2788 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Reich et al.
ethanol was added, by dropping funnel, a solution of NaSH‚H2O
(12.13 g, 163.79 mmol) and NaOH (5.02 g, 125.50 mmol) in
100 mL water over 15 min. The hot reaction mixture was
poured into 500 mL of ice/water and filtered. The filtrate was
slowly added to 1 L of ice water containing 80 mL of
concentrated HCl, forming a yellow precipitate. The mixture
was filtered, and the solid was dissolved in 500 mL of hot 2:1
CCl4/petroleum ether. The aqueous layer was removed, and
the hot organic layer was suction filtered. The filtrate was
allowed to cool, forming yellow crystals which were collected
and dried to give 17.50 g of 24 (112.78 mmol, 58%): mp 55-
56 °C.
trimethylacetyl chloride (0.10 mL, 0.81 mmol). After 20 min,
the reaction mixture was diluted with ethyl acetate, washed
twice with water and then with brine, dried over Na2SO4, and
concentrated. The residue was purified by flash chromatog-
raphy (20% EtOAc/hexanes) to affort 0.16 g (75%) of 29: 1H
NMR (CDCl3) δ 8.91 (1H, br s), 8.46 (1H, dd, J ) 8.3, 1.2 Hz),
8.07 (1H, dd, J ) 7.8, 1.0 Hz), 7.54 (2H, m), 7.38 (2H, m), 7.20
(1H, d, J ) 7.5 Hz), 7.05 (1H, td, J ) 7.6, 1.3 Hz), 4.50 (1H,
m), 3.19 (1H, dd, J ) 13.8, 6.6 Hz), 3.04 (3H, m), 1.36 (9H, s);
IR (neat) 2963, 2878, 1730, 1682, 1580, 1510, 1431, 1300, 1246,
1159, 1121, 1084, 745; HRMS, exact mass calculated for C21H23
-
NO3S, M + H required 370.1480, found 370.1464.
3-[[(2-Nit r op h e n yl)su lfa n yl]m e t h yl]isoch r om a n -1-
on e (25). To a suspension of 24 (0.94 g, 6.05 mmol) in 12 mL
of degassed ethanol at 0 °C was added a solution of 85% KOH
(0.40 g, 6.09 mmol) in 2 mL of water. A solution of 28 (vide
infra) (1.72 g, 5.96 mmol) in 6 mL of EtOH was added by
dropping funnel over 40 min; the mixture was allowed to warm
to 23 °C and stirred for 16 h. The mixture was poured into
0.5 N HCl, extracted twice with CH2Cl2, dried over MgSO4,
and concentrated. Purification by flash chromatography (20%
hexanes/CH2Cl2, preadsorbed onto SiO2 with CH2Cl2) gave 25
as a yellow solid: 1.19 g (3.78 mmol, 62%); mp 172-175 °C;
1H NMR (CDCl3) δ 8.21 (1H, d, J ) 8.2 Hz), 8.10 (1H, d, J )
7.7 Hz), 7.61-7.51 (3H, m), 7.41 (1H, t, J ) 7.6 Hz), 7.35-
7.26 (2H, m), 4.74 (1H, m), 3.61 (1H, dd, J ) 13.8, 4.1 Hz),
3.31-3.09 (3H, m); IR (neat) 1728, 1605, 1460, 1337, 1280,
P r oced u r e A: Rep r esen ta tive P r oced u r e for Am id e
F or m a tion Usin g Tr im eth yla lu m in u m . N-ter t-Bu tyl-2-
{3-[[2-[(2,2-d im eth ylp r op ion yl)a m in o]p h en yl]su lfa n yl]-
2-h yd r oxyp r op yl}ben za m id e (3) tert-Butylamine (0.09 mL,
0.83 mmol) was added to a cooled (-12 °C) solution of
trimethylaluminum (0.86 mmol) in 4 mL of toluene. The
solution was warmed to 23 °C for 45 min, cooled to 0 °C, and
treated with lactone 29 (0.067 g, 0.18 mmol) in 1 mL of toluene.
