1444 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 5
Ma et al.
2.648 (dd, 1H, J ) 11.1 Hz, 16.5 Hz, 9-He), 2.562 (dd, 1H, J )
4.2 Hz, 16.5 Hz, 9-Ha), 1.552 (sex, 2H, J ) 7.5 Hz, 7.2 Hz,
4-CH2CH2CH3), 1.385 (d, 3H, J ) 6.0 Hz, 8-CH3), 0.924 (t, 3H, J
) 7.2 Hz, 4-CH2CH2CH3). ESI-MS (m/z): 289.1 [M + H]+ (calcd
MW ) 288.30). 112: 1H NMR (300 MHz, DMSO-d6, ppm): 13.900
(s, 1H, OH), 6.450 (s, 1H, 10-H), 6.042 (s, 1H, 3-H), 4.753 (m,
1H, 8-H), 2.971 (dd, 1H, J ) 12.3 Hz, 17.4 Hz, 7-He), 2.875 (t,
2H, J ) 7.5 Hz, 4-CH2CH2CH3), 2.793 (dd, 1H, J ) 3.0 Hz, 17.4
Hz, 7-Ha), 1.584 (sex, 2H, J ) 7.5 Hz, 7.2 Hz, 4-CH2CH2CH3),
1.437 (d, 3H, J ) 6.3 Hz, 8-CH3), 0.948 (t, 3H, J ) 7.2 Hz,
4-CH2CH2CH3). ESI-MS (m/z): 289.1 [M + H]+ (calcd MW )
288.30).
under reduced pressure. The residue was redissolved again in ethyl
acetate. The excess TBAF was then washed off with water. The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. The residue was purified to yield 266 mg of
1
compound 19 in 75% (yellow powder) with mp 204–206 °C. H
NMR (300 MHz, DMSO-d6): 10.901 (s, 1H, 7-OH), 10.634 (s, 1H,
5-OH), 6.766 (s, 1H, 3-H), 6.358 (d, 1H, J ) 2.4 Hz, 8-H), 6.344
(d, 1H, J ) 2.4 Hz, 6-H), 2.826 (t, 2H, J ) 7.5 Hz, 9-CH2), 1.578
(sex, 2H, J ) 7.5 Hz, 7.2 Hz, 10-CH2), 0.932 (t, 3H, J ) 7.2 Hz,
11-CH3). ESI-MS (m/z): 237.1 [M + H]+ (calcd MW ) 236.29).
Anal. Calcd for C12H12O3S: C, 61.00; H, 5.12. Found: C, 60.84;
H, 5.14.
With this method, compounds 20, 46–72, 95–109, and 113 were
prepared, respectively.
With this method, compound 187 was also prepared.
Ethyl 2-chloro-3-oxohexanoate (25) was prepared according to
1,1-Diethoxy-3-methyl-2-butene (11) was prepared as previously
described.15,16 Compounds 125–132 were prepared by the same
method.
ref 31 as a light yellow liquid with a yield of 90%.
2,2-Dimethyl-1,3-dioxane-4,6-dione (28) was prepared according
to ref 32 as a white needle crystal with a yield of 62%.
2,2-Dimethyl-5-(4,4,4-trifluorobutanoyl)-1,3-dioxane-4,6-di-
one (29). Compound 28 (288 mg, 2 mmol) and 4,4,4-trifluorobu-
tanoic acid (284 mg, 2 mmol) were dissolved in 5 mL of THF.
EDC ·HCl (340 mg, 2.2 mmol) was then added to the mixture. The
reactants were reacted at room temperature for 5 h. The solvent
was removed through evaporation. The residue was dissolved with
20 mL of ethyl acetate and then washed with 1 M HCl solution (3
× 15 mL). The organic layer was dried with anhydrous Na2SO4.
The solvent was removed, and the residue was then ready for the
next synthesis.
Methyl 6,6,6-Trifluoro-3-oxohexanoate (30). The residue of 29
was dissolved in 10 mL of methanol, and 4-methylbenzenesulfonic
acid in catalytical amount was added. The mixture was reflux for
4 h and then concentrated through evaporation. The residue was
ready for the next synthesis.
