Analogues of Flavone-8-acetic Acid
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3667
7l: starting from 6a and isopropyl bromide, yield 37%; mp
CH-CH2-), 7.05 (broad, 1H, OH), 7.3-8.2 (m, 7H, aromatic).
Anal. (C19H16O3) C, H.
1
66-67 °C; H NMR δ 1.2 (d, J ) 6 Hz, 6H, 2 × CH3), 3.6 (m,
6f: yield 21%; mp 128-129 °C; 1H NMR δ 2.4 (s, 3H, CH3),
3.65 (m, 2H, CH2Ar), 5.1 (m, 2H, CH2dCH-), 6.0 (m, 1H,
CH2dCH-CH2-), 6.5 (broad, 1H, OH), 7.3-8.2 (m, 7H,
aromatic). Anal. (C19H16O3) C, H.
2H, CH2Ar), 4.65 (m, 1H, CH), 5.1 (m, 2H, CH2dCH-), 6.0
(m, 1H, CH2dCH-CH2), 7.35-8.25 (m, 8H, aromatic). Anal.
(C21H20O3) C, H.
7o: yield 80%; mp 133-134 °C; 1H NMR δ 2.6 (s, 3H, CH3),
4.05 (s, 3H, OCH3), 6.65-8.1 (m, 6H, aromatic). Anal.
(C15H12O3S) C, H.
6g: yield 10%; mp 103-105 °C; 1H NMR δ 3.8 (m, 2H, CH2-
Ar), 3.9 (s, 3H, OCH3), 5.15 (m, 2H, CH2dCH-), 6.1 (m, 1H,
CH2dCH-CH2-), 7.0-8.15 (m, 8H, OH and aromatic). Anal.
(C19H16O4) C, H.
2′-Hydr oxy-3′-allyl-2-m eth oxyacetoph en on e (12). A mix-
ture of 1118 (6.6 g, 0.04 mol), dry K2CO3 (5.5 g, 0.04 mol), and
allyl bromide (6.3 g, 0.05 mol) in acetone (40 mL) was refluxed
for 15 h and hot-filtered. The solution was washed with 2 N
NaOH and then with H2O, and the solvent was evaporated to
give 2′-allyloxy-2-methoxyacetophenone, which was heated to
250 °C for 4 h. The residue was then resuspended in ether
and extracted with 2 N NaOH. The aqueous layer was acidified
with HCl and extracted with ether, which was then evaporated
to dryness to give 12 as an oil (33%): 1H NMR δ 3.45 (m, 2H,
CH2Ar), 3.50 (s, 3H, OCH3), 3.70 (s, 2H, COCH2), 5.1 (m, 2H,
CH2dCH-), 6.0 (m, 1H, CH2dCH-CH2-), 6.80-7.60 (m, 3H,
aromatic), 12.10 (s, 1H, OH). Anal. (C12H14O3) C, H.
6h : yield 31%; mp 183-184 °C; 1H NMR δ 3.65 (m, 2H, CH2-
Ar), 3.9 (s, 3H, OCH3), 5.1 (m, 2H, CH2dCH-), 6.0 (m, 1H,
CH2dCH-CH2-), 6.5 (s, 1H, OH), 7.1-8.2 (m, 7H, aromatic).
Anal. (C19H16O4) C, H.
6i: yield 10%; mp 195-198 °C; 1H NMR δ 3.8 (m, 2H, CH2-
Ar), 5.15 (m, 2H, CH2dCH-), 6.1 (m, 1H, CH2dCH-CH2-),
7.05 (broad, 1H, OH), 7.35-8.25 (m, 7H, aromatic). Anal.
(C18H13ClO3) C, H.
6j: yield 15%; mp 120-122 °C; 1H NMR δ 3.7 (m, 2H, CH2-
Ar), 5.1 (m, 2H, CH2dCH-), 6.05 (m, 1H, CH2dCH-CH2-),
6.5 (broad, 1H, OH), 7.35-8.2 (m, 7H, aromatic). Anal. (C18H13
ClO3) C, H.
