R. Di Fabio et al. / Il Farmaco 58 (2003) 723Á
/
738
731
6 (0.6 g, 0.9 mmol) in CH2Cl2 (15 ml) and TEA (0.62 ml,
4.5 mmol) were added and the solution was warmed to
7.11. 2-[8-Chloro-(4-methoxybenzyl)-2-oxo-3-
(diphenyl-tert-butylsilyloxy)-1,2,3,4-tetrahydro-benzo-
[b]-azepin-5-ylidene)]-N-phenyl-acetamide (10a)
ꢁ20 8C. After 30 min a 3 N solution of HCl (20 ml) was
/
added. The organic phase was extracted with CH2Cl2,
dried and evaporated under reduced pressure. The crude
residue was purified by flash chromatography (eluant
cyclohexane/EtOAc 8:2) to give compound 7 as colour-
less oil (0.45 g, 75%): 1H NMR d (CDCl3): 9.77 (m, 1H);
To a suspension of intermediate 9 (0.25 g, 3.02 mmol)
in MeCN (90 ml) was added TEA (0.84 ml, 6.04 mmol)
and Pd(PPh3)4 (0.17 g, 0.15 mmol). The reaction mixture
was heated at reflux for 24 h, then poured into saturated
solution of ammonium chloride and extracted with
EtOAc. The organic phase was washed with brine, dried
and evaporated under reduced pressure. The crude
material was purified by flash chromatography (eluant
cyclohexane/EtOAc 7:3) to obtain compound 10a as
7.58 (d, 2H); 7.45 (d, 2H); 7.42Á7.2 (m, 7H); 7.02 (dd,
/
1H); 7.00 (m, 2H); 6.78 (d, 2H); 5.71 (d, 1H); 5.19 (d,
1H); 4.25 (t, 1H); 4.11 (d, 1H); 3.81 (s, 3H); 2.67 (ddd,
1H); 2.52 (ddd, 1H); 1.003 (s, 9H); MS (FAB/NBA): m/z
664 [Mꢂ
H]ꢂ. Anal. (C34H35BrClNO4Si) C, H, N.
/
white foam (0.52 g, 77%): 1H NMR d (CDCl3): 7.6Á
(m, 4H); 7.55Á7.3 (m, 10H); 7.21 (d, 1H); 7.16Á7.1 (m,
1H); 7.07 (d, 2H); 6.97 (d, 2H); 6.78 (d, 1H); 6.73 (d,
2H); 6.69 (d, 2H); 6.62 (bs, 1H); 5.44Á5.40 (d, 1H); 5.05
(d, 1H); 4.91 (d, 1H); 4.56 (dd, 1H); 4.30 (dd, 1H); 4.22Á
4.02 (m, 3H); 3.89 (d, 1H); 3.69Á3.66 (s, 3H); 2.95 (tt,
1H); 2.74 (tt, 1H); 1.10/0.82 (s, 9H); IR (CDCl3) nmax.
(cmꢁ1): 1682 (CÄ
O); MS (FAB/NBA): m/z 700 [Mꢂ
H]ꢂ. Anal. (C42H41ClN2O4Si) C, H, N.
/
7.57
/
/
7.9. 6-[(2-Bromo-5-chlorophenyl)-(4-methoxybenzyl)-
carbamoyl)-5-(diphenyl-tert-butylsilyloxy)-(E)-hex-2-
enoic acid ethyl ester (8)
/
/
To a solution of intermediate 7 (0.4 g, 0.6 mmol) in
toluene (20 ml) was added (ethoxycarbonylmethylen)-
triphenylphosphorane (0.21 g, 0.6 mmol). The reaction
mixture was heated at 70 8C for 2 h, then the solvent was
evaporated and the crude residue was purified by flash
chromatography (eluant cyclohexane/EtOAc 9:1) to
/
/
/
The endo isomer 10b was also isolated as white foam
(0.087 g, 13%).1H NMR d (CDCl3): 7.69 (m, 3H); 7.6
1
afford compound 8 as colourless oil (0.35 g, 80%): H
(d, 2H); 7.44Á7.12 (m, 12H); 7.06 (dd, 1H); 7.00 (d, 1H);
/
NMR d (CDCl3): 7.55 (dd, 2H); 7.45 (dd, 2H); 7.4Á7.2
/
6.84 (d, 2H); 6.65 (d, 2H); 6.21 (d, 1H); 4.82 (m, 2H);
(m, 7H); 7.03 (dd); 7.00 (d, 2H); 6.77 (d, 2H); 6.67 (dt,
1H); 5.71 (d, 1H); 5.70 (d, 1H); 5.23 (d, 1H); 4.15 (q,
2H); 4.07 (d, 1H); 3.87 (m, 1H); 3.81 (s, 3H); 2.56 (m,
2H); 1.28 (t, 3H); 1.02 (s, 9H); MS (FAB/NBA): m/z 734
4.32 (d, 1H); 3.69 (s, 3H); 3.52 (d, 1H); 3.34 (d, 1H); 1.13
(s, 9H); IR (Nujol) nmax. (cmꢁ1): 1691 and 1664 (CÄ
MS (FAB/NBA): m/z 700 [Mꢂ
H]ꢂ. Anal.
