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J. E. Thompson et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1219–1223
2-(1,1-Dimethylethyl) - 5 - (4 - fluorophenyl) - 3 - N - hydroxy-4-
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(pyrid-3-onyl)-imidazole (4). To 3 (47.3 g, 0.18 mol) in acetic
acid (1 L) under nitrogen was added trimethylacetaldehyde
(21.6 mL, 0.19 mol) followed byammonium acetate (277.5 g,
3.6 mol) and then heated to reflux for 3 h. The acetic acid was
removed under reduced pressure and the remaining material
slurried in water. The pH of the solution was adjusted to 8–10
byaddition of solid ammonium hydroxide and extracted with
ethyl acetate. The volatiles were removed under reduced pres-
sure and the crude product 4 dissolved in methanol with suffi-
cient ethanol added to effect dissolution. The volatiles were
removed under reduced pressure; the product 4 was twice dis-
solved in ethanol and concentrated to a small volume under
20. Venter, J. C.; Adams, M. D.; Myers, E. W.; Li, P. W.;
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reduced pressure to azeotropicallyremove water. Tricycle
4
was recrystallized from ethanol and hexane (28.8g, 49%).1H
NMR (DMSO-d6, 500 MHz) d 11.55 (s, 1H), 11.34 (s, 1H),
7.45 (m, 2H), 7.32 (s, 1H), 7.09 (m, 2H), 6.41 (br s, 1H), 6.02
(br s, 1H), 1.37 (s, 9H). MS: (m/z 328.1 (M+1)). tR=1.57 min,
YMC C18-S-5 column, 10/90!95/5 MeCN/H2O (0.05%
TFA) linear gradient, 2.5 mL/min.
2-(1,1-dimethylethyl)-9-fluoro-1H-benz[h]isoquinolin-3-one-
[5,6-d]imidazole (5). To 4 (28 g, 0.086 mol) in methanol (I L) at
0 ꢃC under nitrogen was added Ti (III) Cl3 (10% w/w in 20%
w/w HCl, 450 mL) over 45 min while maintaining the reaction
temperature under 10 ꢃC. The solution was warmed and aged
overnight. The methanol was removed under reduced pressure
and the solution was made basic with saturated NaHCO3 and
5 N NaOH. Ethyl acetate was added and the reaction aged for
4 h. The solution was filtered through a Solka floc pad to
remove the solids. The filtrate was extracted with ethyl acetate
and the organic layer was then washed twice with saturated
NaCl, dried over Na2SO4 and concentrated to dryness to yield
crude 5. The crude 5 was purified byflash chromatography
using CH2Cl2/2–10% methanol as an eluant to yield pure 5 (26
g, 97%). 1H NMR [DMSO-d6, 500 MHz, mixture of imidazole
tautomers (ꢄ2:1)] d 12.05 (s, 2/3H), 11.91 (s, 1/3H), 11.25 (br
s, 1H), 7.47 (m, 2H), 7.28 (m, 2H), 7.17 (m, 1H), 6.43 (d,
J=1.4 Hz, 1/3H), 6.32 (d, J=1.4 Hz, 2/3H), 6.23 (dd, J1=6.8
Hz, J2=1.8 Hz, 2/3H), 5.98 (dd, J1=6.8 Hz, J2=1.8 Hz, 1/3H),
1.33 (s, 9H). MS: (m/z 312.2 (M+1)). tR=1.49 min, YMC
C18-S-5 column, 10/90!95/5 MeCN/H2O (0.05% TFA) linear
gradient, 2.5 mL/min.
14. 2-(1,1-Dimethylethyl) - 9 - fluoro - 3,6 - dihydro-7H-benz[h]-
imidaz[4,5-f]isoquinolin-7-one (6). To 5 (2.0 g, 6.4 mmol) in a
Pyrex vessel was added THF (2 L) and the solution was irra-
diated with stirring in a Pyrex vessel with light >350 nm for
45 min. During irradiation, the solution transientlyturned a
reddish pink; the color disappeared on further stirring without
irradiation. At this juncture, further irradiation did not rein-
itiate the reaction. Two more batches of 5 (2.0 g, 6.4 mmol)
were treated identically. The solvent was removed under
reduced pressure to yield crude 6. The crude material was
purified byflash chromatographyon silica gel using THF/tol-
uene (3/7!7/3) as an eluant. Pure 6 (2.6 g, 43%) was obtained
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