1850
A. Afonso et al. / Bioorg. Med. Chem. 7 (1999) 1845±1855
2H), 6.87 (s, 1H), 6.96 (d, 1H, J=7.95 Hz), 8.61, (d, 1H,
J=2.1 Hz). 5e (crystalline solid): m.p. 153±159ꢀC; H
1H NMR (300 MHz, CDCl3) d 2.34 (s, 3H), 3.11 (m,
2H), 3.18 (m, 2H), 6.98 (s, 1H), 7.36 (s, 1H), 7.74 (s,
1H), 8.74 (s, 1H); MS (CI) m/z 380 (MH+). 6k (white
1
NMR (300 MHz, CDCl3) d 2.29 (s, 6H), 2.88 (t, 2H),
3.10 (t, 2H), 6.77 (s, 2H), 6.88 (s, 1H), 7.70 (d, 1H,
J=2.1 Hz), 8.60, (d, 1H, J=2.04 Hz); MS(CI) m/z 315,
317 (MH+). Anal. (C16H15BrN2) C, H, N. 5f: (crystal-
1
solid, 40%): H NMR (CDCl3) d 2.33 (s, 3H), 3.09 (m,
2H), 3.21 (m, 2H), 7.24 (s, 1H), 7.31 (s, 1H), 7.75 (s,
1H), 8.71 (s, 1H); MS(CI) m/z 380 (MH+). 6l 1H NMR
(CDCl3): (8.79 (d, J=5.6 Hz, 1H), 7.58 (d, J=7.5 Hz,
1H), 7.43±7.33 (m, 2H), 7.79 (d, J=7.5, 1H), 3.80 (s,
3H), 3.35±3.28 (m, 2H), 3.24±3.16 (m, 2H); 13C NMR
(CDCl3) d 195.1, 123.1, 131.7, 155.5, 148.6, 139.6, 136.7,
136.6, 132.5, 126.2, 123.9, 111.8, 56.57, 32.33, 28.29;
MS(FAB) m/z 274 (MH+).
1
line solid, 71%) H NMR (300 MHz, CDCl3) d 2.95 (t,
2H), 3.13.(q, 2H), 3.79 (s, 3H), 6.72 (m, 3H), 7.22 (q,
1H), 7.71 (d, 1H, J=2.0 Hz), 8.60 (s, 1H); MS(CI) m/z
317, 319 (MH+). 5g (crystalline solid, 85%): mp 106±
107ꢀC; 1H NMR (300 MHz, CDCl3) d 2.92 (t, 2H), 3.15
(t, 2H), 3.80 (s, 6H), 6.31 (d, 2H, J=2.1 Hz), 6.35 (d,
1H, J=2.1 Hz), 7.72 (d, 1H, J=2.1 Hz), 8.61 (d, 1H,
J=2.1 Hz); MS(FAB) m/z 347, 349 (MH+). Anal.
(C16H15BrN2O2) C, H, N. 5h (crystalline solid, 65%):
1H NMR (300 MHz, CDCl3) d 2.31 (s, 3H), 2.90 (m,
2H), 3.12 (m, 2H), 3.78 (s, 3H), 6.51 (s, 1H), 6.57 (s,
1H), 6.61 (s, 1H), 7.71 (d, 1H, J=2.0 Hz), 8.60 (d, 1H,
J=2.0 Hz); MS(CI) m/z 329 (MH+). 5j (white solid,
Method C. A mixture of nitrile 5 (2.5 mmol) and AlCl3
(8.5 mmol) is homogenized with a glass rod and then
heated in an oil bath at 180ꢀC for 1 to 2 min. The mix-
ture is then cooled to room temperature, treated with 4
N HCl and the solution is re¯uxed for 16 h. Basi®cation
with 4 N NaOH, extraction with CH2Cl2 followed by
puri®cation by chromatography aords the tricyclic
ketones 6a (crystalline solid, 77%): 1H NMR (300 MHz,
CDCl3) d 2.34 (s, 3H), 3.15 (s, 4H), 7.26 (m, 3H), 7.35
(s, 1H), 7.78 (s, 1H), 8.67 (s, 1H); MS(CI) m/z 302, 304
(MH+). Anal. (C15H12NOBr) C, H, N. 6b: (pale-yellow
solid, 95%): 1H NMR (300 MHz, CDCl3) d 2.38 (s, 3H),
3.17 (m, 4H), 7.05 (s, 1H), 7.20 (d, 1H, J=8 Hz), 7.79 (s,
1H), 8.03 (d, 1H, J=8 Hz), 8.72 (s, 1H); MS(CI) m/z
302 (MH+). 6c (crystalline solid, 78%): 1H NMR
(300 MHz, CDCl3) d 2.38 (s, 3H), 3.14 (m, 2H), 3.21 (m,
2H), 7.13 (d, 1H, J=7.7 Hz), 7.28 (d, 1H, J=7.9 Hz),
7.79 (s, 1H), 7.78 (s, 1H), 7.86 (s, 1H), 8.72 (d, 1H,
J=2.0 Hz); MS(CI) m/z 302, 304 (MH+). Anal.
1
82%): H NMR (300 MHz, CDCl3) d 2.30 (s, 3H), 2.90
(m, 2H), 3.07 (m, 2H), 6.90 (s, 1H), 7.10 (s, 1H), 7.20 (s,
1H), 7.72 (d, 1H, J=2.3 Hz), 8.62 (d, 1H, J=2.2 Hz);
MS(CI) m/z 379 (MH+).
