6800 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27
Leonetti et al.
6.88 (m, 2H); 7.39 (d, 1H, J ) 8.5); 7.78 (s, 1H). IR: cm-1 1699,
1614, 850.
General Procedure for the Synthesis of Fluorenyl-
triazole Derivatives 15-17. Anhydrous DMF (5 mL) was
added under argon to NaH (11.7 mmol, 0.28 g). To the mixture
was added 1H-1,2,4-triazole or 1H-1,2,3-triazole (9.4 mmol),
followed by careful heating until cessation of the gas evolution.
Compound 11 (2.3 mmol, 0.8 g) was added, and the reaction
mixture was stirred at 90 °C for 3 h. The solvent was removed
under vacuum. The residue was dissolved in EtOAc, washed
with water, dried over Na2SO4, and concentrated under
vacuum. Title compounds 15 and 17 were obtained through a
chromatographic separation (eluent: hexane/EtOAc/2-propanol
7.5:2.5:0.5) of the reaction mixture and recrystallized from
EtOAc:
4-(Bromomethyl)-7-phenoxy-2H-chromen-2-one. The
reaction crude was purified by chromatography using CHCl3/
hexane 1:1 as eluent. 40%, yield. 1H NMR (CDCl3): δ 4.45 (s,
2H); 6.39 (s, 1H); 6.86 (d, 1H, J ) 2.5); 6.98 (dd, 1H, J ) 2.5,
8.5); 7.20 (d, 2H, J ) 8.5); 7.39-7.45 (m, 3H); 7.66 (d, 1H, J )
8.5). IR: cm-1 1725, 1614, 843.
7-(Bromomethyl)-2H-chromen-2-one. The crude com-
pound was recrystallized from ethanol. 70%, yield.1H NMR
(CDCl3): δ 4.80 (s, 2H), 6.50 (d, 1H, J ) 9.0), 6.45 (m, 2H),
6.75 (d, 1H, J ) 7.5), 8.10 (d, 1H, J ) 9.0). IR: cm-1 1715,
1620.
5-Bromo-2-methyl-5H-indeno[1,2-d]pyrimidine (5). The
4-(9-Phenyl-9H-fluoren-9-yl)-4H-1,2,4-triazole (15). 21%,
yield. Mp 220-221 °C. 1H NMR (DMSO-d6): δ 7.13-7.19 (m,
2H); 7.35-7.40 (m, 3H); 7.42 (td, 2H, J ) 7.6, 0.9); 7.54 (td,
2H, J ) 7.4, 0.9); 7.66 (s, 1H); 7.68 (s, 1H); 7.94 (s, 1H); 7.98
(s, 1H); 8.32 (s, 2H). IR: cm-1 3107, 1491, 1451. Anal.
(C21H15N2) C, H, N.
1-(9-Phenyl-9H-fluoren-9-yl)-1H-1,2,3-triazole (16). 43%,
yield. Mp 210-211 °C. 1H NMR (DMSO-d6): δ 6.87-6.90 (m,
2H); 7.29-7.32 (m, 3H); 7.38 (td, 2H, J ) 7.5, 1.0); 7.51 (td,
2H, J ) 7.5, 1.0); 7.63 (s, 1H); 7.66 (s, 1H); 7.78 (s, 1H); 7.95
(s, 1H); 7.97 (s, 1H); 8.09 (s, 1H). IR: cm-1 3158, 1489, 1450.
Anal. (C21H15N2) C, H, N.
1-(9-Phenyl-9H-fluoren-9-yl)-1H-1,2,4-triazole (17). 30%,
yield. Mp 239-240 °C. 1H NMR (DMSO-d6): δ 6.92-6.98 (m,
2H); 7.27-7.32 (m, 3H); 7.39 (td, 2H, J ) 7.6, 1.0); 7.52 (td,
2H, J ) 7.6, 1.0); 7.70 (s, 1H); 7.72 (d, 1H, J ) 0.9); 7.92 (d,
1H, J ) 0.9); 7.94 (d, 1H, J ) 0.9); 8.00 (s, 1H); 8.22 (s, 1H).
IR: cm-1 3149, 1497, 1449. Anal. (C21H15N2) C, H, N.