6,6,10-Trimethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyr-
ano[2,3-f:2′,3′-h]chromene-2,12-dione (15). To the compound 16
(14 mg, 0.05 mmol) and 11 (0.2 mmol) in a microwave reaction
tube was added 2 mL of toluene and 2 drops of pyridine. The
reaction was continued for 20 min under the conditions of 150 W
and 140 °C. The reactants were purified by silica gel chromography
to gain compound 15 as an off-white powder with mp 114–116
1
°C. The yield was 86%. H NMR (300 MHz, DMSO-d6, ppm):
6.566 (d, 1H, J ) 9.9 Hz, 8-H), 6.086 (s, 1H, 3-H), 5.774 (d, 1H,
J ) 9.9 Hz, 7-H), 4.707 (m, 1H, J ) 6.3 Hz, 12.0 Hz, 3.9 Hz,
10-H), 2.837 (t, 2H, J ) 7.5 Hz, 4-CH2CH2CH3), 2.708 (dd, 1H, J
) 12.0 Hz, 16.5 Hz, 11-He), 2.606 (dd, 1H, J ) 3.9 Hz, 16.5 Hz,
11-Ha), 1.537 (sex, 2H, J ) 7.5 Hz, 7.2 Hz, 4-CH2CH2CH3), 1.488,
1.450 (2s, 6H, CH3), 1.439 (d, 3H, J ) 6.3 Hz, 10-CH3), 0.963 (t,
3H, J ) 7.2 Hz, 4-CH2CH2CH3). ESI-MS (m/z): 355.1 [M + H]+
(calcd MW ) 354.41).
5-Hydroxy-8-methyl-4-(piperazin-1-ylmethyl)-8,9-dihydro-
2H,10H-pyrano[2,3-f]chromene-2,10-dione (73). Compound 52
(0.05 mmol) was dissolved in 10 mL of THF, and 2 mL of
piperazine was added to the solution. The reaction mixture was
refluxed for 4 h and then purified by column chromatography.
Compound 73 was obtained as a light yellow powder with mp
256–258 °C. The yield was 68%. 1H NMR (400 MHz, DMSO-d6,
ppm): 12.820 (s, 1H, 5-OH), 9.520 (s, 1H, NH), 7.652 (s, 1H, 6-H),
6.643 (s, 1H, 3-H), 4.605 (m, 1H, J ) 6.0 Hz, 12.4 Hz, 2.4 Hz,
8-H), 3.810 (m, 4H, CH2), 3.121 (s, 2H, 4-CH2), 3.029 (m, 4H,
CH2), 2.869 (dd, 1H, J ) 12.4 Hz, 17.2 Hz, 9-He), 2.709 (dd, 1H,
J ) 2.4 Hz, 17.2 Hz, 9-Ha), 1.409 (d, 3H, J ) 6.0 Hz, 8-CH3).
ESI-MS (m/z): 345.2 [M + H]+ (calcd MW ) 344.37). HRESIMS
With this method, compounds 23, 76–91, 114–124, 133–183,
and 186 were prepared, respectively.
2-Oxo-4-propyl-2H-chromene-5,7-diyl Bis(4-methylbenzene-
sulfonate) (17). Compound 7 (5 mmol) was dissolved in pyridine
and cooled down in an ice bath. p-Methylbenzenesulfonyl chloride
(6 equiv) was then added with stirring. The reaction was continued
at room temperature overnight. The reactants were poured into
ice–water under strong stirring. The precipitate was filtered and
washed with water. After completely drying, a white solid (17)
was obtained as 2.45 g, yield 93%, mp 239–241 °C. 1H NMR (300
MHz, DMSO-d6): 7.762 (m, 4H, Ar-H), 7.499 (m, 4H, Ar-H), 7.150
(d, 1H, J ) 2.4 Hz, 8-H), 6.781 (d, 1H, J ) 2.4 Hz, 6-H), 6.322 (s,
1H, 3-H), 2.691 (t, 2H, J ) 7.5 Hz, 9-CH2), 2.429, 2.408 (2s, 6H,
14, 17-CH3), 1.413 (sex, 2H, J ) 7.5 Hz, 7.2 Hz, 10-CH2), 0.792
(t, 3H, J ) 7.2 Hz, 11-CH3). ESI-MS (m/z): 529.1 [M + H]+ (calcd
MW ) 528.60). IR (KBr) cm-1: 3087, 2962, 2877, 1743, 1612,
1421, 1379, 1194.
