August 2010
1109
Ltd. QP5050A mass spectrometer. Wakogel® C-300 (45—75 mm) was used 207.
for column chromatography and flash column chromatography. The chemi-
5,4
-Difluoroflavone 7a Colorless crystals; mp 190.0—191.0 °C. 1H-
cals used, were purchased from Sigma-Aldrich Co., Wako Pure Chemical In- NMR d: 6.71 (1H, s), 7.05—7.12 (1H, m), 7.20—7.26 (2H, m), 7.37 (1H, d,
dustries, Ltd., Tokyo Chemical Industry Co., Ltd., and Apollo Scientific Ltd.
companies.
Jϭ8.6 Hz), 7.60—7.67 (1H, m), 7.88—7.94 (2H, m). MS m/z: 258 (Mϩ),
110. Anal. Calcd for C15H8O2F2: C, 69.77; H, 3.12. Found: C, 69.56; H,
Typical Procedure for the Intramolecular ipso-Substitution Reaction 3.21.
To a stirred suspension of 2-fluoro-6-hydroxyacetophenone 5 (98 mg,
5-Fluoro-4
-chloroflavone 7b Colorless crystals; mp 195.0—196.0 °C.
0.64 mmol) and 4-methylbenzoyl chloride 2i (120 mg, 0.78 mmol) in acetone
(10 ml), was added cesium carbonate (635 mg, 1.95 mmol) at room tempera-
ture. The reaction mixture was stirred at 70 °C for 3 h, and quenched with
1 M HCl, then extracted with AcOEt. The organic layer was washed with
1H-NMR d: 6.74 (1H, s), 7.05—7.12 (1H, m), 7.38 (1H, d, Jϭ8.6 Hz),
7.50—7.53 (2H, m), 7.60—7.68 (1H, m), 7.83—7.86 (2H, m), MS m/z: 274
(Mϩ), 138, 110.
5-Fluoro-4
-cyanoflavone 7c Colorless crystals; mp 201.8—202.0 °C.
brine, dried with sodium sulfate and concentrated in vacuo. The residue was 1H-NMR d: 6.81 (1H, s), 7.08—7.15 (1H, m), 7.38—7.42 (1H, m), 7.63—
purified by recrystallization from ethyl acetate to give 5-hydroxy-4Ј- 7.72 (1H, m), 7.82—7.85 (2H, m), 8.00—8.04 (2H, m). MS m/z: 265 (Mϩ),
methylflavone 3i16) (110 mg, 68% yield) as yellow crystals; mp 172.0—
237, 138, 110.
1
173.0 °C. H-NMR d: 2.45 (3H, s), 6.71 (1H, s), 6.81 (1H, d, Jϭ7.6 Hz),
5-Methoxy-4
-fluoroflavone 10a20) Pale yellow crystals; mp 149.0—
1
7.00 (1H, d, Jϭ7.8 Hz), 7.31 (2H, d, Jϭ8.6 Hz), 7.54 (1H, t, Jϭ8.4 Hz), 7.82
150.0 °C. H-NMR d: 4.01 (3H, s), 6.68 (1H, s), 6.84 (1H, d, Jϭ8.1 Hz),
(2H, d, Jϭ8.6 Hz), 12.62 (1H, s). MS m/z: 252 (Mϩ), 136.
7.11—7.23 (3H, m), 7.58 (1H, t, Jϭ8.1 Hz), 7.87—7.94 (2H, m). Anal.
Calcd for C16H11O3F: C, 71.11; H, 4.10. Found: C, 71.35; H, 4.26.
5-Hydroxy-4
-fluoroflavone 3a9) Yellow crystals; mp 158.0—160.0 °C.