The reaction mixture was heated to reflux for 3 h during which
all of 29 was consumed. The mixture was poured into 0.5 N
HCl, extracted three times with ethyl acetate, dried over
MgSO4, and concentrated. Purification by flash chromatog-
raphy (5% EtOAc/CH2Cl2) gave 3 as a white foam: 0.059 g
(74%); 1H NMR (CDCl3) δ 9.07 (1H, br s), 8.43 (1H, d, J ) 7.4
Hz), 7.59 (1H, dd, J ) 7.7, 1.3 Hz), 7.38-7.18 (5H, m), 7.04
(1H, td, J ) 7.5, 1.2 Hz), 5.91 (1H, br s), 5.84 (1H, d, J ) 5.0
Hz), 3.79 (1H, m), 3.00-2.81 (4H, m), 1.45 (9H, s), 1.35 (9H,
s); IR (neat) 3333, 2965, 2870, 1676, 1634, 1580, 1512, 1433,
1366, 1302, 1223, 1161, 1096, 1036, 920, 733; HRMS, exact
mass calculated for C25H34N2O3S, M + H required 443.2371,
found 443.2352. Anal. (C25H34N2O3S‚0.25H2O) C, H, N, S.
2-[[(1-Oxoisoch r om a n -3-yl)m et h yl]su lfa n yl]b en zoic
Acid Meth yl Ester (30). A solution of 85% KOH (0.19 g, 2.88
mmol) in 10 mL of ethanol/2 mL of water (degassed) at 0 °C
was treated with methyl thiosalicylate (0.40 mL, 2.91 mmol),
and the resulting yellow solution was stirred for 20 min. Iodo
lactone 2 in 5 mL of ethanol was introduced, and the mixture
was warmed to 23 °C and stirred for 4 h. The reaction mixture
was poured into 1 N HCl, extracted twice with ethyl acetate,
dried over MgSO4, and concentrated. The product was purified
by flash chromatography (20% f 40% EtOAc/hexanes, pread-
sorbed onto SiO2 with CH2Cl2) to give 0.805 g of 30 as a white
solid (2.45 mmol, 84%): mp 79-82 °C; 1H NMR (CDCl3) δ 8.09
(1H, d, J ) 7.7 Hz), 7.98 (1H, dd, J ) 7.8, 1.4 Hz), 7.57-7.38
(4H, m), 7.26-7.18 (2H, m), 4.74 (1H, m), 3.93 (3H, s), 3.59
(1H, dd, J ) 13.6, 3.9 Hz), 3.35-3.05 (3H, m); IR (neat) 1721,
1607, 1460, 1433, 1283, 1246, 1121, 1063, 743, 693. Anal.
(C18H16O4S) C, H, S.
1244, 1119, 1084, 733; HRMS, exact mass calculated for C16H13
NO4S, M+ required 315.0566, found 315.0553. Anal. (C16H13
NO4S) C, H, N, S.
-
-
Meth yl 2-P r op en ylben zoa te (27). A solution of methyl
2-bromobenzoate (12.0 mL, 83.42 mmol), allyltributyltin (32.0
mL, 103.22 mmol), and palladium tetrakis(triphenylphos-
phine) (1.92 g, 1.66 mmol) in 30 mL of benzene was heated to
100 °C in a sealed tube for 16 h. The mixture was filtered
through a pad of silica gel (eluted with hexanes), and the
solvent was removed. Distillation of the crude material at 1
mmHg gave a clear oil (79-90 °C), which contained ap-
proximately 90% product (14.3 g). The compound was further
purified by flash chromatography (600 g SiO2, 5% f 10% Et2O/
hexanes) to give 11.48 g of pure 27 (65.16 mmol, 78% yield
based on methyl 2-bromobenzoate): 1H NMR (CDCl3) δ 7.88
(1H, m), 7.44 (1H, m), 7.28 (2H, m), 6.01 (1H, m), 5.02 (2H,
m), 3.88 (3H, s), 3.75 (2H, d, J ) 6.4 Hz); IR (neat) 3075, 2951,
1723, 1435, 1262, 1076, 916, 748.
3-(Iod om eth yl)isoch r om a n -1-on e (28). A solution of 27
(2.00 g, 11.35 mmol) in 8 mL of acetonitrile at 23 °C was
treated with iodine (5.70 g, 22.46 mmol) and stirred for 30 min.
The reaction mixture was diluted with ethyl acetate (200 mL),
washed twice with a saturated solution of sodium bisulfite,
dried over MgSO4, and concentrated to a pale yellow oil (3.22
g, 11.18 mmol, 98%) which needed no further purification: 1H
NMR (CDCl3) δ 8.10 (1H, d, J ) 7.7 Hz), 7.57 (1H, td, J ) 7.5,
1.4 Hz), 7.41 (1H, t, J ) 7.6 Hz), 7.28 (1H, d, J ) 7.5 Hz), 4.55
(1H, m), 3.52 (1H, dd, J ) 10.6, 4.6 Hz), 3.18 (1H, dd, J )
10.6, 7.2 Hz), 3.14-3.20 (2H, m); IR (neat) 3028, 1726, 1607,
1460, 1275, 1240, 1119, 1084, 745; HRMS, exact mass calcu-
lated for C10H9O2I, M+ required 287.9648, found 287.9655.
