 23.7 (q), 23.7 (q), 18.5 (q), 18.2 (t); HRMS (ESI) m/z
404.2634 [M+H]+, calcd for C27H34NO2: 404.2590. The
NMR and MS data agree with those reported in the
literature [11].
acid was added dropwise to a solution of nitro-acetamide
12 (1.1 g, 3.0 mmol) in 12 mL of acetic acid. The mixture
was stirred at room temperature for one hour and heated at
60 ºC for 17 h. Then, the mixture was poured into water
and ice, and extracted with chloroform. The combined
organic extracts were washed with brine, dried over
Na2SO4 and concentrated. The resulting crude oil was
purified by flash chromatography, using hexane-ethyl
acetate (15:85) as eluent, to give ketone 13 (330 mg, 30%)
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as a light orange foam: []20 +27.4 (c 5.0, CHCl3); H
D
NMR (300 MHz) 8.05 (1H, s), 7.63 (1H, s), 6.33 (1H,
m), 3.26 (1H, m), 3.14 (2H, m), 2.34 (1H, br d, J = 12.0),
1.94 (3H, s), 1.32-1.25 (9H, m), 1.05 (3H, s); 13C NMR
(75 MHz) C 197.3 (s), 170.6 (s), 154.1 (s), 152.8 (s), 139.6
(s), 132.9 (s), 127.0 (d), 119.0 (d), 48.9 (t), 43.5 (d), 37.5
(s), 37.4 (s), 37.1 (t), 35.7 (t), 35.4 (t), 28.2 (d), 23.6 (q),
23.2 (q), 23.2 (q), 23.1 (q), 18.3 (q), 17.8 (t); HRMS (EI)
m/z 387.2245 [M+H]+, calcd for C22H31N2O4: 387.2284.
N-acetyl-dehydroabietylamine (11). To a solution of
dehydroabietylamine (6) (1.45 g,
5
mmol) and
triethylamine (1.4 mL, 10 mmol) in THF (25 mL) at 0 ºC,
acetyl chloride (0.4 mL, 5.5 mmol) was added dropwise.
Then, it was allowed to warm to rt and stirred overnight (16
h). The resulting reaction mixture was treated with 1 M
HCl (20 mL), phases separated, and the aqueous phase was
extracted twice with ethyl acetate. The combined organic
extracts were washed with brine, dried over Na2SO4 and
concentrated. The resulting yellowish crude oil was
purified by flash chromatography, using hexane-ethyl
N-acetyl-dehydroabietylamine-7-one (14). A solution of
CrO3 (0.45 g, 4.5 mmol) in 20 mL of acetic acid was added
dropwise to a solution of acetamide 11 (740 mg, 2.2 mmol)
in 10 mL of acetic acid. The mixture was stirred at room
temperature for one hour and heated at 60 ºC for 17 h.
Then, the mixture was poured into water and ice, and
extracted with chloroform. The combined organic extracts
were washed with brine, dried over Na2SO4 and
concentrated. The resulting yellowish crude oil was
purified by flash chromatography, using hexane-ethyl
acetate (4:6) as eluent, to give acetamide 11 (1.59 g, 96%)
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as a yellowish foam: []20 +18.2 (c 0.55, CHCl3); H
D
NMR (300 MHz) 7.29 (1H, d, J = 8.5), 7.12 (1H, dd, J =
8.5, 1.5), 7.02 (1H, br s), 6.89 (1H, t, J = 6.0), 3.40 (1H, dd,
J = 15.0, 6.0), 3.16 (1H, dd, J = 15.0, 6.0), 2.41 (1H, br d, J
= 12.0), 2.08 (3H, s), 1.36 (6H, d, J = 6.0), 1.35 (3H, s),
1.07 (3H, s); 13C NMR (75 MHz) C 170.2 (s), 146.8 (s),
145.0 (s), 134.4 (s), 126.5 (d), 123.7 (d), 123.4 (d), 53.1 (s),
49.6 (t), 44.8 (d), 37.9 (t), 37.0 (s), 35.8 (t), 33.0 (d), 29.8
(t), 25.0 (q), 23.6 (q), 23.6 (q), 22.7 (q), 18.6 (t), 18.4 (q),
18.3 (t); HRMS (ESI) m/z 328.2621 [M+H]+, calcd for
C22H34NO: 328.2640. The NMR and MS data agree with
those reported in the literature [14].
