1182
R. A. Dodean et al. / Bioorg. Med. Chem. 16 (2008) 1174–1183
not isolated, but used in the next step to prepare 9. GC–
MS: initial temp. = 100 ꢂC, Rf = 16.81 min; 324 (M+,
10%); 293 (M ꢀ CH3O+, 100%); 183 (C6H2(OCH3)2F-
CO+, 17%); 168 (C6H2(OCH3O)FCO+, 47%); 156 (C6
H3(OCH3)2F+, 48%); 125 (C6H2(OCH3)F+, 14%); 28
(CO+, 2%).
4.5.12. 3,6-Bis-(e-N,N-diethylaminoamyloxy)-4,5-difluo-
roxanthone (12). Seventy-five milligrams (0.00013 mol)
of 3,6-bis-(e-bromoamyloxy)-4,5-difluoroxanthone dis-
solved in 5 ml DMSO with 2 ml of diethylamine was
stirred at room temperature for 24 h. The end of the
reaction was confirmed by TLC, with the formation of
only one product (hexane, ethyl acetate, acetone,
6:2.5:1.5). The mixture was poured in 50 ml water and
extracted with 3 · 50 ml ethyl acetate. Drying under
high vacuum at room temperature for one half hour
gave a light yellow oil (12) that was further converted
into 13 without purification.
4.5.9. 3,6-Dimethoxy-4,5-difluoroxanthone (9). To the
quenched mixture of 2-hydroxy-20,4,40-trimethoxy-
3,30-difluorobenzophenone obtained in the previous
step, 100 ml of 2 N NaOH solution was added. The mix-
ture was boiled until all of the CH2Cl2 had evaporated,
and then refluxed for 1 h. A white solid (9) precipitated
in pure form and was filtered, washed with water, and
air-dried; 440 mg was obtained, in 51% yield. GC–MS:
initial temp. = 100 ꢂC, Rf = 17.06 min; 292 (M+, 100%);
249 (M ꢀ C2H3O+, 52%); 234 (M ꢀ C3H6O+, 11%);
4.5.13. Hydrochloride of 3,6-bis-(e-N,N-diethylaminoam-
yloxy)-4,5-difluoroxanthone (13). The 3,6-bis-(e-N,N-
diethylaminoamyloxy)-4,5-difluoroxanthone was dis-
solved in a few drops of methanol and acidified to pH 3
with dilute HCl solution. Drying under high vacuum with
heating gave 30 mg of a light yellow solid that was con-
firmed by NMR to be the hydrochloride of 3,6-bis-e-
N,N-diethylaminoamyloxy-4,5-difluoroxanthone; yield
36% (from 11). Melting point: 115 ꢂC. IR (cmꢀ1): 1668
(C@O), 1295, 1102 (C–F). 19F NMR (D2O): u =
206 (M ꢀ C4H6O+, 15%); 150 (M ꢀ C4H8O3F þ, 5%);
2
28 (CO+, 8%). 19F NMR (CDCl3) u = ꢀ157.6 ppm (mul-
tiplet, unresolved). 1H NMR (CDCl3): d1 = d8 = 8.07
ppm (d-d, 2H), J12 = 9.00 Hz, JF1 = 2.14 Hz; d2 = d7 =
7.05 ppm (d-d, 2H), J12 = 9.00 Hz, JF2 = 6.87 Hz;
12
1
d3ðOCH Þ = d5ðOCH Þ = 4.05 ppm (s, 6H). HRMS:
C
15
3
3
1
H1016O419F2: Calcd 292.05472, measured 292.05393.
ꢀ157.8 ppm (br m, unresolved). H NMR (D2O): d1 = d8
= 7.49 ppm (d-d, 2H), J12 = 9.15 Hz, JF1 = 1.83 Hz;
d2 = d7 = 6.98 ppm (d-d, 2H), J12 = 9.15 Hz, JF2 = 7.35 Hz;
4.5.10. 3,6-Dihydroxy-4,5-difluoroxanthone (10). 0.22 g
(0.0007 mol) of 3,6-dimethoxy-4,5-difluoroxanthone,
2.0 g phenol, and 8.3 ml of 57% hydriodic acid were
heated to reflux for one half hour, when the reaction
was complete (TLC). The mixture was poured in
100 ml water, extracted with 4 · 50 ml ethyl acetate,
and washed with 3 · 20 ml sodium bisulfite solution.
