A Convenient Preparation of Xanthene Dyes
A catalytic amount of benzoyl peroxide (∼10 mg) is added. The
reaction mixture is heated at reflux for 1 h with vigorous
stirring. It is cooled to room temperature and quenched with
50 mL of saturated NH4Cl (aq). The mixture is extracted with
CH2Cl2 (3 × 15 mL). The combined extracts are dried over
MgSO4 and filtered, and the filtrate is evaporated to dryness.
The solid residue is purified by flash column chromatography
(silica gel; CH2Cl2) to give 72 mg (14%) of 4 along with 18 mg
(6%) of 5 and 43 mg (15%) of 6. The structures of 5 and 6 were
verified via independent syntheses (vide infra). Data for 4: 1H
NMR (DMSO-d6, 250 MHz) δ 7.23-7.16 (m, 5H), 7.05 (s, 2H),
6.76 (s, 2H), 5.52 (s, 1H), 3.88 (s, 6H); 13C NMR (DMSO-d6,
62.9 MHz) δ 156.6, 154.4, 146.0, 129.0, 127.3, 127.3, 127.0,
126.4, 111.3, 98.8, 78.0, 56.2, 55.9. MALDI-TOF m/z 431.517
[M - OH]+, 447.544 [M]+.
5-Chloro-2,4-dimethoxybenzophenone (5). A 20-mL vol-
ume of CH3CN solution containing 2,4-dimethoxybenzophen-
one (0.500 g, 2.07 mmol) and NCS (0.200 g, 2.17 mmol) is
mixed with 100 mg of 60 Å silica gel. The reaction mixture is
heated at reflux for 5 h with vigorous stirring and cooled to
room temperature. Silica gel is removed via suction filtration,
and CH3CN is removed under reduced pressure. The residue
is purified by flash column chromatography (silica gel; CH2-
Cl2) to afford 0.470 g (82%) of 5. 1H NMR (DMSO-d6, 250 MHz)
δ 7.68-7.60 (m, 3H), 7.52-7.70 (m, 2H), 7.39 (s, 1H), 6.89 (s,
1H), 3.97 (s, 3H), 3.69 (s, 3H); 13C NMR (DMSO-d6, 62.9 MHz)
δ 193.6, 157.7, 157.6, 137.6, 133.1, 130.1, 129.1, 128.5, 121.0,
112.5, 98.1, 56.6, 56.2. MALDI-TOF m/z 276.1 [M] +, 277.4 [M
+ H]+, 299.0 [M + Na]+, 314.9 [M + K]+.
and then quenched with 100 mL of distilled water and
neutralized with 2 N HCl. The unreacted 2,4-dimethoxybro-
mobenzene as well as THF are removed by steam distillation.
The resulting mixture is extracted with CH2Cl2 (3 × 30 mL).
The combined extracts are dried over MgSO4 and filtered, and
the filtrate is evaporated to dryness. The residue is purified
by flash chromatography (silica gel; EtOAc-hexane, 20:80) to
afford 3.49 g (96%) of 9. Compound 9 was prepared previously
via other methodology.25 NMR data is in agreement with the
assigned structure: 1H NMR (DMSO-d6, 300 MHz) δ 7.21-
7.10 (m, 5H), 6.86 (d, J ) 8.6 Hz, 2H), 6.52 (d, J ) 2.2 Hz,
2H), 6.42 (dd, J ) 8.6, 2.2 Hz, 2H), 5.17 (s, 1H), 3.73 (s, 6H),
3.40 (s, 6H); 13C NMR (DMSO-d6, 75.5 MHz) δ 159.7, 157.9,
147.4, 129.2, 127.4, 126.7, 127.9, 104.1, 99.5, 79.1, 55.4, 55.1.
