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O. Tabarrini et al. / Bioorg. Med. Chem. 9 (2001) 2921–2928
5-Amino-3,4-dihydro-1H-thiopyran[3,4-b]quinoline-4-ol
(5ag). A solution of LiAlH4 in Et2O (1.8 mL of 1.0 M,
1.8 mmol) was added dropwise to a solution of thio-
pyranoquinolinones 4ag (0.4 g, 1.8 mmol) in dry THF
(20 mL) maintained at 0 ꢀC. After 1 h at room tem-
perature, the reaction was quenched by adding 10%
HCl, then made basic with 30% NaOH and extracted
with EtOAc. The combined organic layers were dried
and evaporated to dryness giving a residue which was
purified by column chromatography eluting with
CH2Cl2/MeOH (9:1) to give 0.376 g (90%) of 5ag: mp
m), 4.90–5.05 (1H, m), 5.40 (1H, d, J=8 Hz), ), 6.84
(2H, bs), 7.40 (1H, dd, J=1.4 and 7.8 Hz), 7.69(1H, d,
J=1.4 Hz), 8.30 (1H, d, J=7.8 Hz). Anal. calcd for
C12H11ClN2OS: C, 54.03; H, 4.16; N, 10.50. Found: C,
54.30; H, 4.25; N, 10.50.
1
5dg. H NMR (DMSO-d6) d 2.95 (1H, dd, J=5 and
13.5 Hz), 3.10 (1H, dd, J=4 and 13.5 Hz), 3.65–3.92
(2H, m), 5.48 (1H, d, J=7.8 Hz), 6.80 (2H, bs), 7.55
(1H, dd, J=2 and 8 Hz), 7.68 (1H, d, J=8 Hz), 8.35
(1H, J=2 Hz). Anal. calcd for C12H11ClN2OS: C, 54.03;
H, 4.16; N, 10.50. Found: C, 54.27; H, 4.40; N, 10.35.
204–205 ꢀC; H NMR (DMSO-d6) d 2.90–3.25 (2H, m),
1
3.70–4.00 (2H, m), 4.95–5.10 (1H, m), 5.50 (1H, bs),
6.60–6.90 (2H, s), 7.30–7.45 (1H, m), 7.50–7.80 (2H, m),
8.15–8.30 (1H, m). 13C NMR (DMSO-d6) d 154.6,
150.9, 145.9, 129.1, 127.9, 123.4, 122.1, 118.0, 110.9,
63.1, 35.1, 33.7. Anal. calcd for C12H12N2OS: C, 62.05;
H, 5.21; N, 12.06. Found: C, 62.25; H, 5.15; N, 12.05.
1
5eg. H NMR (DMSO-d6) d 2.88–3.24 (2H, m), 3.80
(2H, s), 4.75–4.96 (1H, m), 5.58–5.78 (1H, m), 7.00 (2H,
s), 7.38 (1H, dd, J=1.5 and 8.2 Hz), 7.50 (1H, t, J=8.2
Hz), 7.65 (1H, dd, J=1.5 and 8.2 Hz). Anal. calcd for
C12H11ClN2OS: C, 54.03; H, 4.16; N, 10.50. Found: C,
54.10; H, 4.25; N, 10.43.
The other hydroxy compounds 5ah, 5bg, 5cg, 5dg, 5eg,
5fg, and 5ai, were prepared from the analogous thio-
pyranoquinolinones 4 in a similar fashion. Starting
from compound 4ah two diastereoisomers were
obtained. After column chromatography purification,
one of two diastereoisomers, referred to as 5ahI, was
obtained as pure compound in a small amount (15%),
together with a mixture (1:1) of both diastereoisomers
referred to as 5ah (50%).
1
5fg. H NMR (DMSO-d6) d 2.88–3.20 (2H, m), 3.90
(3H, s), 3.70–3.90 (2H, m), 4.90–5.05 (1H, m), 5.50 (1H,
bs), 6.78 (2H, bs), 7.25 (1H, dd, J=2.6 and 8.5 Hz),
7.54–7.70 (2H, m). Anal. calcd for C13H14N2O2S: C,
59.52; H, 5.38; N, 10.68. Found: C, 59.70; H, 5.40; N,
10.42.
1
5aiI. H NMR (DMSO-d6) d 2.86–3.05 (1H, m), 3.15–
3.35 (2H, m), 3.72 (1H, AB system), 4.04 (1H, AB sys-
tem), 4.65–4.78 (1H, m), 5.00 (1H, d, J=7 Hz), 6.40
(2H, s), 7.16–7.40 (6H, m), 7.56 (1H, dt, J=1.4 and 7.8
Hz), 7.70 (1H, dd, 1.4 and 7.8 Hz), 8.12 (1H, dd, 1.4 and
7.8 Hz). Anal. calcd for C19H18N2OS: C, 70.78; H, 5.63;
N, 8.69. Found: C, 70.90; H, 5.75; N, 8.68.