1H-NMR d: 6.69 (1H, s), 6.83 (1H, d, Jϭ8.1 Hz), 7.00 (1H, d, Jϭ10.8 Hz),
7.22 (2H, d, Jϭ8.1 Hz), 7.56 (1H, t, Jϭ8.1 Hz), 7.91—7.96 (2H, m), 12.53
5-Methoxy-4
-trifluoromethylflavone 10b20) Yellow crystals; mp 171.0—
172.0 °C. 1H-NMR d: 4.02 (3H, s), 6.79 (1H, s), 6.86 (1H, d, Jϭ8.1 Hz),
(1H, s). Anal. Calcd for C15H9O3F: C, 70.31; H, 3.54. Found: C, 70.41; H, 7.16 (1H, d, Jϭ10.8 Hz), 7.61 (1H, t, Jϭ8.1 Hz), 7.78 (2H, d, Jϭ8.1 Hz),
3.73. 8.02 (2H, d, Jϭ8.1 Hz), Anal. Calcd for C17H11O3F3: C, 63.75; H, 3.46.
5-Hydroxy-4
-chloroflavone 3b16) Yellow crystals; mp 175.0— Found: C, 63.49; H, 3.60.
1
176.0 °C. H-NMR d: 6.72 (1H, s), 6.84 (1H, d, Jϭ7.6 Hz), 6.92 (1H, m),
7.49—7.60 (3H, m), 7.84—7.89 (2H, m), 12.50 (1H, s). MS m/z: 272 (Mϩ),
274 (Mϩ)ϩ2, 136, 108.
Acknowledgements This research was partially supported by the Min-
istry of Education, Culture, Sports, Science and Technology, Grant-in-Aid
for Scientific Research (C), 20580115, and the fund for Agriomics project.
5-Hydroxy-4
-cyanoflavone 3c Yellow crystals; mp 195.0—196.0 °C.
1H-NMR d: 6.79 (1H, s), 6.86 (1H, d, Jϭ8.4 Hz), 7.03 (1H, d, Jϭ8.1 Hz), We thank Prof. Shuji Akai, Shizuoka Pharmaceutical University, for the ele-
7.60 (1H, t, Jϭ8.1 Hz), 7.85 (2H, d, Jϭ8.1 Hz), 8.04 (2H, d, Jϭ8.1 Hz), mental analysis. We also thank The Uehara Memorial Foundation for fund-
12.37 (1H, s). MS m/z: 263 (Mϩ), 136, 108. Anal. Calcd for C16H9O3N: C, ing this work.
73.00; H, 3.45; N, 5.32. Found: C, 72.64; H, 3.41; N, 5.28.
5-Hydroxy-4
-nitroflavone 3d9) Yellow crystals; mp 226.0—227.0 °C.
1H-NMR d: 6.83 (1H, s), 6.88 (1H, d, Jϭ8.1 Hz), 7.04 (1H, d, Jϭ7.6 Hz),
7.61 (1H, t, Jϭ8.1 Hz), 8.10 (2H, d, Jϭ7.0 Hz), 8.40 (2H, d, Jϭ7.0 Hz),
12.34 (1H, s). MS m/z: 283 (Mϩ), 237, 108.
References and Notes
1) Cohen M. B., Rokhlin O. W., J. Cell. Biochem., 3, 363—371 (2006).
2) Mooradian A. D., Morley J. E., Korenman S. G., Endocr. Rev., 8, 1—
28 (1987).
5-Hydroxy-4
-trifluoromethylflavone 3e Yellow crystals; mp 138.0—
139.0 °C. 1H-NMR d: 6.79 (1H, s), 6.85 (1H, d, Jϭ8.1 Hz), 7.03 (1H, d, Jϭ
10.8 Hz), 7.59 (1H, t, Jϭ8.1 Hz), 7.81 (2H, d, Jϭ8.1 Hz), 8.04 (2H, d, Jϭ
8.1 Hz), 12.43 (1H, s). Anal. Calcd for C16H9O3F3: C, 62.75; H, 2.96. Found:
C, 62.81; H, 3.09.
3) Kao Y. C., Zhou C., Sherman M., Laughton C. A., Chen S., Environ.
Health Perspect., 106, 85—92 (1998).