9-Phenyl-6-methoxy-3-fluorone (10). A solution of 8
(0.178 g, 0.468 mmol) in 10 mL of dry CH2Cl2 is cooled to -78
°C using a dry ice/acetone bath before BBr3 (0.935 g, 3.74
mmol) is added dropwise. The mixture is allowed to warm to
room temperature gradually before being quenched with 20
mL of distilled H2O. The mixture is extracted with CH2Cl2 (3
× 10 mL). The combined extracts are dried over MgSO4 and
filtered, and the filtrate is concentrated under reduced pres-
sure. The residue is purified by flash chromatography (silica
gel, EtOAc), affording 90 mg (64%) of 10. 1H NMR (DMSO-d6,
250 MHz) δ 7.63-7.61 (m, 3H), 7.47-7.43 (m, 2H), 7.21 (d, J
) 2.4 Hz, 1H), 7.08 (d, J ) 9.0 Hz, 1H), 7.01 (d, J ) 9.7 Hz,
1H), 6.94 (dd, J ) 9.0, 2.4 Hz, 1H), 6.42 (dd, J ) 9.7, 1.8 Hz,
1H), 6.21 (d, J ) 1.8 Hz, 1H), 3.90 (s, 3H); 13C NMR (DMSO-
d6, 62.9 MHz) δ 183.8, 164.1, 158.4, 154.0, 149.2, 132.4, 130.8,
129.7, 129.6, 129.5, 129.4, 128.8, 117.0, 113.9, 113.6, 104.7,
100.6, 56.3. MALDI-TOF m/z 303.154 [M + H]+.
9-Phenyl-6-hydroxy-3-fluorone (11). To a stirred solution
of 8 (0.400 g, 1.05 mmol) in 10 mL of dry CH2Cl2 at -78 °C,
BBr3 (4.20 g, 16.8 mmol) is added dropwise. The mixture is
warmed to room temperature gradually before being quenched
with 20 mL of distilled H2O. After being stirred for 20 min,
filtration leads to a collection of a red precipitate (11). A sample
for analytical purposes is obtained by flash chromatography
(silica gel, EtOAc-MeOH 9:1). A quantity of 197 mg (65%) of
11 is collected. Compound 11 is known; however, no charac-
terization data was previously reported via the older synthetic
methods.26 1H NMR (DMSO-d6, 250 MHz) δ 7.63-7.60 (m, 3H),
7.46-7.43 (m, 2H), 7.01 (d, J ) 9.2 Hz, 2H), 6.60 (dd, J ) 9.2,
2.1 Hz, 2H) 6.60 (d, J ) 2.1 Hz, 2H); 13C NMR (DMSO-d6, 62.9
MHz) δ 156.3, 149.8, 132.5, 130.5, 129.5, 129.3, 128.8, 114.6,
103.4.
1-Bromo-5-chloro-2,4-dimethoxy-benzene (6). This com-
pound was prepared following the procedures above for
compound 5 except that 2,4-dimethoxybromobenzene (1.507
g, 6.9 mmol) is used instead of 2,4-dimethoxybenzophenone.
1
The yield of 6 (1.22 g) is 70%. H NMR (DMSO-d6, 250 MHz)
δ 7.55 (d, J ) 1.2 Hz, 1H), 6.83 (d, J ) 1.2 Hz, 1H), 3.89 (s,
3H), 3.88 (s, 3H); 13C NMR (DMSO-d6, 62.9 MHz) δ 155.4,
155.0, 132.1, 112.7, 100.5, 98.6, 56.6, 56.5. MALDI-TOF m/z
247.890 [M]+.
2,2′,4,4′-Tetramethoxytrityl Alcohol (9). Magnesium turn-
ings (0.543 g, 22.3 mmol) and a few crystals of I2 are placed in
a 250-mL three-neck round-bottom flask fitted with a dropping
funnel and a condenser. A solution of 2,4-dimethoxybromoben-
zene (5.0 g, 23.0 mmol) in 20 mL of anhydrous THF is added
dropwise to the magnesium. The mixture is stirred for 20-30
min. The resulting Grignard reagent (2,4-dimethoxyphenyl-
magnesium bromide) is cooled in a dry ice/acetone bath before
a solution of methyl benzoate (1.25 g, 9.38 mmol) in 40 mL of
dry THF is added dropwise. The mixture is stirred overnight
2,2′,4,4′-Tetramethoxy-4′′-bromotrityl Alcohol (13a).
This compound was prepared following the protocol described
above for compound 9 except that 4-bromo methyl benzoate
12a (2.01 g, 9.38 mmol) was used as the ester. The yield of
1
(20) Selected references: (a) Brown, H. C. Organic Synthesis via
Boranes; Wiley-Interscience: New York, 1975. (b) Negishi, E. In
Comprehensive Organometallic Chemistry; Wilkinson, G., Stone, F. G.
A., Abel, E. W., Eds.; Pergamon Press: Oxford, 1982; Vol. 5, p 255. (c)
Pelter, A.; Smith, K.; Brown, H. S. Borane Reagents; Academic Press:
London, 1988.