2,2-Dim et h yl-N-[[(1-oxoisoch r om a n -3-yl)m et h yl]su lf-
a n yl]p h en yl]p r op ion a m id e (29). A solution of 25 (0.15 g,
0.48 mmol) in 4 mL of glacial acetic acid at 23 °C was treated
with zinc (0.15 g, 2.33 mmol) and stirred for 1 h. The mixture
was filtered through Celite, and the acetic acid was removed
under vacuum. The residue was dissolved in ethyl acetate,
washed with a saturated solution of NaHCO3, dried over
MgSO4, and concentrated. The crude aniline was purified by
flash chromatography (20% EtOAc/hexanes) to give a 25b as
a yellow oil: 0.08 g (0.29 mmol, 60%); 1H NMR (CDCl3) δ 8.07
(1H, d, J ) 7.1 Hz), 7.53 (1H, dt, J ) 7.5, 1.1 Hz), 7.39 (2H, t,
J ) 7.8 Hz), 7.26-7.11 (2H, m), 6.77-6.66 (2H, m), 4.40 (2H,
brs), 4.55 (1H, m), 3.25-2.98 (4H, m); IR (neat) 3462, 3358,
3067, 2926, 1718, 1607, 1480, 1283, 1246, 1121, 1084, 745;
HRMS, exact mass calculated for C16H15NO2S, M + H required
286.0903, found 286.0890. Anal. (C16H15NO2S‚H2O) C, H, N,
S. To a solution of 25b (0.168 g, 0.59 mmol) and pyridine (0.07
mL, 0.69 mmol) in 4 mL of CH2Cl2 at 0 °C was added
ter t-Bu t yl-2-[3-[[2-(ter t-Bu t ylca r b a m oyl)p h en yl]su lf-
a n yl]-2-h yd r oxyp r op yl]ben za m id e (4). Using procedure A
described above for 3, alcohol 4 was obtained as a white solid
after flash chromatography (5-20% EtOAc/CH2Cl2) (81%
yield): mp 69-76 °C; 1H NMR (CDCl3) δ 7.57 (1H, d, J ) 7.8
Hz), 7.43-7.16 (7 H, m), 6.77 (1 H, br s), 6.17 (1 H, br s), 5.83
(1 H, d, J ) 4.3 Hz), 3.89 (1H, m), 3.14 (1H, dd, J ) 13.6, 4.5
Hz), 3.00 (1H, dd, J ) 13.6, 8.2 Hz), 2.88 (2H, m), 1.46 (9H, s);
IR (neat) 3297, 1638, 1545, 1452, 1364, 1321, 1223, 1096, 1044,
911, 878, 733; HRMS, exact mass calculated for C25H34N2O3S,
M + H required 443.2370, found 443.2383. Anal. (C25H34
N2O3S) C, H, N, S.
-
1-(Allyloxy)n a p h th a len e (34). A solution of 1-naphthol
(11.00 g, 76.29 mmol), allyl bromide (6.60 mL, 76.29 mmol),
and K2CO3 (13.70 g, 99.18 mmol) in 100 mL of acetone was
heated for 12 h at reflux. The mixture was filtered through
Celite and concentrated to give 13.70 g (98% yield) of 34 as a
colorless oil: 1H NMR (CDCl3) δ 8.21 (1H, m), 7.81 (1H, m),
7.46 (3H, m), 7.23 (1H, m), 6.12 (1H, m), 5.56 (1H, s), 5.30
(2H, m), 3.58 (2H, t, J ) 5.8 Hz).
2-Allyln a p h th a len -1-ol (35). The allyl ether 34 (10.00 g
crude, 54.28 mmol) was added to 75 mL of dimethylaniline
and refluxed for 4 h. The mixture was poured into 150 mL of
water and extracted with diethyl ether. The organic layer was
washed with 3 N HCl, dried over MgSO4, and concentrated to
the red oil 35 (9.40 g, 94% yield): 1H NMR (CDCl3) δ 8.32 (1H,