4) Bovee Toine F. H., Schoonen Willem G. E. J., Hamers Astrid R. M.,
Bento Marta J., Peijnenburg Ad A. C. M., Anal. Bioanal. Chem., 390,
1111—1119 (2008).
5-Hydroxy-4
-methylthioflavone 3f Yellow crystals; mp 166.0—
167.0 °C. H-NMR d: 2.56 (3H, s), 6.71 (1H, s), 6.82 (1H, d, Jϭ8.4 Hz),
6.98—7.01 (1H, m), 7.34—7.37 (2H, m), 7.55 (1H, t, Jϭ8.4 Hz), 7.81—
7.85 (2H, m), 12.61 (1H, s). MS m/z: 284 (Mϩ), 148. Anal. Calcd for
C16H12O3S: C, 67.60; H, 4.25. Found: C, 67.30; H, 4.20.
5) Nishizaki Y., Ishimoto Y., Hotta Y., Hosoda A., Yoshikawa H., Aka-
matsu M., Tamura H., Bioorg. Med. Chem. Lett., 19, 4706—4710
(2009).
6) Hammett L. P., Chem. Rev., 17, 125—136 (1935).
7) Hansch C., Leo A., Unger S. H., Kim K. H., Nikaitani D., Lien E. J., J.
Med. Chem., 16, 1207—1216 (1973).
1
5-Hydroxy-4
-dimethylaminoflavone 3g Yellow crystals; mp 184.0—
1
185.0 °C. H-NMR d: 3.09 (6H, s), 6.59 (1H, s), 6.75 (3H, t, Jϭ8.1 Hz),
8) Hansch C., Rockwell S. D., Jow P. Y. C., Leo A., Steller E. E., J. Med.
Chem., 20, 304—306 (1977).
6.96 (1H, d, Jϭ8.1 Hz), 7.49 (1H, d, Jϭ9.5 Hz), 7.80 (2H, d, Jϭ8.9 Hz),
12.87 (1H, s). MS m/z: 281 (Mϩ), 207. Anal. Calcd for C17H15NO3: C,
72.58; H, 5.37; N, 4.98. Found: C, 72.46; H, 5.41; N, 5.00.
9) Bois F., Beney C., Mariotte A., Boumendjel A., Synlett, 9, 1480—
1482 (1999).
5-Hydroxy-4
-phenylflavone 3h17) Pale yellow crystals; mp 177.0— 10) Typical Experimental Procedure; Preparation of 5-hydroxy-4Ј-fluo-
178.0 °C. 1H-NMR d: 6.78 (1H, s), 7.01 (1H, d, Jϭ10.8 Hz), 7.37—7.57
(4H, m), 7.64 (2H, d, Jϭ8.1 Hz), 7.65 (2H, d, Jϭ8.1 Hz), 7.98 (2H, d, Jϭ
8.1 Hz), 12.57 (1H, s). MS m/z: 314 (Mϩ), 178.
roflavone 3a: To a stirred suspension of 2,6-dihydroxyacetophenone 1a
(229 mg, 1.5 mmol) and 4-fluorobenzoyl chloride 2a (357 mg, 2.25
mmol) in acetone (10 ml), was added potassium carbonate (2.1 g, 15.2
mmol) at room temperature. The reaction mixture was stirred at 70 °C
for 24 h, and quenched with 1 M HCl, then extracted with AcOEt. The
organic layer was washed with brine, dried with sodium sulfate and
concentrated in vacuo. The residue was purified by recrystallization
from ethyl acetate/n-hexane to give 5-hydroxy-4Ј-fluoroflavone 3a
(86 mg, 22% yield) as yellow crystals.
5-Hydroxy-4
-tert-butylflavone 3j18) Yellow crystals; mp 155.0—
1
156.0 °C. H-NMR d: 1.37 (9H, s), 6.72 (1H, s), 6.82 (1H, d, Jϭ8.4 Hz),
7.00 (1H, d, Jϭ7.8 Hz), 7.52—7.58 (3H, m), 7.86 (2H, d, Jϭ8.4 Hz), 12.63
(1H, s). MS m/z: 294 (Mϩ), 279.