13a (3.97 g) is 92%. H NMR (DMSO-d6, 300 MHz) δ 7.25 (d,
J ) 8.5 Hz, 2H), 6.94 (d, J ) 8.5 Hz, 2H), 6.83 (d, J ) 8.6 Hz,
2H), 6.42 (d, J ) 2.0 Hz, 2H), 6.34 (dd, J ) 8.6, 2.0 Hz, 2H),
5.17 (s, 1H), 3.63 (s, 6H), 3.32 (s, 6H); 13C NMR (DMSO-d6,
75.5 MHz) δ 159.9, 157.8, 147.2, 129.7, 129,4, 129.1, 125.9,
118.9, 104.2, 99.4, 78.5, 55.3, 55.1. MALDI-TOF m/z 457.880
[M]+, 441.521 [M - OH]+, 481.532 [M + K]+.
(21) Matteson, D. S.; Mah, R. W. H. J. Am. Chem. Soc. 1963, 85,
2599.
(22) (a) Kitatani, K.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc. Jpn.
1977, 50, 1600 and 2158. (b) Negishi, E.; Akiyoshi, K. J. Am. Chem.
Soc. 1988, 110, 646. (c) Negishi, E.; Akiyoshi, K.; O’Connor, B.; Takagi,
K.; Wu, G. J. Am. Chem. Soc. 1989, 111, 3089. (d) Kocienski, P.;
Wadman, S.; Cooper, K. J. Am. Chem. Soc. 1989, 111, 2363. (e) Miller,
J. A. J. Org. Chem. 1989, 54, 998. (f) Knochel, P.; Jeong, N.; Rozema,
M. J.; Yeh, M. C. P. J. Am. Chem. Soc. 1989, 111, 6474. (g) Stocks, M.;
Kocienski, P.; Donald, K. K. Tetrahedron Lett. 1990, 31, 1637. (h)
AchyuthaRao, S.; Rosema, M. J.; Knochel, P. J. Org. Chem. 1993, 58,
2694. (i) Kakiya, H.; Inoue, R.; Shinokubo, H.; Oshima, K. Tetrahedron
Lett. 1997, 38, 3275. (j) Harada, T.; Kaneko, T.; Fujiwara, T.; Oku, A.
J. Org. Chem. 1997, 62, 8966. (k) Fillion, E.; Carson, R. J.; Trepanier,
V. E.; Goll, J. M.; Remorova, A. A. J. Am. Chem. Soc. 2004, 126, 15354.
(23) (a) Harada, T.; Hara, D.; Hattori, K.; Oku, A. Tetrahedron Lett.
1988, 29, 3821. (b) Harada, T.; Katsuhira, T.; Osada, A.; Iwazaki, K.;
Maejima, R.; Oku, A. J. Am. Chem. Soc. 1996, 118, 11377.
(24) (a) Harada, T.; Kaneko, T.; Fujiwara, T.; Oku, A. Tetrahedron
1998, 54, 9317. (b) Harada, T.; Chiba, M.; Oku, A. J. Org. Chem. 1999,
64, 8210.
2,2′,4,4′-Tetramethoxy-4′′-phenyltrityl Alcohol (13b).
This compound is prepared following the procedure described
above for compound 9 except that 4-phenyl methyl benzoate
12b (1.13 g, 5.33 mmol) is used. The yield of 13b (2.43 g) is
99%. 1H NMR (DMSO-d6, 250 MHz) δ 7.64 (d, J ) 7.6 Hz,
2H), 7.47 (d, J ) 8.4 Hz, 2H), 7.43 (t, J ) 7.8 Hz, 2H), 7.32 (t,
J ) 7.1 Hz, 1H), 7.19 (d, J ) 8.4 Hz, 2H), 6.93 (d, J ) 8.6 Hz,
2H), 6.55 (d, J ) 2.3 Hz, 2H), 6.45 (dd, J ) 8.6, 2.3 Hz, 2H);
13C NMR (DMSO-d6, 62.9 MHz) δ 159.7, 157.9, 146.7, 140.0,
137.6, 129.2, 128.9, 128.1, 127.1, 126.6, 126.5, 125.0, 104.1,
99.5, 78.9, 55.4, 55.1. MALDI-TOF m/z 439.654 [M - OH]+,
479.599 [M + Na]+.
(25) Yonezawa, N.; Hino, T.; Matsuda, K.; Matsuki, T.; Narushima,
O.; Kobayashi, M.; Ikeda, T. J. Org. Chem. 2000, 65, 941.
(26) Ramart-Lucas, P. Bull. Soc. Chim. 1945, 12, 477.
J. Org. Chem, Vol. 70, No. 17, 2005 6911