General Procedure for the Preparation of (1H-Imida-
zol-1-ylmethyl)coumarin Derivatives (18-20, 24-27,
30-32, 34). To a solution of imidazole (1.2 mmol, 83 mg) in
THF (2 mL) were added K2CO3 (2.4 mmol, 0.33 g) and 0.41
mmol of a suitable bromo(or chloro)methylcoumarin deriva-
tives. The reaction mixture was refluxed for 5-7 h, the
K2CO3 was filtered, and the solution was concentrated under
vacuum. The crude residue was recrystallized from ethanol,
unless otherwise stated.
crude material was purified by chromatography using EtOAc/
1
hexane 1:1. 70% yield. H NMR (CDCl3) δ 2.84 (s, 3H); 6.02
(s, 1H); 7.50-7.65 (m, 2H); 7.74 (dd, 1H, J ) 8.4, 0.8); 8.06
(dd, 1H, J ) 6.0, 1.4); 8.82 (s, 1H). IR: cm-1 1720, 1410.
3-(Bromomethyl)-5H-indeno[1,2-c]pyridazin-5-one (9).
The crude reaction mixture was purified by chromatography
using EtOAc/hexane 1:1 as eluent. 50%, yield. 1H NMR (CDCl3)
δ 4.78 (s, 2H); 7.57 (td, 1H, J ) 7.6, 0.9); 7.74 (td, 1H, J ) 7.4,
1.1); 7.77 (s, 1H); 7.85 (dd, 1H, J ) 7.8, 0.8); 8.17 (dd, 1H, J )
8.0, 0.8). IR: cm-1 1590, 1420.
General Procedure for the Synthesis of Indenodiazine
Derivatives 6, 7, and 10. To a solution of 5 or 9 (2 mmol) in
dioxane (8 mL) was added imidazole (6 mmol, 0.41 g), followed
by heating at reflux for 1 h until the starting material
disappeared. The solvent was removed under vacuum and then
dissolved in EtOAc and extracted with a saturated solution
of NaHCO3. The organic layer was separated, dried over
Na2SO4, and concentrated under vacuum. Compounds 6 and
7 were separated and purified through column chromatogra-
phy (eluent: CHCl3/EtOAc/MeOH 90:5:5).
4-(1H-Imidazol-1-yl)-2-methyl-5H-indeno[1,2-d]pyrimi-
dine (6). 30%, yield. Mp 181-183 °C. 1H NMR (CDCl3): δ 2.82
(s, 3H); 4.1 (s, 2H); 7.25 (s, 1H); 7.48-7.60 (m, 2H); 7.65 (d,
1H, J ) 7.3); 7.90 (d, 1H, J ) 1.2); 8.15 (dd, 1H, J ) 6.9, 1.1);
8.57 (s, 1H). IR: cm-1 1600, 1580, 1545.
5-(1H-Imidazol-1-yl)-2-methyl-5H-indeno[1,2-d]pyrimi-
dine (7). The crude compound was recrystallized from
1
CH3CN. 36%, yield. Mp dec 186 °C. H NMR (CDCl3): δ 2.83
3-(1H-Imidazol-1-ylmethyl)-7-methoxy-2H-chromen-2-
one (18). The crude residue was purified by flash chromatog-
raphy using CHCl3/CH3OH 97.5:2.5. Finally, the product was
recrystallized from CHCl3/hexane. 42%, yield. Mp 136-138 °C.
1H NMR (CDCl3): δ 3.87 (s, 3H); 5.04 (s, 2H); 6.83-6.86 (m,
2H); 7.02 (s, 1H); 7.14 (s, 2H); 7.30 (d, 1H, J ) 8.5); 7.62 (s,
1H). IR: cm-1 1705, 1610, 817. Anal. (C14H12N2O3) C, H, N.
(s, 3H); 6.27 (s, 1H); 6.68 (s, 1H); 7.18 (s, 1H); 7.44 (dd, 1H, J
) 7.7, 1.0); 7.55 (td, 1H, J ) 7.4, 1.4); 7.59 (td, 1H, J ) 7.3,
1.1); 7.70 (s, 1H); 8.14 (dd, 1H, J ) 7.7, 1.0); 8.58 (s, 1H). IR:
cm-1 1720, 1410. Anal. (C15H12N4) C, H, N.
3-(1H-Imidazol-1-ylmethyl)-5H-indeno[1,2-c]pyridazin-
5-one (10). The crude compound was recrystallized from
EtOH. 40%, yield. Mp dec 186 °C. 1H NMR (CDCl3): δ 5.52 (s,
2H); 7.01 (s, 1H); 7.15 (s, 1H); 7.24 (s, 1H); 7.56 (td, 1H, J )
7.6, 0.9); 7.66 (s, 1H); 7.73 (td, 1H, J ) 7.2, 0.9); 7.82 (d, 1H,
J ) 7.3); 8.15 (d, 1H, J ) 7.7). IR: cm-1 3090, 1590, 1420.
