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L. Costantino et al. / Bioorg. Med. Chem. 10 (2002) 3923–3931
(4-Hydroxyphenylthio)-benzoic and-acetic acids (2–7).
To a stirred mixture of the appropriate iodobenzoic or
iodophenylacetic acid (4.00 mmol) and 4-hydro-
xythiophenol (4.00 mmol) in water (30 mL), KOH was
added (8.00 mmol), and Cuꢁ (0.31 mmol). The reaction
mixture was then refluxed for 12 h, cooled, filtered
and the filtrate acidified. The precipitate thus formed
was collected, washed with water and purified as
described.
reaction mixture was extracted with EtOAc (3 ꢂ 25
mL), the organic layer was dried (Na2SO4) and the sol-
vent removed under reduced pressure. The residue thus
obtained was purified as described.
4-(20-Nitro-40-hydroxyphenylmercapto)phenol (11). This
compound was prepared as described above, starting
from 4-(20-nitro-40-acetoxyphenylmercapto)phenol, which
in turn was prepared from 4-chloro-3-nitrophenol 14a,
following standard procedures. Purification by means of
column chromatography (CH2Cl2/CH3OH 97.5/2.5,
then cyclohexane/EtOAc 60/40). Yield 6%; mp 178–
181 ꢁC (diethyl ether/petroleum ether); 1H NMR: d
10.35 (1H, s), 10.00 (1H, s), 7.55 (1H, d, J 2.00), 7.38
(2H, m), 7.06 (1H, dd, J 2.00, J 8.28), 6.90 (2H, m), 6.75
(1H, d, J 2.00). Anal. calcd for C12H9NO4S: C 54.75; H,
3.45; N, 5.32; found: C, 54.96, H, 3.36; N, 5.20.
3-(40-Hydroxyphenylmercapto)benzoic acid (2). Yield
86%; mp 174–175 ꢁC (EtOAc/petroleum ether); 1H
NMR: d 12.95 (1H, s), 9.90 (1H, s), 7.70 (1H, m), 7.59
(1H, m), 7.38(4H, m), 6.8(2H, m). Anal. calcd for
C13H10O3S: C 63.40; H, 4.09; found: C, 63.01, H, 4.15.
3-(40-Hydroxyphenylmercapto)phenylacetic acid (3).
Yield 58%; mp 150–152 ꢁC (EtOAc/petroleum ether);
1H NMR: d 11.00 (2H, broad s), 7.35 (2H, m), 7.20 (1H,
m), 7.06 (2H, m), 6.96 (1H, m), 6.84 (2H, m), 3.50 (2H,
s). Anal. calcd for C14H12O3S: C 64.60; H, 4.65; found:
C, 64.32, H, 4.78.
Ethyl 3-nitro-4-(40-hydroxyphenylmercapto)benzoate (12).
Purification by means of column chromatography
(CH2Cl2/CH3OH 95/5). Yield 60%; mp 148–150 ꢁC (di-
1
ethyl ether/petroleum ether); H NMR (CDCl3): d 8.86
(1H, d, J 1.83), 7.95 (1H, dd, J 8.60, J 1.83), 7.45 (2H, m),
7.05 (2H, m), 6.95 (1H, d, J 8.78), 6.11 (1H, broad s), 4.45
(2H, q), 1.43 (3H, t). Anal. calcd for C15H13NO5S: C
56.42; H, 4.10; N, 4.39; found: C, 56.20, H, 4.18; N, 4.48.
2-(40-Hydroxyphenylmercapto)benzoic acid (4). Yield
80%; mp 238–240 ꢁC (acetone/petroleum ether) (193 ꢁC
ref. 18); IR (nujol) (cmꢀ1): 3622, 3356, 2649, 2360, 1673;
1H NMR: d 13.12 (1H, s), 9.99 (1H, s), 7.96 (1H, d, J
7.56), 7.36 (3H, m), 7.13 (1H, t), 6.92 (2H, m), 6.64 (1H,
d, J 8.00). Anal. calcd for C13H10O3S: C 63.40; H, 4.09;
found: C, 63.06, H, 4.15.
4-(40-Carboxamide-20-nitrophenylmercapto)phenol (13).
ꢁ
1
Yield 10%; mp 250–252 C; H NMR: d32;10.16 (1H,
s), 8.72 (1H, d, J 2.03), 8.15 (1H, s), 7.98 (1H, dd, J 2.00,
J 8.78), 7.55 (1H, s), 7.45 (2H, m), 6.95 (2H, m), 6.85 (1H,
d, J 8.60). Anal. calcd for C13H10N2O4S: C 53.79; H, 3.47;
N, 9.65; found: C, 53.70, H, 3.55; N, 9.60.
