4-Pyridones as Potential Antimalarials
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 9 2849
NMR (200 MHz, CDCl3): δ 6.95–7.4 (m, 8H), 6.2 (s, 1H), 2.3 (s,
3H), 2.2 (s, 3H).
7.44–7.36 (m, 3H), 7.11 (d, 2H), 7.01–6.97 (m, 2H), 6.87 (t, 1H),
2.40 (s, 3H), 2.08 (s, 3H).
4a–l were prepared in a similar manner to 4h from the
appropriate ketones.
Bromo derivative 7p was prepared in a similar manner to 7o
from 5p.
3-(3-Bromophenyl)-2,6-dimethyl-4H-pyran-4-one (4m). A so-
lution of 1-(3-bromophenyl)-2-propanone (1g, 4.7 mmol) in acetic
anhydride (2.6 mL, 27.5 mmol) was added to a solution of Eaton’s
reagent (5 mL, 7.7 wt % P2O5 in methanesulfonic acid; Aldrich)
and acetic anhydride (2 mL, 27.5 mmol) and the mixture heated at
50 °C for 1 h. Water and diethyl ether were added, and the organic
phase was separated, dried (Na2SO4), and evaporated under reduced
pressure. Chromatography of the residue on silica gel (10:1 CH2Cl2/
MeOH eluant) gave 4m (640 mg, 49%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ 7.50–7.46 (m, 1H), 7.38 (t, 1H), 7.28 (t,
1H), 7.16 (dt, 1H), 6.21 (s, 1H), 2.29 (s, 3H), 2.18 (s, 3H).
4n was prepared in a similar manner to 4m from 1-(2-
bromophenyl)-2-propanone.
2,6-Dimethyl-3-{3-[4-(trifluoromethoxy)phenoxy]phenyl}-4H-
pyran-4-one (4o). A mixture of 4m (240 mg, 0.86 mmol), cesium
carbonate (560 mg, 1.72 mmol), 2,4-pentanedione (36 µL, 0.34
mmol), 4-(trifluoromethoxy)phenol (306 mg, 1.72 mmol), and CuCl
(43 mg, 0.43 mmol) in N-methylpyrrolidine (5 mL) was heated
under argon at 120 °C for 48 h. Diethyl ether was added and the
mixture filtered to remove a black residue. The filtrate was washed
with 1 M aqueous HCl, 1 M NaOH, and brine and concentrated
under reduced pressure. The residue was chromatographed on silica
gel (6:1 hexane/ethyl acetate eluant) to give 4o (82 mg, 25%) as a
colorless oil.
3-[4-(4-Chlorophenoxy)phenyl]-1-hydroxy-2,6-dimethylpyri-
din-4(1H)-one (8h). A mixture of the pyrone 4h (1.0 g, 3 mmol),
hydroxylamine hydrochloride (1.06 g, 15.2 mmol), sodium acetate
(1.25 g, 15.2 mmol), water (5 mL), and ethanol (10 mL) was heated
to reflux for 3 days. After the mixture was cooled to room
temperature, water (20 mL) was added and the precipitate collected
by filtration, washed with ethyl acetate, and recrystallized from
DMF to afford 8h (0.2 g, 22%) as white crystals, mp 232–236 °C.
1H NMR (200 MHz, DMSO-d6): δ 7.5–7.4 (d, J ) 8.0 Hz, 2H),
7.3–7.2 (d, J ) 8.0 Hz, 2H), 7.15–7.0 (m, 4H), 6.75 (s, 1H), 2.35
(s, 3H), 2.15 (s, 3H).
