Novel Bidentate Ligands for Cell-Labeling
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3667
Ta ble 7. Syntheses of 2,6-Alkyl-3-hydroxy-4H-pyran-4-ones
the reaction mixture effervesced producing hydrogen. The
slurry was left stirring for 2-3 h at 60 °C. The excess zinc
was removed from the pale green reaction mixture by hot
filtration. The filtrate was adjusted to pH 1 and extracted with
dichloromethane (3 × 100 mL). The organic extracts were
combined, dried over anhydrous sodium sulfate, filtered, and
concentrated. Recrystallization from 2-propanol gave 16 as a
white solid (9.8 g, 62%): mp 153-155 °C. Anal. (C6H6O3) C,
H.
2-(H yd r oxym et h yl)-3-h yd r oxy-6-m et h yl-4H -p yr a n -4-
on e (17). To a three-necked round-bottomed flask (250 mL)
fitted with a pressure-equalized dropping funnel (50 mL) and
containing a magnetic stirring bar were added 16 (9.4 g, 0.074
mol) and water (100 mL). The pH of the mixture was adjusted
to 10.5 by treatment with 10 M sodium hydroxide. A solution
of 37% aqueous formaldehyde (5.5 mL, 0.074 mol) was added
slowly dropwise via the dropping funnel. The solution was
left to stir at 25 °C for 24 h. The reaction mixture was acidified
to pH 1 using concentrated hydrochloric acid, cooled, and
allowed to crystallize. The product was removed by filtration
to yield a yellow solid (10 g, 86%): mp 157-158 °C. 1H NMR
(DMSO-d6) δ 8.8 (1H, sbr, OH), δ 6.2 (1H, s, 5-H), δ 5.7 (1H,
sbr, CH2OH), δ 4.4 (2H, d, CH2OH), δ 2.3 (3H, s, CH3); νmax
(Nujol) 1660, 1610, 1580.
compd
R
R′
mp, °C %yield formula anal.
5
12
13
14
15
16
21
22
23
24
H
H
H
H
H
H
H
Me
Et
113
57
34
46
67
30
62
53
45
50
47
C5H4O3
C7H8O4
C8H10O4 C, H
C9H12O4 C, H
C10H14O4 C, H
C6H6O3
C7H8O3
C8H10O3 C, H
C9H12O3 C,a
C
10H14O3 C,b H
C, H
C, H
CH2OMe
CH2OEt
CH2On-Pr
CH2On-Bu
Me
Me
Me
Me
Me
79-80
73-74
63-64
34-35
153-155
163-164
107-108
C, H
C, H
n-Pr 129-130
n-Bu 79-80
H
a
b
C: calcd, 64.27; found 63.63. C: calcd, 65.92; found 65.41.
a pressure equalized dropping funnel and containing a mag-
netic stirring bar were added benzyl kojic acid (10 g, 0.043
mol) and dry N,N-dimethylformamide (200 mL). Iodomethane
(14 mL, 0.215 mol) was added via the dropping funnel. The
resulting light brown solution was stirred at 25 °C for 30 min.
Sodium hydride (80% dispersion in mineral oil) (2.6 g, 0.086
mol) was placed in a three-necked round-bottomed flask (500
mL) and washed with hexane (3 × 10 mL) to remove the
mineral oil. The flask was then equipped with a pressure-
equalized dropping funnel (250 mL) and a condenser and then
flushed with nitrogen. The light brown solution prepared
above was added to the flask via the dropping funnel over a
period of 1.5 h under nitrogen with vigorous stirring. During
the addition the reaction mixture effervesced and became red.
Toward the end of the addition the intensity of the red
coloration diminished. The contents of the flask were stirred
under nitrogen for a further 24 h. The reaction mixture was
concentrated by high vacuum rotary evaporation, and the
residue was dissolved in water (100 mL). The resulting
solution was adjusted to pH 12 by treatment with 10 M sodium
hydroxide and extracted with dichloromethane (3 × 200 mL).
The organic extracts were combined, dried over anhydrous
sodium sulfate, filtered, and evaporated to dryness. Recrys-
tallization from ethanol afforded a white powder (5.8 g, 58%):
m.p. 67-68 °C; 1H NMR (DMSO-d6) δ 8.20 (1H, s, 2-H), δ 7.40
(5H, s, benzyl CH), δ 6.40 (1H, s, 5-H), δ 4.95 (2H, s, benzyl
CH2), δ 4.28 (2H, s, CH2O), δ 3.32 (3H, s, OCH3); νmax (Nujol)
Analogous syntheses of 16 with acetaldehyde, propionalde-
hyde, butyraldehyde gave compounds 18-20.
