634
O. Bruno et al. / Bioorg. Med. Chem. 9 (2001) 629±636
Mp=127±129ꢀC. Anal. calcd for C18H17 NO2: C, 77.40;
H, 6.13; N, 5.01. Found: C, 77.41; H, 6.16; N, 4.97.
(2 mL). The freshly distilled relevant amine (5 mL) in
dry toluene (5 mL) was then added and the coloured
resulting mixture (orange with primary and green with
secondary amines) was treated with 9 (2.15 g, 10 mmol)
and a further excess of the same amine (3 mL) in dry
toluene (10 mL).
Preparation of 5-hydroxy-2-methylthio-5H-[1]benzopyr-
ano[4,3-d]pyrimidine (9) and (2-hydroxyphenyl)-(2-methyl-
thio-pyrimidin-5-yl)-methanone (10)
Method A. S-Methylisothiourea sulfate (1.39 g, 5 mmol)
was added to a suspension of chromone-3-carbaldehyde 8
(1.74 g, 10 mmol) in 1 M NaOH (10 mL), followed by H2O
(20 mL) and triethylamine (0,5 mL). The reaction mixture
was heated under stirring for 3 h at 70±80ꢀC. After cooling
the 5-hydroxy-2-methylthio-5H-[1] benzopyrano[4,3-d]
pyrimidine 9 precipitated as a rose-white solid which was
®ltered and recrystallized by ethanol (yield: 2.13 g, 87%).
After re¯uxing for 6 h, the orange-yellow suspension
was cooled and then concentrated ammonia solution
(3 mL), isopropanol (2 mL) and Kieselgur (2 g) were
added in succession by stirring.
The resulting slurry was ®ltered and washed with tolu-
ene. The organic phase was washed once with little water,
dried (MgSO4), concentrated under reduced pressure
and chromatographed on Florisil (100±200 mesh).
Finally the solvent was evaporated under reduced pres-
sure and the yellow oil so obtained was crystallized from
absolute ethanol. Compound 4d is an oil which do not
crystallize, so the puri®cation was achieved by distillation
in vacuo.
The basic mother-waters were acidi®ed to pH 5±6 with
1 M HCl and extracted twice with CHCl3. The organic
phases were dried (MgSO4) and concentrated under
reduced pressure to give a yellow oil which crystallized,
with ether:petroleum ether (1:1) (5 mL), as a yellow
solid corresponding to (2-hydroxyphenyl)-(2-methyl-
thio-pyrimidin-5-yl)-methanone 10 (yield: 0.25 g, 10%).
Compounds 4d and 4e have been converted into their
corresponding hydrochlorides with a saturated hydro-
gen chloride ethereal solution. When these salts have
been heated for recrystallization in absolute ethanol at
70±80 ꢀC both were converted into the same 5-ethoxy-2-
methylthio-5H-[1]benzopyrano[4,3-d]pyrimidine 14: white
crystals, mp=96±97 ꢀC. 1H NMR, d (CDCl3):1.20 (t,
J=6.6, 3H, CH3), 2.66 (s, 3H, SCH3), 3.85 (q, J=6.6,
2H, CH2), 6.17 (s, 1H, H5), 7.00±7.70 (m, 3H,
H7+H8+H9), 8.20±8.55 (m, 2H, H10+H4). Anal. calcd
for C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21. Found:
C, 61.12 ; H, 5.05; N, 10.42.
Method B. S-methylisothiourea sulfate (1.39 g, 5 mmol)
was added to a solution of sodium ethoxide obtained by
dissolving sodium (0.23 g, 10 mmol) in dry ethanol; after
stirring at room temperature for 10 min. the white solid
obtained (Na2SO4) was removed by ®ltration and chro-
mone-3-carbaldehyde 8 (1.74 g, 10 mmol) was added to
the ethanolic solution. The mixture was re¯uxed for 6 h,
then the solvent was evaporated under reduced pressure
to give a orange-red solid as a mixture of compounds 9
and 10 (TLC: Kieselgel, CHCl3:CH3OH 9.5:0.5) The
solid was dissolved in CHCl3 and the organic phase was
washed twice with 1 M NaOH (10 mL), dried (MgSO4)
and evaporated under reduced pressure to give a solid
corresponding to the sole 9 which was recrystallized by
ethanol (yield: 1.25 g, 51%). The basic solution was
acidi®ed (pH=5±6) with 1 M HCl and extracted twice
with CHCl3 (10 mL). The organic phase was dried
(MgSO4) and evaporated under reduced pressure to give
a yellow solid, recrystallized by ethanol, equivalent to
the compound 10 (yield: 0.85 g, 35%).
