G. Roma et al. / Bioorg. Med. Chem. 11 (2003) 123–138
135
removed in vacuo and the residue subjected to column
chromatography on an aluminium oxide column, eluting
with dichloromethane. The eluate collected, evaporated
to dryness in vacuo, afforded the pure compound 28
(0.64 g, 88%); yellow crystals, mp 186–187 ꢂC (ethyl
acetate). 1H NMR (CDCl3) d 4.06 (s, 3H, OCH3),
6.80 (s, 1H, H-3), 7.23–8.10 (m, 4H, H-6,7,8,9), 7.80
(s, 1H, H-10), 8.31 (s, 1H, H-5). IR (KBr) 1631, 1611,
1588, 1548, 1105 s (CS) cmꢀ1. Anal. (C14H10O2S) C,
H, S.
Compound 4a. Whitish crystals, mp 197–199 ꢂC dec.
(ethyl acetate). H NMR (CDCl3) d 1.83 (s, 1H, NH;
disappeared with D2O), 2.99 (m, 4H, CH2NHCH2),
3.59 (m, 4H, CH2NCH2), 5.52 (s, 1H, H-3), 7.20–8.20
(m, 4H, H-6,7,8,9), 7.71 (s, 1H, H-10), 8.73 (s, 1H, H-5).
IR (KBr) 3290 w (NH), 1643, 1596 s, br (CO), 1564 s,
1502w cm ꢀ1. Anal. (C17H16N2O2) C, H, N.
1
Compound 4b. Whitish crystals, mp 234–235 ꢂC dec.
(dichloromethane/ethyl acetate). 1H NMR (CDCl3) d
1.89 (s, 1H, NH; disappeared with D2O), 2.67 (s, 3H,
10-CH3), 3.01 (m, 4H, CH2NHCH2), 3.60 (m, 4H,
CH2NCH2), 5.51 (s, 1H, H-3), 7.24–7.72 (m, 2H, H-
7,8), 7.86–8.20 (m, 2H, H-6,9), 8.62 (s, 1H, H-5). IR
(KBr) 3285 w (NH), 1633 w, 1592 s, br (CO), 1560 s, br,
1502w cm ꢀ1. Anal. (C18H18N2O2) C, H, N.
4-Hydroxy-2H-naphtho[2,3-b]pyran-2-thione (29).
A
mixture of compound 28 (0.73 g, 3.0 mmol) and 15 g of
pyridine hydrochloride was heated at 230 ꢂC, under
nitrogen. The solution obtained was further stirred at
230 ꢂC for 5 min, then allowed to cool. The resulting
solid mixture was treated with water (50 mL) at room
temperature until the nearly pure compound 29 sepa-
rated out as amorphous solid which was recovered by
filtration, washed with water and dried (0.67 g, 98%);
yellow solid, mp 223–225 ꢂC. (tetrahydrofuran/petro-
4-Chloro-2H-naphtho[2,3-b]pyran-2-one (31a). A mix-
ture of compound 2521 (0.64 g, 3.0 mmol), triethylamine
(0.30 g, 3.0 mmol) and phosphorus oxychloride (3.0
mL) was heated at 130 ꢂC for 1 h, while stirring. The
dark solution obtained was poured onto ice-water and
the resulting mixture was stirred few min at room tem-
perature, then thoroughly extracted with dichloro-
methane. The combined extracts, after drying and
removal of solvent, afforded a thick oil which was
chromatographed on a silica gel column, eluting with
dichloromethane. The eluate collected, after evapora-
tion to dryness in vacuo, gave compound 31a (0.30 g,
43%); whitish crystals, mp 198–198.5 ꢂC (ethyl acetate).
1H NMR (CDCl3) d 6.66 (s, 1H, H-3), 7.56 and 7.66 (2
dd, 1H+1H, H-7,8), 7.74 (s, 1H, H-10), 7.90 and 8.00 (2
near d, 1H+1H, H-6,9), 8.36 (s, 1H, H-5). IR (CHCl3)
1750 sh, 1722 s (CO), 1631, 1609, 1567 w cmꢀ1. Anal.
(C13H7ClO2) C, H, Cl.
1
leum ether). H NMR (DMSO-d6) d 6.69 (s, 1H, H-3),
7.62and 7.68 (2dd, 1H+1H, H-7,8), 8.05 and 8.21 (2
near d, 1H+1H, H-6,9), 8.07 (s, 1H, H-10), 8.56 (s, 1H,
H-5); OH signal was not detectable. IR (KBr) 3100–
2400 s, br, complex (OH), 1634, 1609, 1593, 1552, 1536,
1088 s (CS) cmꢀ1. Anal. (C13H8O2S) C, H, S.