General methods to prepare ketones 6
Method A. Aluminum chloride (8 mmol) is added in
small lots during 10 min to a well stirred solution of ni-
trile 5 (8 mmol) in dichloroethane (100 mL). The pale-
yellow solution is stirred at room temperature for 1 h
and is then worked up by the addition of ice/water and
10% sodium hydroxide to pH 10. The mixture is
extracted several times with dichloromethane, and the
crude product obtained on evaporation of the combined
extracts is ¯ash chromatographed on silica gel (100 mL).
Elution with 10% methanol±2% ammonium hydroxide±
ethylacetate aords the intermediate imine which is dis-
solved in 2 N hydrochloric acid (100 mL). The solution
is heated in an oil bath (120ꢀC) for 1.5 h, cooled, basi-
®ed with 10% sodium hydroxide and extracted with
dichloromethane (4Â50 mL). The crude product is
obtained by concentration of the combined extract ®l-
tered through a silica gel plug; evaporation of the ®l-
trate aords the ketones 6f (amorphous solid, 28%): 1H
NMR (300 MHz, CDCl3) d 3.12 (m, 2H), 3.21 (m, 2H),
3.07 (s, 3H), 6.70 (d, 1H, J=2.3 Hz), 6.88 (q, 1H, J=
3.2, 8.9 Hz), 7.78 (d, 1H, J=1.8 Hz), 8.19 (d, 1H, J=
8.9 Hz), 8.71 (s, 1H); MS(CI) m/z 318 (MH+). 6g
(amorphous solid, 91%): 1H NMR (300 MHz, CDCl3) d
3.10 (m, 2H), 3.20 (m, 2H), 3.79 (s, 3H), 3.85 (s, 3H),
6.33 (d, 1H, J=1.8 Hz), 6.38 (d, 1H, J=1.8 Hz), 7.73 (d,
1H, J=1.8 Hz), 8.71 (d, 1H, J=1.8 Hz); MS(CI) m/z
348 (MH+). Anal. (C16H14BrNO3) C, H, N.
1
(C15H12NOBr) C, H, N. 6d (crystalline solid, 68%): H
NMR (300 MHz, CDCl3) d 2.29 (s, 3H), 2.35 (s, 3H),
3.14 (m, 2H), 3.21 (m, 4H), 7.01 (d, 1H, J=7.7 Hz), 7.14
(d, 1H, J=7.7 Hz), 7.72 (d, 1H, J=1.8 Hz), 8.67 (d, 1H,
J=2 Hz); MS(CI) m/z 316, 318 (MH+). Anal.
1
(C16H14NOBr) C, H, N. 6e (crystalline solid, 63%): H
NMR (300 MHz, CDCl3) d 2.32 (s, 6H), 3.09 (m, 2H),
3.17 (m, 2H), 6.87 (s, 3H), 6.96 (s, 3H), 7.73 (d, 1H,
J=2.1 Hz), 8.70 (d, 1H, J=1.9 Hz); MS(FAB) m/z 316,
318 (MH+). Anal. (C16H14NOBr) C, H, N.
Method D. A suspension of 5i (0.93 g) in TiCl4 (6 mL) is
heated at 100ꢀC for 15 min; the resulting dark solution
is then cooled, carefully diluted with ice, basi®ed with
NaOH and extracted with CH2Cl2. The crude imine
intermediate is then hydrolyzed at 140ꢀC in 4 N HCl
(50 mL) for 7 h, basi®ed with NaOH followed by
extraction with CH2Cl2 and chromatography on silica-
gel to aord 6h (crystalline solid, 60%): mp 116±117ꢀC;
1H NMR (300 MHz, CDCl3) d 2.37 (s, 3H), 3.09 (m,
2H), 3.21 (m, 2H), 3.83 (s, 3H), 6.57 (d, 1H, J=2.2 Hz),
6.66 (d, 1H, J=2.0 Hz), 7.74 (s, 1H), 8.71 (d, 1H,
J=1.9 Hz); MS(CI) m/z 332, 334 (MH+) and 6i (solid,
Method B. A solution of the nitrile 5 (2.64 mmol) in
tri¯ic acid (10 mL) is stirred at 60ꢀC for 3 h, the solution
is then cooled to 20ꢀC, carefully diluted with ice (20 g)
and MeOH (10 mL) followed by re¯uxing for 24 h. The
solution is then cooled, poured into ice (100 g) and
basi®ed with 50% NaOH at 0ꢀC. The precipitated white
solid is ®ltered, washed with water, dried and puri®ed
by chromatography eluting with 20% EtOAc±hexanes
to aord the tricyclic ketones 6j (white solid, 60%):
1
12%): H NMR (300 MHz, CDCl3) d 2.35 (s, 3H), 3.06
(m, 2H), 3.17 (m, 2H), 3.79 (s, 3H), 6.62 (s, 1H), 6.65 (s,
1H), 7.61 (s, 1H), 8.57 (s, 1H); MS(CI) m/z 332, 334
(MH+).
Ketone 6m. Step i: TFAA (5.42 mL, 1.05 equiv) is added
dropwise to 6l (10.0 g, 36.53 mmol) and Bu4N+NO3
(12.8 g, 1.1 equiv) in CH2Cl2 (100 mL) at 0ꢀC. The