1
5-Hydroxyflavone 3k9) Yellow crystals; mp 145.0—146.0 °C. H-NMR
d: 6.75 (1H, s), 6.83 (1H, d, Jϭ8.1 Hz), 7.01 (1H, d, Jϭ8.6 Hz), 7.53—7.59
(4H, m), 7.90—7.94 (2H, m), 12.57 (1H, s). MS m/z: 238 (Mϩ), 136, 108.
5-Hydroxy-4
-aminoflavone 3l Yellow crystals; mp 195.0—196.0 °C.
1H-NMR d: 4.13—4.23 (2H, m), 6.60 (1H, s), 6.77 (3H, t, Jϭ8.5 Hz), 6.96
(1H, d, Jϭ8.1 Hz), 7.51 (1H, t, Jϭ8.5 Hz), 7.75 (2H, d, Jϭ8.6 Hz), 12.78
(1H, s). MS m/z: 253 (Mϩ), 207, 117.
11) 5-Hydroxy-3-(4-methylbenzoyl)-2-p-tolyl-4H-chromen-4-one (4i)16)
:
1
Pale yellow crystals; mp 223.0—224.0 °C. H-NMR d: 2.34 (3H, s),
2.39 (3H, s), 6.85 (1H, d, Jϭ8.1 Hz), 7.02 (1H, d, Jϭ7.6 Hz), 7.15—
7.26 (4H, m), 7.53—7.63 (3H, m), 7.84 (2H, d, Jϭ8.4 Hz), 12.23 (1H,
s). MS m/z: 370 (Mϩ), 341. 2-(4-tert-Butylphenyl)-5-hydroxy-3-(4-
methylbenzoyl)-4H-chromen-4-one (4j): Pale yellow crystals; mp
5-Hydroxy-4
-N,N-diacetylaminoflavone 3m Yellow crystals; mp
1
1
202.0—203.0 °C. H-NMR d: 2.05 (3H, s), 2.30 (3H, s), 6.72 (1H, s), 6.82
228.0—229.0 °C. H-NMR d: 1.28 (9H, s), 1.33 (9H, s), 6.85 (1H, d,
(1H, d, Jϭ8.1 Hz), 7.00 (1H, d, Jϭ8.1 Hz), 7.56 (1H, t, Jϭ8.1 Hz), 7.63—
7.68 (2H, m), 7.92—7.97 (2H, m), 12.51 (1H, s). MS m/z: 295ϩ42 (Mϩ),
253, 117.
Jϭ8.4 Hz), 7.02 (1H, d, Jϭ8.6 Hz), 7.39 (2H, d, Jϭ7.8 Hz), 7.47 (2H,
d, Jϭ8.6 Hz), 7.59—7.61 (3H, m), 7.90 (2H, d, Jϭ8.4 Hz), 12.22 (1H,
s). MS m/z: 454 (Mϩ), 397, 207. Anal. Calcd for C30H32O4: C, 78.92;
H, 7.06. Found: C, 78.73; H, 6.58.
5-Hydroxy-4
-N-acetylaminoflavone 3n Yellow crystals; mp 230.0—
1
231.0 °C. H-NMR d: 2.24 (3H, s), 6.70 (1H, s), 6.82 (1H, d, Jϭ8.1 Hz),
12) Moodie R. B., Schofield K., Accounts of Chemical Research, 9, 287—
292 (1976).
7.00 (1H, d, Jϭ8.1 Hz), 7.31 (1H, s), 7.55 (1H, t, Jϭ8.1 Hz), 7.70 (2H, d,
Jϭ8.1 Hz), 7.90 (2H, d, Jϭ8.1 Hz), 12.61 (1H, s). MS m/z: 295 (Mϩ), 253, 13) Kagawa H., Shigematsu A., Ohta S., Harigaya Y., Chem. Pharm. Bull.,