2-(Methylthio)-4H-naphtho[2,3-b]pyran-4-one (30a). A
mixture of 3.0 mmol (0.68 g) of thione 29, 0.70 g of
anhyd K2CO3, 1.0 mL of iodomethane and 50 mL of
dry acetone was stirred at reflux for 1 h. After cooling,
the solvent was removed in vacuo and the residue par-
titioned between water and dichloromethane. The
organic layer was collected and the aqueous one was
extracted twice with dichloromethane. From the com-
bined extracts, after removal of solvent, an oily residue
was obtained which was chromatographed on a silica
gel column eluting first with dichloromethane to remove
some impurities, then with the mixture dichloro-
methane–ethyl acetate (1:1). The eluate collected, eva-
porated to dryness in vacuo, afforded the pure 30a as a
pale-brown solid (0.55 g, 74%); whitish crystals, mp
Preparation of 4-(1-piperazinyl)-2H-naphtho[2,3-b]pyran-
2-one (8a) and 10-methyl-4-(1-piperazinyl)-2H-naphtho[2,3-
b]pyran-2-one (8b). A mixture of 1.5 mmol of the chloro
derivative 31a (0.35 g) or 31b14 (0.37 g), 15.0 mmol (1.29
g) of piperazine and 60 mL of ethanol was stirred at
room temperature for 2h. The solution obtained was
poured into water (200 mL) and the mixture exhaustively
extracted with chloroform. The extracts, after drying and
removal of solvents, afforded a solid residue which was
taken up in a little ethyl ether and filtered to yield com-
pound 8a (0.29 g, 69%) or 8b (0.29 g, 66%), respectively.
155–156 ꢂC (isopropyl ether with charcoal). H NMR
1
(CDCl3) d 2.59 (s, 3H, SCH3), 6.21 (s, 1H, H-3), 7.52
and 7.63 (2dd, 1H+1H, H-7,8), 7.86 (s, 1H, H-10), 7.91
and 8.04 (2near d, 1H+1H, H-6,9), 8.76 (s, 1H, H-5).
IR (CHCl3) 1650, 1627 s (CO), 1608, 1581 w, 1555, 1503
w cmꢀ1. Anal. (C14H10O2S) C, H, S.
Compound 8a. Whitish crystals, mp 170–172 ꢂC (ethyl
acetate). 1H NMR (CDCl3) d 2.54 (s, 1H, NH; dis-
appeared with D2O), 2.92–3.48 (m, 8H, piperazine
CH2’s), 5.79 (s, 1H, H-3), 7.29–8.10 (m, 4H, H-6,7,8,9),
7.74 (s, 1H, H-10), 8.18 (s, 1H, H-5). IR (KBr) 3250
Preparation
of
2-(1-piperazinyl)-4H-naphtho[2,3-
b]pyran-4-one (4a) and 10-methyl-2-(1-piperazinyl)-4H-
naphtho[2,3-b]pyran-4-one (4b). A mixture of 1.5 mmol of
the (methylthio) derivative 30a (0.37 g) or 30b14 (0.39 g),
15.0 mmol (1.29 g) of piperazine and 10 mL of ethylene
(NH), 1706 s,br (CO), 1636, 1610, 1588, 1558 cmꢀ1
Anal. (C17H16N2O2) C, H, N.
.
ꢂ
glycol was heated at 160 C for 1 h, with stirring. The
solution obtained was poured onto ice-water and the
resulting mixture was thoroughly extracted with
chloroform. The combined extracts, after drying and
removal of solvent, afforded a nearly solid residue
which was taken up in a little ethyl ether and filtered to
yield compound 4a (0.25 g, 59%) or 4b (0.33 g, 75%),
respectively.
Compound 8b. Whitish crystals, mp 192–193 ꢂC (ethyl
acetate). 1H NMR (CDCl3) d 1.77 (s, 1H, NH; dis-
appeared with D2O), 2.77 (s, 3H, 10-CH3), 3.00–3.48
(m, 8H, piperazine CH2’s), 5.82 (s, 1H, H-3), 7.22–8.24
(m, 4H, H-6,7,8,9), 8.04 (s, 1H, H-5). IR (KBr) 3330
(NH), 1700 s,br (CO), 1622, 1607, 1593 sh, 1563 cmꢀ1
Anal. (C18H18N2O2) C, H, N.
.