The reduction of ketone 4ai only gave one diastereo-
isomer, 5aiI.
The physical properties of the target thiopyrano-
quinolone-4-ols are summarized in Table 3, while their
spectral data are enumerated below.
5-Amino-4-hydroxy-3,4-dihydro-1H-thiopyran[3,4-b]quino-
line-2-one (6ag). 70% MCPBA (0.250 g, 1 mmol) was
added portionwise to a stirred solution of 5ag (0.232 g,
1 mmol) in MeOH (10 mL) maintained at 0 ꢀC. After 10
min a saturated solution of NaHCO3 was added and the
reaction mixture was extracted with EtOAc. The
organic layers were dried, evaporated to dryness and the
residue was purified by column chromatography eluting
with CH2Cl2/MeOH (9:1) to give 0.160 g (70%) of 6ag
5ah. 1H NMR (CDCl3/DMSO-d6) d 1.50 and 1.48 (each
3H, d, J=7.2 Hz), 3.30 (2H, bs) 3.10–3.28 (2H, m), 3.75,
3.80, 4.08, and 4.15 (each 1H, AB system), 4.60 (1H, d,
J=7 Hz), 4.65–4.72 (1H, m), 6.41 (2H, bs), 6.00 (2H,
bs), 7.82–7.96, 7.53–7.68, 7.73–7.84, and 8.00–8.12 (each
2H, m). Anal. calcd for C13H14N2OS: C, 63.39; H, 5.73;
N, 11.37. Found: C, 63.50; H, 6.00; N, 11.20.
5ahI. 1H NMR (CDCl3/DMSO-d6) d 1.48 (3H, d,
J=7.2 Hz), 3.18 (1H, dq, J=3 and 7.2 Hz), 3.75 (1H,
AB system), 4.15 (1H, AB system), 4.48 (1H, bs), 4.62–
4.72 (1H, m), 6.22 (2H, bs), 7.48 (1H, dt, J=1.5 and 7.8
Hz), 7.58 (1 H, dt, J=1.5 and 7.8 Hz), 7.75 (1H, dd,
J=1.5 and 7.8 Hz), 8.04 (1 H, dd, J=1.5 and 7.8 Hz).
Anal. calcd for C13H14N2OS: C, 63.39; H, 5.73; N,
11.37. Found: C, 63.42; H, 5.70; N, 11.35.
as a mixture of diastereoisomers: mp 244–247 ꢀC; H
1
NMR (DMSO-d6) d 2.80–3.40 (6H, m), 4.00–4.35 (4H,
m), 4.90 (2H, bs), 6.75 (4H, bs), 7.25–7.65 (4H, m),
7.76–7.80 (1H, m), 7.82–8.08 (2H, m), 8.18–8.30 (1H,
m). Anal. calcd for C12H12N2O2S: C, 58.05; H, 4.87; N,
11.28. Found: C, 58.15; H, 4.72; N, 11.20.
The other sulphoxide derivatives 6bg and 6cg were pre-
pared from the analogous sulfphur 5bg and 5cg in a
similar fashion. Two diastereoisomers were separated
by column chromatography eluting with a gradient of
CH2Cl2/MeOH (98:2) to CH2Cl2/MeOH (90:10). Their
physical properties are reported in Table 3, while their
spectral data are enumerated below:
1
5bg. H NMR (DMSO-d6) d 2.95 (1H, dd, J=6 and 13
Hz), 3.12 (1 H, dd, J=5.5 and 13 Hz), 3.76 (1H, AB
system), 3.88 (1H, AB system), 4.90–5.05 (1H, m), 5.48
(1H, d, J=7 Hz), 6.84 (2H, bs), 7.32 (1H, t, J=7.5 Hz),
7.75 (1H, dd, J=1.5 and 7.5 Hz), 8.18 (1H, dd, J=1.5
and 7.5 Hz). Anal. calcd for C12H11ClN2OS: C, 54.03;
H, 4.16; N, 10.50. Found: C, 54.03; H, 4.30; N, 10.45.
6bgI (first eluted diastereoisomer). 1H NMR (DMSO-d6)
d 3.25–3.50 (2H, m), 4.20 (1H, AB system), 4.40 (1H,
AB system), 5.20–5.45 (1H, m), 5.60 (1H, m), 7.00 (2H,
bs), 7.40 (1H, dd, J=8.2 Hz), 7.55 (1H, t, J=8.2 Hz),
5cg. 1H NMR (DMSO-d6) d 2.90 (1H, dd, J=7.4 and 16
Hz), 3.10 (1H, dd, J=5.5 and 16 Hz), 3.70–3.90 (2H,