Anal. (C15H10N4O) C, H, N.
Synthesis of 1-(9H-Fluoren-9-yl)-1H-imidazole (13) and
1-(9-Phenyl-9H-fluoren-9-yl)-1H-imidazole (14). To a solu-
tion of 0.9 mmol of the bromofluorenyl derivatives 11 or 12 in
dioxane (5 mL), was added imidazole (2.6 mmol, 0.18 g)
followed by heating at reflux for 3 h. The solvent was removed
under vacuum. The residue was dissolved in CHCl3 and
extracted with a saturated solution of NaHCO3. The organic
layer was dried over Na2SO4 and concentrated under vacuum.
The solid residue was purified by chromatography using
CHCl3/CH3OH 9:1 as eluent. The major isolated product was
recrystallized from EtOAc:
4-(1H-Imidazol-1-ylmethyl)-2H-chromen-2-one (19). The
crude residue was purified by flash chromatography using
CHCl3/CH3OH 9:1 as eluent, then recrystallized from CHCl3/
1
hexane. 50%, yield. Mp 179-180 °C. H NMR (DMSO-d6): δ
5.58 (s, 2H); 5.60 (s, 1H); 6.99 (s, 1H); 7.27 (s, 1H); 7.40 (t, 1H,
J ) 7.9); 7.44 (d, 1H, J ) 8.4); 7.66 (td, 1H, J ) 7.9, 1.5); 7.80
(s, 1H); 7.85 (dd, 1H, J ) 7.9, 1.5). IR: cm-1 1709, 1608. Anal.
(C13H10N2O2) C, H, N.
4-(1H-Imidazol-1-ylmethyl)-7-methoxy-2H-chromen-2-
one (20). 40%, yield. Mp 176-177 °C. 1H NMR (DMSO-d6): δ
3.85 (s, 3H); 5.42 (s, 1H); 5.52 (s, 2H); 6.98-7.05 (m, 3H); 7.26
(s, 1H); 7.75 (s, 1H); 7.74-7.84 (m, 1H). IR: cm-1 1704, 1620,
1610. Anal. (C14H12N2O3) C, H, N.
4-(1H-Imidazol-1-ylmethyl)-7-phenoxy-2H-chromen-2-
one (24). The reaction crude was purified by column chroma-
tography using EtOAc/CHCl3 7:3 as eluent. The oil residue
afford a solid upon treatment with a solution of ether and
ethanol. 40%, yield. Mp 150-151 °C. 1H NMR (CDCl3): δ 5.28
(s, 2H); 5.75 (s, 1H); 6.88 (d, 1H, J ) 2.5); 6.94-6.97 (m, 2H);
7.07-7.10 (m, 2H); 7.19 (s, 1H); 7.20-7.30 (1H, partially
masked by the solvent peak); 7.43-7.45 (m, 3H); 7.59 (s, 1H).
IR: cm-1 1725, 1616, 849. Anal. (C19H14N2O3) C, H, N.
1-(9H-Fluoren-9-yl)-1H-imidazole (13). 60%, yield. Mp
154-155 °C. 1H NMR (CDCl3): δ 6.10 (s, 1H); 6.68 (s, 1H);
7.03 (s, 1H); 7.20-7.40 (m, 4H); 7.45 (td, 2H, J ) 6.7, 0.2);
7.67 (s, 1H); 7.75 (d, 2H, J ) 7.6). IR: cm-1 3090, 1470, 1430.
Anal. (C16H12N2) C, H, N.
1-(9-Phenyl-9H-fluoren-9-yl)-1H-imidazole (14). 42%,
1
yield. Mp 201-202 °C. H NMR (DMSO-d6): δ 6.99 (m, 1H);
5-(1H-Imidazol-1-ylmethyl)-7-methoxy-2H-chromen-2-
one (25). 43%, yield. Mp 139-140 °C. 1H NMR (CDCl3): δ
3.82 (s, 3H); 5.25 (s, 2H); 6.29 (d, 1H, J ) 7.5); 6.50 (s,
7.08 (m, 1H); 7.12-7.18 (m, 2H); 7.26-7.32 (m, 5H); 7.39-
7.46 (m, 4H); 7.51-7.55 (m, 1H); 7.72 (s, 1H); 7.76 (s, 1H). IR:
cm-1 1480, 1450. Anal. (C22H16N2) C, H, N.