After extraction of the solvent, the residual phenol was
removed by boiling the product in 100 ml water for
1 h. Suction filtration gave 120 mg of 10 as a white-gray
solid, in 60% yield. Melting point: decomposes at about
325 ꢂC. IR: (cmꢀ1): 1634 (C@O), 1246, 1082 (C–F). 19F
NMR (CDCl3): u = ꢀ160.39 ppm (multiplet, unre-
solved). 1H NMR (CDCl3): d1 = d8 = 7.92 ppm (d-d,
2H), J12 = 8.85 Hz, JF1 = 1.92 Hz; d2 = d7 = 7.07 ppm
d
= 4.17 ppm (t, 4H), J = 6.11 Hz;d
= 3.14 ppm
ðOCH2Þ
ðNCH2Þ
(t,4H), J = 8.24 Hz; d
1.77 ppm (m, 4H); d
3.18 ppm (q, 8H), J = 7.32 Hz; d
12H), J = 7.32 Hz. HRMS:
Calcd 547.3347, measured 547.3358.
=1.87 ppm (m,4H); d
= 1.55 ppm (m, 4H); d
=
=
ðCH2Þ
ðCH2Þ
ðCH2Þ
ðCH2-ethylÞ
= 1.24 ppm (t,
ðCH3-ethylÞ
12
C
1H4614N216O419F2–2Cl:
31
References and notes
1. Chambers, R. D.; Hutchinson, J.; Batsanov, A. S.;
Lehmann, C. W.; Naumov, D. Y. J. Chem. Soc., Perkin
Trans. 1: Org. Bioorg. Chem. 1996, 2271–2275.
2. Connors, K. A. Binding Constants—The measurement of
Molecular Complex Stability: New York, NY, 1987.
3. Dolphin, D. The Porphyrins. Physical Chemistry, Part B:
New York, NY, 1979; Vol. IV.
(d-d, 2H), J12 = 8.85 Hz, JF2 = 7.17 Hz; d(OH)
=
12
9.91 ppm (s, 2H). HRMS:
264.02342, measured 264.02308.
C
1H616O419F2: Calcd
13
4. Dorn, A.; Vippagunta, S. R.; Matile, H.; Jaquet, C.;
Vennerstrom, J. L.; Ridley, R. G.; Pharma Division,
P.R.F.H.-L.R.L.B.S. Biochem. Pharmacol. 1998, 55(6),
727–736.
5. Greenwood, B.; Mutabingwa, T. 2002, 415, 670–672.
6. Ignatushchenko, M.; Winter, R.; Riscoe, M. Am. J. Trop.
Med. Hyg. 2000, 62, 77–81.
7. Ignatushchenko, M. V.; Winter, R. W.; Bachinger, H. P.;
Hinrichs, D. J.; Riscoe, M. K. FEBS Lett. 1997, 409, 67–73.
8. Kelly,J.X.;Winter,R.;Peyton,D.H.;Hinrichs,D.J.;Riscoe,
M. Antimicrob. Agents Chemother. 2002, 46, 144–150.
9. Knell, A. J. Malaria: A Publication of the Tropical
Programme of the Welcome Trust: New York, NY, 1991.
10. Leed, A.; DuBay, K.; Ursos, L. M.; Sears, D.; De Dios, A.
C.; Roepe, P. D. Biochemistry 2002, 4132, 10245–10255.
11. Moreau, S.; Perly, B.; Biguet, J. Biochimie 1982, 64, 1015–
1025.
4.5.11. 3,6-Bis-(e-bromoamyloxy)-4,5-difluoroxanthone
(11). 0.140 g (0.0005 mol) of 3,6-dihydroxy-4,5-difluo-
roxanthone dissolved in 25 ml acetone, 0.39 g
(0.0028 mol) of potassium carbonate, and 1.74 g
(0.0076 mol) of 1,5-dibromopentane was refluxed for
20 h, when the reaction was complete (TLC). The solid
residue was removed by suction filtration, and the
product was purified by column chromatography using
a mixture of hexane, ethyl acetate, and acetone
(6:2.5:1.5). One hundred and twenty milligrams of 11 as
white-yellow solid was obtained, in 47% yield. 19F
NMR (DMSO): u = ꢀ156.15 ppm (d-m), J2F = 6.9 Hz.
1H NMR (DMSO): d1 = d8 = 7.92 ppm (d-d, 2H),
J12 = 9.15 Hz, JF1 = 1.83 Hz; d2 = d7 = 7.36 ppm (d-d,
2H), J12 = 9.15Hz, JF2 = 7.33 Hz; d
= 4.26 ppm
ðOCH2Þ
= 3.58 ppm (t, 4H), J = 6.71 Hz;
12. Moreau, S.; Perly, B.; Chachaty, C.; Deleuze, C. Biochim.
Biophys. Acta 1985, 840, 107–116.
13. Olliaro, P. L.; Goldberg, D. E. Parasitol. Today 1995, 11,
294–297.
(t, 4H), J = 6.71Hz; d
ðBrCH2Þ
d
d
=1.90 ppm (m, 4H); d
= 1.57 ppm (m, 4H).
= 1.83 ppm (m, 4H);
ðCH2Þ
ðCH2Þ
ðCH2Þ