-
3-Met h oxy-8-a llyl-3′-t r iflu or om et h ylfla von e (7m ). A
mixture of 12 (2.75 g, 13.4 mmol), 3-trifluoromethylbenzoyl
chloride (6 g, 26.8 mmol, prepared by refluxing 6 g of the
corresponding acid with 60 mL of SOCl2 for 8 h and evaporat-
ing to dryness), and the sodium salt of 3-trifluoromethylbenzoic
acid (8.5 g, 40.1 mmol, prepared by stirring at room temper-
ature 10 g of the corresponding acid and 1.21 g of Na in EtOH)
was heated to 180-190 °C for 7 h. The solid was then
resuspended in H2O and extracted with CH2Cl2. The organic
layer was washed with H2O, dried, and evaporated. The
residue was purified by column chromatography (petroleum
ether/ethyl acetate 9:1) to give 0.5 g (10%) of 7m : mp 76-77
6o: yield 40%; mp 206-208 °C; 1H NMR δ 2.6 (s, 3H, CH3),
7.25-8.1 (m, 6H, aromatic). Anal. (C14H10O3S) C, H.
Gen er a l Meth od for th e P r ep a r a tion of 3-Alk oxy-8-
a lk ylfla von es (7a -l,o). A mixture of the appropriate 8-alkyl-
flavonol 6 (1.8 mmol), dry K2CO3 (1.8 mmol), and dimethyl
sulfate (1.8 mmol) or the selected alkyl halide (3.6 mmol) in
acetone (50 mL) was refluxed for 7-9 h and hot-filtered. The
solvent was evaporated, and the residue was crystallized from
EtOH.
7a : yield 95%; mp 99-100 °C; 1H NMR δ 3.75 (m, 2H, CH2-
Ar), 3.92 (s, 3H, OCH3), 5.15 (m, 2H, CH2dCH), 6.1 (m, 1H,
CH2dCH-CH2-), 7.35-8.15 (m, 8H, aromatic). Anal. (C19H16O3)
C, H.
1
°C; H NMR δ 3.70 (m, 2H, CH2Ar), 3.90 (s, 3H, OCH3), 5.05
(m, 2H, CH2dCH-), 6.0 (m, 1H, CH2dCH-CH2-), 7.25-8.45
(m, 7H, aromatic). Anal. (C20H15F3O3) C, H.
7b: yield 83%; mp 128-129 °C; 1H NMR δ 2.4 (s, 3H, CH3),
3.7 (m, 2H, CH2Ar), 3.9 (s, 3H, OCH3), 5.1 (m, 2H, CH2dCH-
), 6.05 (m, 1H, CH2dCH-CH2-), 7.3-8.1 (m, 7H, aromatic).
Anal. (C20H18O3) C, H.
3-Meth oxy-8-a llyl-3′-ch lor ofla von e (7n ). By use of the
same procedure and starting from 12 (1.6 g, 7.76 mmol),
3-chlorobenzoyl chloride (2.8 g, 16 mmol), and the sodium salt
of 3-chlorobenzoic acid (4.25 g, 23.8 mmol, prepared by stirring
at room temperature 5 g of the corresponding acid and 0.74 g
of Na in EtOH), 1.7 g (67%) of 7n was obtained: mp 109-112
7c: yield 90%; mp 169-171 °C; 1H NMR δ 2.5 (s, 3H, CH3),
3.85 (s, 3H, OCH3), 7.15-8.2 (m, 7H, aromatic). Anal. (C17H13
-
FO3) C, H.
1
7d : quantitative yield; mp 147-150 °C; H NMR δ 2.5 (s,
3H, CH3), 3.85 (s, 6H, OCH3), 7.0-8.2 (m, 7H, aromatic). Anal.
(C18H16O4) C, H.
1
°C; H NMR δ 3.70 (m, 2H, CH2Ar), 3.90 (s, 3H, OCH3), 5.20
(m, 2H, CH2dCH-), 6.10 (m, 1H, CH2dCH-CH2-), 7.25-8.20
(m, 7H, aromatic). Anal. (C19H15ClO3) C, H.
1
7e: yield 83%; mp 95-96 °C; H NMR δ 2.5 (s, 3H, CH3),
Gen er a l Meth od for th e P r ep a r a tion of Su bstitu ted
3-Alk oxyfla von e-8-a cetic Acid s (4a ,b,e-n ). Solid KMnO4
(0.1 mol) was added portionwise over 6 h to an ice-cold solution
of the allyl derivative (0.02 mol) in a mixture of acetic acid
(45 mL), acetone (90 mL), and water (35 mL). The mixture
was stirred at room temperature for another 1 h and poured
into water. The aqueous solution was then decolorated with
H2O2, extracted with CH2Cl2, and evaporated to dryness (or
the precipitate was filtered). The crude products were crystal-
lized from EtOH (see Table 1).