3-Bromo-5-[4-(4-chlorophenoxy)phenyl]-1-hydroxy-2,6-di-
methylpyridin-4(1H)-one (9h). To a stirred solution of the
pyridone 8h (0.5 g, 1.6 mmol) in acetic acid (10 mL) was added
dropwise a solution of bromine (0.08 mL, 1.6 mmol) in acetic acid
(1 mL). After 1.5 h a few drops of a saturated aqueous sodium
sulfite solution was added to discharge excess bromine. The mixture
was diluted with water and the precipitate filtered, washed with
water, dried, and recrystallized from DMF to afford 9h (0.32 g,
52%) as white crystals, mp 246–250 °C dec. 1H NMR (200 MHz,
DMSO-d6): δ 7.5–7.4 (d, J ) 8.0 Hz, 2H). 7.25–7.15 (d, J ) 8.0
Hz, 2H), 7.15–7.0 (m, 4H), 2.6 (s, 3H), 2.1 (s, 3H).
3-Iodo-2,6-dimethyl-5-{4-[4-(trifluoromethoxy)phenoxy]phenyl}-
pyridin-4(1H)-one (10l). To a stirred solution of the pyridone 5l
(0.775 g, 2.06 mmol) in glacial acetic acid (15 mL) at room
temperature was added portionwise N-iodosuccinimide (0.473 g,
2.1 mmol). After the mixture was stirred for 2 h, the precipitate
was filtered, washed with acetic acid and then acetonitrile, and dried
in vacuo to provide 10l (0.75 g, 73%) as a white powder. 1H NMR
(200 MHz, DMSO-d6): δ 11.61 (bs, 1H), 7.40 (m, 2H), 7.20 (m,
2H), 7.13 (m, 2H), 7.03 (m, 2H), 2.49 (m, 3H + DMSO-d6), 2.09
(s, 3H).
4p was prepared from 4n in a similar manner to 4o.
3-[4-(4-Chlorophenoxy)phenyl]-2,6-dimethylpyridin-4(1H)-
one (5h). The pyrone 4h (10 g, 30.6 mmol) was heated at 150 °C
with 30% aqueous ammonia (200 mL, ∼3 M) in an autoclave for
18 h. The precipitate was filtered off, washed with water, dried,
and recrystallized from DMF to afford 5h (6.6 g, 66%) as white
crystals, mp 271–273 °C. Rf (silica gel, 9:1 CHCl3/MeOH) ) 0.2.
1H NMR (200 MHz, DMSO-d6): δ 7.42 (m, 2H), 7.18 (m, 2H),
6.95–7.1 (m, 4H), 5.95 (s, 1H), 2.2 (s, 3H), 2.1 (s, 3H). Anal.
(C19H16ClNO2) C, H, N.
Iodo derivative 10k was prepared in a similar manner to 10l
from 5k.
5a-l,o,p were prepared in a similar manner to 5h from the
2,6-Dimethyl-3-{4-[4-(trifluoromethoxy)phenoxy]phenyl}-5-
(trifluoromethyl)pyridin-4(1H)-one (11l). A mixture of the iodo
derivative 10l (0.526 g, 1.04 mmol) and CuI (0.247 g, 1.3 mmol)
in dry DMF (10 mL) was stirred and heated to 70 °C, and
hexamethylphosphoramide (0.913 mL, 5.2 mmol) was added,
followed by methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.668
mL, 5.2 mmol; Aldrich). The mixture was stirred and heated for a
further 6 h and allowed to cool. Then 1 M aqueous NH4Cl was
added. The resulting precipitate was isolated by filtration, washed
with 30% aqueous ammonia and then water, dried in air, then
dissolved in acetone and the solution filtered through Celite and
concentrated. The residual pale-brown solid was dissolved in MeOH
and treated with activated charcoal; filtration, evaporation, and
trituration with ethyl acetate provided 11l (0.195 g, 41%) as a white
crystalline solid. 1H NMR (300 MHz, DMSO-d6): δ 11.42 (bs, 1H),
7.39 (m, 2H), 7.20 (m, 2H), 7.13 (m, 2H), 7.04 (m, 2H), 2.41 (q,
3H), 2.10 (s, 3H).