4a. Yield: 82%. Mp=93 ꢀC (from absolute ethanol). 1H
NMR, d (CDCl3): 0.90±1.35 (m, 6H, 2CH3), 2.13 (br s,
1H, NH, disappears with D2O), 2.61 (s, 3H, S-CH3),
3.10±3.70 (m, 1H, CH-isop.), 6.03 (br s, 1H, H5, became s
after exchange with D2O), 6.90±7.70 and 8.10±8.50 (2m,
4H, Ar), 8.45 (s, 1H, H4). Anal. calcd for C15H17N3OS:
C, 62.69; H, 5.96; N, 14.62. Found: C, 62.80; H, 5.88; N,
14.67.
4b. Yield: 81%. Mp=117±118 ꢀC (from absolute etha-
9. Mp=196±197 ꢀC (lit: 196±198 ꢀC20). 1H NMR, d
(DMSO-d6): 2.67 (s, 3H, SCH3), 6.61 (s, 1H, H5), 7.05±
7.80 (m, 4H, H7+H8+H9+OH, 1H disappears with
D2O), 8.20±8.50 (m, 1H, H10), 8.74 (s, 1H, H4). IR,
cmÀ1 (CHCl3): 3000±3400 (OH).
nol). H NMR, d (CDCl3): 1.26 (s, 9H, 3CH3), 1.80±
1
2.16 (br s, 1H, NH, disappears with D2O), 2.63 (s, 3H,
S-CH3), 6.20 (br s, 1H, H5 became s after exchange with
D2O), 6.85±7.56 and 8.10±8.50 (2m, 4H, Ar), 8.41 (s,
1H, H4). Anal. calcd for C16H19N3OS: C, 63.76; H,
6.35; N, 13.94. Found: C, 63.52; H, 6.30; N, 13.83.
ꢀ
1
10. Mp=112±114 C. H NMR, d (CDCl3):2.67 (s, 3H,
SCH3), 6.80±7.30 and 7.45±7.85 (2m, 4H, Ar), 8.87 (s,
2H, pyrim.), 11,70 (s, 1H, OH, disappears with D2O).
IR, cmÀ1 (CHCl3): 3460±2760 (OH); 1617 (CO). Anal.
calcd for C12H10N2O2S: C, 58.58; H, 4.09; N, 11.37.
Found: C, 58.43; H, 3.95; N, 11.22.
4c. Yield: 69%. Mp=104±105ꢀC (from absolute etha-
1
nol). H NMR, d (CDCl3): 0.30±0.70 (m, 4H, 2CH2),
2.40±3.10 (m, 2H, CH-Cyclop.+NH, disappears with
D2O), 2.61 (s, 3H, S-CH3), 5.96 (s, 1H, H5), 6.90±7.60 and
8.15±8.48 (2m, 4H, Ar), 8.38 (s, 1H, H4). Anal. calcd for
C15H14N3OS: C, 63.36; H, 4.96; N, 14.78. Found: C,
63.07; H, 5.24; N, 14.62.
General procedure for N-substituted 2-methylthio-5H-[1]
benzopyrano[4,3-d]pyrimidin-5-amines (4a±f)
4d. Yield: 69%. Bp=190 ꢀC/0.1 mmHg. 1H NMR, d
(CDCl3): 1.60±1.95 (m, 4H, 2CH2), 2.63 (s, 3H, S-CH3),
2.60±3.20 (m, 4H, 2CH2N), 6.20 (s 1H, H5), 6.83±7.60
TiCl4 (1.20 mL, 11 mmol) was added by stirring to an
ice-cooled solution of dry toluene (40 mL) and anisole