acetate (4:6 to 3:7) as eluent, to give ketone 14 (565 mg,
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73%) as a yellowish oil: []20 -26.7 (c 0.6, CHCl3); H
D
NMR (300 MHz) 7.70 (1H, d, J = 2.0), 7.38 (1H, dd, J =
8.5, 2.0), 7.31 (1H, d, J = 8.5), 6.64 (1H, t, J = 6.0), 3.33
(1H, dd, J = 15.0, 6.0), 3.00 (1H, dd, J = 15.0, 6.0), 2.36
(1H, br d, J = 12.0), 1.95 (3H, s), 1.27 (3H, s), 1.19 (6H, d,
J = 6.0), 1.04 (3H, s); 13C NMR (75 MHz) C 199.3 (s),
170.7 (s), 153.5 (s), 146.4 (s), 132.6 (d), 130.2 (s), 124.5
(d), 123.6 (d), 48.7 (t), 43.7 (d), 2 x 37.5(s), 37.4 (t), 35.8
(t), 35.5 (t), 33.3 (d), 2 x 23.6 (q), 23.5 (q), 23.1 (q), 18.5
(q), 18.1 (t); HRMS (ESI) m/z 342.2417 [M+H]+, calcd for
C22H32NO2: 342.2433. The NMR and MS data agree with
those reported in the literature [15].
N-acetyl-12-nitrodehydroabietylamine (12). Powdered
cupric nitrate trihydrate (1.10 g, 4.55 mmol) was added in
portions to a stirred solution of acetamide 11 (745 mg, 2.27
mmol) in acetic anhydride (30 mL) and the blue solution
was stirred at 5 ºC for 17 h. Then, the mixture was poured
into water and extracted with ethyl acetate. The organic
extracts were washed with brine, dried over Na2SO4 and
concentrated. The resulting residue was purified by
chromatography eluting with hexane-ethyl acetate (4:6) to
N-(((1R,4aS,13cR)-12-fluoro-7-isopropyl-1,4a-dimethyl-
2,3,4,4a,9,13c-hexahydro-1H-dibenzo[a,c]carbazol-1-
yl)methyl)acetamide (15). It was followed a method
reported in the literature [12]. To a solution of 4-
fluoroaniline (50 mmol) in 50 ml of 20% HCl was added
dropwise the solution of NaNO2 (3.63 g, 52.5 mmol) in 8
ml of water while cooling with an ice-water bath. The
reaction mixture was stirred at 0 ºC for 1 h to give a clear
solution. Then to the solution was added dropwise a
solution of SnCl2 (19 g, 0.1 mol) in 30 ml of 35% HCl at 0
ºC. Then, the mixture was stirred at room temperature for
1-2 h. The solid product was filtered, washed with 35%
HCl for 3 times and dried in a vacuum desiccator
containing phosphorous pentoxide. The product (7 g) could
be used in subsequent reactions without further
purification.
give 0.64 g (76%) of pure nitro derivative 12 as a slightly
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orange foam: []20 +45.3 (c 0.75, CHCl3); H NMR (300
D
MHz) 7.62 (1H, s), 7.08 (1H, s), 5.48 (1H, m), 3.48-3.30
(2H, m), 2.27 (1H, br d, J = 12.0), 1.97 (3H, s), 1.27-1.21
(9H, m), 0.94 (3H, s); 13C NMR (75 MHz) C 170.2 (s),
148.4 (s), 147.6 (s), 141.0 (s), 139.5 (s), 127.9 (d), 120.2
(d), 49.8 (t), 44.7 (d), 38.1 (t), 37.5 (s), 37.3 (s), 36.0 (t),
30.0 (t), 28.0 (d), 25.1 (q), 23.6 (q), 23.5 (q), 18.6 (q), 18.6
(t), 18.3 (q); HRMS (EI) m/z 373.2472 [M+H]+, calcd for
C22H33N2O3: 373.2491. The NMR and MS data agree with
those reported in the literature [14].
N-acetyl-12-nitrodehydroabietylamine-7-one (13).
A
solution of CrO3 (600 mg, 6.0 mmol) in 28 mL of acetic