3-Methoxy-2,6-dimethyl-5-{4-[3-(trifluoromethyl)phenoxy]-
phenyl}pyridin-4(1H)-one (13k). To a solution of sodium meth-
oxide prepared from sodium (0.048 g, 2.1 mmol) and MeOH (1
mL) were added the iodo derivative 10k (0.266 g, 0.55 mmol) and
CuI (0.015 g, 0.08 mmol). The mixture was heated at 110 °C for
18 h and cooled, and 1 M aqueous NH4Cl was added. The resulting
precipitate was recovered by filtration, washed with water, and
subjected to chromatography on silica gel (75:1 to 20:1 CH2Cl2/
MeOH eluant) to afford 13k (0.088 g, 41%) as a white powder.
1H NMR (300 MHz, CD3OD): δ 7.54 (m, 1H), 7.39 (m, 1H),
7.30–7.24 (m, 4H), 7.10 (m, 2H), 3.78 (s, 3H), 2.36 (q, 3H), 2.16
(s, 3H). ESIMS m/z: 390 (MH+), 388 (MH-).
appropriate pyrones (4a-l,o,p).
3-Chloro-5-[4-(4-chlorophenoxy)phenyl]-2,6-dimethylpyridin-
4(1H)-one (6h). To a stirred solution of 5h (0.8g, 2.45 mmol) in
acetic acid (10 mL) was added N-chlorosuccinimide (0.39 g, 2.9
mmol). The mixture was heated at 100 °C for 30 min and cooled
to room temperature, and the precipitate was filtered and dried in
vacuo to afford 6h (0.33 g, 37%) as white crystals, mp 340–343
°C. Rf (silica gel, 9:1 CHCl3/MeOH) ) 0.36. 1H NMR (200 MHz,
DMSO-d6): δ 11.3 (br s, 1H), 7.42 (m, 2H), 7.2 (m, 2H), 6.95–7.12
(m, 4H), 2.4 (s, 3H), 2.1 (s, 3H). Anal. (C19H15Cl2NO2) C, H, N.
Choro derivatives 6a-l were prepared in a similar manner to
6h from the corresponding pyridones (5a-l).
3-Bromo-5-[4-(4-chlorophenoxy)phenyl]-2,6-dimethylpyridin-
4(1H)-one (7h). To a stirred solution of 5h (6.5 g, 20 mmol) in
acetic acid (50 mL) was added dropwise, over 30 min, a solution
of bromine (1.2 mL, 23.3 mmol) in acetic acid (10 mL). After 3 h
the mixture was poured into 1% aqueous sodium sulfite (250 mL)
and the precipitate filtered, washed with water, dried in air, and
recrystallized from DMF to afford 7h (6.6 g, 81.5%) as white
crystals, mp 306–308 °C. Rf (silica gel, 9:1 CHCl3/MeOH) ) 0.37.
1H NMR (200 MHz, DMSO-d6): δ 11.3 (br s, 1H), 7.42 (m, 2H),
7.2 (m, 2H), 6.95–7.12 (m, 4H), 2.42 (s, 3H), 2.1 (s, 3H). Anal.
(C19H15BrClNO2) C, H, N.
Bromo derivatives 7f-l were prepared in a similar manner to
7h from the corresponding pyridones (5f-l).
3-Bromo-2,6-dimethyl-5-{3-[4-(trifluoromethoxy)phenoxy]-
phenyl}pyridin-4(1H)-one (7o). To a stirred solution of 5o (50
mg, 0.13 mmol) in CH2Cl2 (1 mL) and MeOH (0.25 mL) was added
in portions N-bromosuccinimide (30 mg, 0.13 mmol). After 3 h
the solvent was evaporated and the residue chromatographed on
silica gel (10:1 CH2Cl2/MeOH eluant) to afford 7o (37 mg, 63%)
as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.60 (s, 1H),
2,6-Dimethyl-3-nitro-5-{4-[4-(trifluoromethoxy)phenoxy]phenyl}-
pyridin-4(1H)-one (12l). To a solution of 3-iodo-2,6-dimethyl-5-
nitropyridin-4(1H)-one44 (0.735 g, 2.5 mmol) in dry DMF (40 mL)
were added the boronic acid 17 (1.15 g, 3.9 mmol) and powdered