+
obsd m/z 345.1454, calcd for C18H21N2O5 345.1450.
With this method, compounds 74, 75, 92, and 93 were prepared,
respectively.
4-(4-Aminophenyl)-6,6,10-trimethyl-10,11-dihydro-2H,6H,12H-
dipyrano[2,3-f:2′,3′-h]chromene-2,12-dione (94). To a solution
of compound 86 (0.02 mmol) in a sufficient volume of ethanol
was added 5 equiv of 38% HCl and 15 equiv of SnCl2 ·2H2O. After
refluxing for 2 h, the reactants were poured into a 40% NaOH
solution under stirring. The product was extracted with DCM (3 ×
20 mL) and purificed by silica gel chromography to gain 5.1 mg
of the final product (white powder, mp 149–151 °C). The yield
With this method, compound 21 was also prepared.
4-Propyl-2-thioxo-2H-chromene-5,7-diyl Bis(4-methylben-
zenesulfonate) (18). Compound 17 (3 mmol) was dissolved in
xylene, and 5 equiv of P2S5 was added. The reaction was continued
for 4 h at room temperature. The excess P2S5 was then filtered off.
The filtrate was concentrated under reduced pressure. The residue
was finally purified by silica gel chromatography to attain 1.14 g
of compound 18 with mp 198–201 °C. The yield is 70%. 1H NMR
(300 MHz, DMSO-d6): 7.768 (dd, 4H, J ) 8.4 Hz, 6.9 Hz, Ar-H),
7.496 (dd, 4H, J ) 8.1 Hz, 6.6 Hz, Ar-H), 7.345 (d, 1H, J ) 2.7
Hz, 8-H), 7.082 (s, 1H, 3-H), 6.859 (d, 1H, J ) 2.4 Hz, 6-H), 2.637
(t, 2H, J ) 7.5 Hz, 9-CH2), 2.426, 2.403 (2s, 6H, 14, 17-CH3),
1.403 (sex, 2H, J ) 7.5 Hz, 7.2 Hz, 10-CH2), 0.785 (t, 3H, J ) 7.2
Hz, 11-CH3). ESI-MS (m/z): 545.1 [M + H]+ (calcd MW )
544.67). IR (KBr) cm-1: 3087, 2974, 2881, 1614, 1597, 1385, 1144.
Anal. Calcd for C26H24O7S3 ·0.5H2O: C, 56.40; H, 4.55. Found: C,
56.52; H, 4.40.
1
was 63%. H NMR (400 MHz, DMSO-d6): 7.089 (m, 2H, 4-Ar-
H), 6.492 (m, 2H, 4-Ar-H), 6.477 (d, 1H, J ) 10.0 Hz, 8-H), 6.275
(d, 1H, J ) 8.4 Hz, 3-H), 5.577 (d, 1H, J ) 10.0 Hz, 7-H), 5.495
(d, 2H, J ) 6.0 Hz, NH2), 4.647 (m, 1H, J ) 6.0 Hz, 3.2 Hz, 12.4
Hz, 10-H), 2.840 (dd, 1H, J ) 12.4 Hz, 15.6 Hz, 11-He), 2.677
(dd, 1H, J ) 3.2 Hz, 15.6 Hz, 11-Ha), 1.453 (d, 3H, J ) 6.0 Hz,
10-CH3), 1.273, 1.224 (2s, 6H, 6-CH3). ESI-MS (m/z): 404.1 [M
+ H]+ (MW ) 403.44). HRESIMS obsd m/z 404.1495, calcd for
+
C24H22NO5 404.1498.
With this method, compound 184 was also prepared.
5-Hydroxy-4-propyl-9,10-dihydro-2H,8H-pyrano[2,3-
f]chromene-2,8-dione (110). To the mixture of compound 7 (0.2
mmol) and acrylic acid (0.2 mmol) was added 5 mL of CF3SO3H.
After the reaction was continued for 4 h at 60 °C, the reactants
were poured into ice–water under stirring. The crude was then
With this method, compound 22 was also prepared.
5,7-Dihydroxy-4-propyl-2H-chromene-2-thione (19). Com-
pound 18 (1.5 mmol) was dissolved in THF, and 3 equiv of TBAF
was added. The reaction was refluxed for 10 h and then concentrated