(C42H41ClN2O4Si) C, H, N.
/
O);
/
[Mꢂ
H]ꢂ. Anal. (C38H41BrClNO5Si) C, H, N.
/
7.10. (E)-Hex-2-enedioic acid, 6-[(2-bromo-5-
chlorophenyl)-(4-methoxybenzyl)-amide]-5 (diphenyl-
tert-butylsilyloxy)-1-phenylamide (9)
7.12. 2-[6-Chloro-2-oxo-3-hydroxy-1,2,3,4-tetrahydro-
benzo-[b]-azepin-5-ylidene)]-N-phenyl-acetamide (11)
To a solution of intermediate 10a (0.1 g, 0.22 mmol)
in CF3COOH (8.6 ml) were added anisole (234 ml) and
12 N H2SO4 (359 ml). The reaction mixture was heated
at 80 8C for 1 h, then poured into crushed ice. Saturated
solution of NaHCO3 was added until pH 7 and the
resulting solution was extracted with EtOAc, washed
with brine, dried and evaporated under reduced pres-
sure. The crude residue was purified by flash chromato-
graphy (eluant cyclohexane/EtOAc) to obtain
To a solution of aniline (0.22 ml, 2.44 mmol) in
CH2Cl2 (10 ml) was added Et2AlCl (1 M solution in
hexane, 3.67 ml, 3.67 mmol). The reaction mixture was
stirred at r.t. for 30 min, then a solution of intermediate
8 (0.9 g, 1.22 mmol) in toluene (20 ml) was added and
the resulting solution was heated at 80 8C for 1 h. A 1 M
solution of HCl (20 ml) was added and the mixture was
extracted with CH2Cl2; the organic phase was washed
with brine, dried and evaporated under reduced pres-
sure. The crude material was purified by flash chroma-
tography (eluant cyclohexane/EtOAc 8:2) to give
compound 11 as white solid (0.05 g, 67%): m.p. 243Á
/
1
245 8C; H NMR d (acetone-d6): 9.33 (bs, 2H); 7.72 (d,
2H); 7.44 (d, 1H); 7.34Á7.23 (m, 3H); 7.22 (d, 1H); 7.06
(t, 1H); 6.1 (dd, 1H); 4.45 (m, 1H); 3.98 (d, 1H); 3.79
(ddd, 1H); 3.60 (ddd, 1H); IR (Nujol) nmax. (cmꢁ1)
3441Á3198 (NH), 1670 and 1661 (CÄO); MS (FAB/
NBA): m/z 343 [Mꢂ
H]ꢂ. Anal. (C18H15ClN2O3) C, H,
N.
1
compound 9 as colourless oil (0.744 g, 78%): H NMR
/
d (CDCl3): 7.6Á7.06 (m, 18H); 7.03 (d, 2H); 6.79 (d,
/
2H); 6.53 (m, 1H); 5.83 (d, 1H); 5.79 (d, 1H); 5.30 (d,
1H); 4.06 (d, 1H); 3.92 (t, 1H); 3.81 (s, 3H); 2.56 (m,
2H); 1.02 (s, 9H); IR (CDCl3) nmax. (cmꢁ1): 1678 and
:
/
/
1603 (CÄ
/
O); MS (FAB/NBA): m/z 781 [Mꢂ
H]ꢂ. Anal.
/
/
(C42H42BrClN2O4Si) C, H, N.