2-(40-Hydroxyphenylmercapto)phenylacetic acid (5).
Yield 67%; mp 172–173 ꢁC (acetone/petroleum ether);
1H NMR: d 12.00 (1H, s), 9.50 (1H, s), 7.23 (5H, m),
7.00 (1H, m), 6.81 (2H, m), 3.78 (2H, s). Anal. calcd for
C14H12O3S: C 64.60; H, 4.65; found: C, 64.51, H, 4.68.
4-(40-Amino-20-nitrophenylmercapto)phenol (14). Yield
ꢁ
1
5%; mp 172–175 C; H NMR: d 9.88 (1H, broad s),
7.30 (3H, m), 6.85 (2H, m), 6.78 (1H, d, J 2.56), 6.68
(1H, d, J 8.60), 5.73 (2H, s). Anal. calcd for
C12H10N2O3S: C 54.95; H, 3.84; N, 10.68; found: C,
54.59, H, 3.90; N, 10.88.
4-(40-Hydroxyphenylmercapto)benzoic acid (6). Yield
75%; mp 192–194 ꢁC (diethyl ether/petroleum ether); IR
(cmꢀ1) (Nujol): 3328, 2677, 2565, 1684; 1H NMR: d 7.05
(2H, m), 6.60 (2H, m), 6.30 (2H, m), 6.12 (2H, m), 4.06
(2H, s). Anal. calcd for C13H10O3S: C 63.40; H, 4.09;
found: C, 63.36, H, 4.19.
3-Nitro-4-(40-hydroxyphenylmercapto)benzoic acid (15).
The ethyl 3-nitro-4-(40-hydroxyphenyl)benzoate 15
(0.10 g, 0.31 mmol) was treated with NaOH 2 N (3 mL)
and EtOH (3 mL) at rt with stirring. After 15 min the
solution thus obtained was acidified and the solid thus
formed was collected and washed with water. Yield
0.040 g (44%); mp 238–240 ꢁC (acetone/petroleum
4-(40-Hydroxyphenylmercapto)phenylacetic acid (7).
Yield 81%; mp 185–187 ꢁC (EtOAc/petroleum ether);
1H NMR: d 12.25 (1H, s), 9.80 (1H, s), 7.33 (2H, m),
7.18(2H, m), 7.06 (2H, m), 6.84 (2H, m), 3.60 (2H, m).
Anal. calcd for C14H12O3S: C 64.60; H, 4.65; found: C,
64.33, H, 4.78.
1
ether); H NMR: d 13.40 (1H, s), 10.05 (1H, s), 8.66
(1H, d, J 1.80), 8.04 (1H, dd, J 1.80, J 8.49), 7.45 (2H,
m), 6.95 (3H, m). Anal. calcd for C13H9NO5S: C 53.61;
H, 3.11; N, 4.81; found: C, 53.36, H, 3.20; N, 4.99.
4-(20-Nitrosubstitutedphenylmercapto)phenols
(11–14,
15–19 and 22, 23). To a stirred solution of the appro-
priate aryl halide 11a–14a, 15a–19a and 22a, 23a (chlo-
ride or bromide) (2.36 mmol) in EtOH (10 mL), a
solution of 4-hydroxythiophenol (7.93 mmol) in EtOH
(2 mL) was added, followed by K2CO3 (7.93 mmol).
The reaction mixture was then refluxed for 6 h, (in the
case of 2,4-dinitro-1-(40-hydroxyphenylthio)naphthalene
22 the reaction was performed at 0 ꢁC for 30 min, in the
case of 7-nitro-6-(40-hydroxyphenylmercapto)quinox-
aline 23 at 40 ꢁC for 1 h), then cooled. Water was added;
the pH was brought to 6.00 with HCl 1 N. Then the
4-(30-Methyl-20-nitrophenylmercapto)phenol (16). Pur-
ification by means of column chromatography (CH2Cl2/
CH3OH 97.5/2.5 then cyclohexane/EtOAc 75/25). Yield
5%; 1H NMR (CDCl3): d7.44 (2H, m), 7.20 (1H, t), 7.10
(1H, d), 6.94 (1H, d), 6.88 (2H, m), 5.33 (1H, s), 2.40
(3H, s). Anal. calcd for C13H11NO3S: C 59.76; H, 4.24;
N, 5.36; found: C, 59.98, H, 4.21; N, 5.30.
4-(40-Methyl-20-nitrophenylmercapto)phenol (17). Pur-
ification by means of column chromatography