3.75 (m, 2H, CH2Ar), 3.9 (s, 3H, OCH3), 5.2 (m, 2H, CH2dCH-
), 6.05 (m, 1H, CH2dCH-CH2-), 7.35-8.2 (m, 7H, aromatic).
Anal. (C20H18O3) C, H.
7f: yield 50%; mp 82-85 °C; 1H NMR δ 2.4 (s, 3H, CH3), 3.6
(m, 2H, CH2Ar), 3.72 (s, 3H, OCH3), 5.1 (m, 2H, CH2dCH-),
6.0 (m, 1H, CH2dCH-CH2), 7.35-8.2 (m, 7H, aromatic). Anal.
(C20H18O3) C, H.
7g: quantitative yield; mp 76-78 °C; 1H NMR δ 3.7 (m, 2H,
CH2Ar), 3.9 (s, 6H, 2 × OCH3), 5.1 (m, 2H, CH2dCH-), 6.1
(m, 1H, CH2dCH-CH2-), 7.05-8.15 (m, 7H, aromatic). Anal.
(C20H18O4) C, H.
3,4′-Dim eth oxyfla von e-8-a cetic Acid (4d ). A mixture of
7d (3 g, 10 mmol), N-bromosuccinimide (7.6 g, 0.04 mol), and
a catalytic amount of benzoyl peroxide in CCl4 (300 mL) was
refluxed for 5 h and hot-filtered. The precipitate formed was
filtered and crystallized from EtOH to give the bromo deriva-
tive (2.6 g, 70%): mp 189-191 °C. To a solution of this
compound (1.8 g, 5 mmol) in EtOH (400 mL), KCN (0.4 g, 5.9
mmol) in water (10 mL) was added and the mixture was
refluxed for 20 h. Then the solvent was evaporated, and the
residue was resuspended in H2O and extracted with CH2Cl2.
The organic layer was dried and evaporated, and the residue
was crystallized from EtOH/H2O to give the corresponding
nitrile (1.1 g, 75%): mp 148-153 °C. The resulting compound
(1.1 g, 3 mmol) was then dissolved in a mixture of acetic acid
(4 mL), H2O (4 mL), and concentrated H2SO4 (4 mL), and the
mixture was refluxed for 2 h. H2O was then added, and a
precipitate was formed, which was filtered and resuspended
in aqueous NaHCO3. The solution was filtered and acidified
1
7h : quantitative yield; mp 104-105 °C; H NMR δ 3.6 (m,
2H, CH2Ar), 3.85 (s, 3H, OCH3), 3.9 (s, 3H, OCH3), 5.1 (m,
2H, CH2dCH-), 6.0 (m, 1H, CH2dCH-CH2-), 7.1-8.2 (m, 7H,
aromatic). Anal. (C20H18O4) C, H.
7i: yield 25%; mp 132-134 °C; 1H NMR δ 3.72 (m, 2H, CH2-
Ar), 3.9 (s, 3H, OCH3), 5.15 (m, 2H, CH2dCH-), 6.1 (m, 1H,
CH2dCH-CH2-), 7.35-8.2 (m, 7H, aromatic). Anal. (C19H15
-
ClO3) C, H.
7j: yield 71%; mp 96-98 °C; 1H NMR δ 3.6 (m, 2H, CH2Ar),
3.85 (s, 3H, OCH3), 5.1 (m, 2H, CH2dCH-), 6.0 (m, 1H, CH2d
CH-CH2-), 7.35-8.2 (m, 7H, aromatic). Anal. (C19H15ClO3)
C, H.
7k : starting from 6a and ethyl bromide, yield 36%; mp 88-
89 °C; 1H NMR δ 1.3 (t, J ) 7 Hz, 3H, CH3), 3.7 (m, 2H, CH2-
Ar), 4.15 (q, J ) 7 Hz, 2H, OCH2CH3), 5.1 (m, 2H, CH2dCH-
), 6.05 (m, 1H, CH2dCH-CH2-), 7.3-8.15 (m, 8H, aromatic).
Anal. (C20H18O3) C, H.