3-Hyd r oxy-6-m eth yl-2-p r op yl-4H-p yr a n -4-on e (23). To
a three-necked round-bottomed flask (500 mL) equipped with
a thermometer, a pressure-equalized dropping funnel and
containing a magnetic stirring bar were added 19 (7.9 g, 0.042
mol) and water (100 mL). Activated zinc dust (13.72 g, 0.21
mol) was added, and the mixture was stirred vigorously and
heated to 60 °C in an oil bath. Concentrated hydrochloric acid
(40 mL, 10 mol equiv) was added dropwise via the dropping
funnel over a period of about 40-50 min during which the
reaction mixture effervesced with the evolution of hydrogen.
The mixture was stirred and heated at 60 °C for 24 h. The
excess zinc was removed by filtration. The filtrate was
adjusted to pH 1 and extracted with dichloromethane (3 × 100
mL). The organic layers were combined, dried over anhydrous
sodium sulfate, filtered, and concentrated to dryness by rotary
evaporation. Recrystallization from petroleum ether (60-80
°C) and toluene afforded a colorless solid 23 (3.5 g, 50%): mp
129-130 °C. Anal. (C9H12O3) C, H.
Analogous reactions of 17, 18, and 20 gave compounds 21,
22, and 24, respectively as shown in Table 7.
3-Meth oxy-1-p r op yl-2H-p yr id in -2-on e (27). To a three-
1630 cm-1
.
necked round-bottomed flask (500 mL) equipped with
a
pressure-equalized dropping funnel and a condenser carrying
a calcium chloride drying tube were added 3-methoxy-2(1H)-
pyridone (2 g, 0.015 mol), potassium hydroxide (1.2 g, 0.022
mol), and 100 mL of dry propanol. Propyl iodide (3 mL, 0.03
mol) was added via the dropping funnel. The contents of the
flask were concentrated by rotary evaporation, and the residue
was extracted with dichloromethane (3 × 50 mL). The organic
extracts were combined, washed with water (20 mL) and
saturated sodium chloride solution (10 mL), dried over anhy-
drous sodium sulfate, filtered, and evaporated to dryness
yielding a pale oil (2.5 g, 68%). 1H NMR (DMSO-d6) δ 7.30
(1H, d, 6-H), δ 6.85 (1H, d, 4-H), δ 6.20 (1H, t, 5-H), δ 3.94
(2H, t, NCH2), δ 3.70 (3H, s, OCH3), δ 1.75 (2H, m, CH2CH3),
δ 0.91 (3H, t, CH2CH3).
Analogous reactions of 3-methoxy-2(1H)-pyridone with meth-
yl iodide, ethyl iodide, and butyl iodide in the corresponding
dry alkanol gave intermediates 25, 26, and 27.
3-Hyd r oxy-1-p r op yl-2H-p yr id in -2-on e (31). Compound
27 (2.5 g, 0.015 mol) was dissolved in dry dichloromethane
(100 mL) in a three-necked round-bottomed flask (500 mL)
fitted with a nitrogen inlet, bubbler and “Suba-Seal” pierced
by a 4 in. 18 gauge needle and containing a magnetic stirring
bar. The flask was flushed with nitrogen and then a small
positive pressure of nitrogen maintained. The mixture was
Analogous syntheses of benzyl kojic acid with ethyl iodide,
propyl iodide, and butyl iodide gave the intermediates 9, 10,
and 11, respectively.
3-Hyd r oxy-6-(m eth oxym eth yl)-4H-p yr a n -4-on e (12). In
a three-necked round-bottomed flask (500 mL) fitted with a
condenser were placed 8 (8 g, 0.03 mol) and 4 M hydrochloric
acid (150 mL). The mixture was refluxed for 2 h. After
cooling, the reaction mixture was adjusted to pH 11 using 10
M sodium hydroxide and extracted with dichloromethane (2
× 50 mL). The aqueous layer was treated with concentrated
hydrochloric acid to obtain pH 1 and extracted with dichlo-
romethane (3 × 100 mL). The organic extracts were combined,
dried over anhydrous sodium sulfate, filtered, and concen-
trated to dryness by rotary evaporation. Recrystallization from
toluene afforded 12 white needles (1.7 g, 34%): mp 79-80 °C.
Anal. (C7H8O4) C, H.
Analogous reactions with 9, 10, and 11 gave compounds 13,
14, and 15 as shown in Table 7.
3-Hyd r oxy-6-m eth yl-4H-p yr a n -4-on e (a llom a ltol) (16).
To a three-necked round-bottomed flask (500 mL) equipped
with a thermometer, pressure-equalized dropping funnel,
condenser, and magnetic stirring bar were added chlorokojic
acid (20 g, 0.125 mol) and water (150 mL). The mixture was
stirred and heated to a temperature of 40 °C in an oil bath.
Zinc dust (16.29 g, 0.25 mol) was added, and the reaction
mixture was stirred vigorously at 60 °C. Concentrated hy-
drochloric acid (37 mL, 3 mol equiv) was added dropwise via
the addition funnel over a period of about 1 h during which
cooled to -70 °C by application of dry ice and acetone.
A
polypropylene syringe (50 mL) was charged with nitrogen and
this was used to pressurize a Sure-Seal bottle containing a 1
M solution of boron tribromide in dichloromethane. Boron