purple reaction mixture was stirred for 2 h at room temperature,
diluted with Et2O (10 mL), and poured into H2O containing 170
mg of NaHCO3. The pH of the aqueous layer was adjusted to
5-6 by dropwise addition of concentrated HCl, and organics were
extracted with EtOAc (3 × 40 mL). The combined extracts were
dried over MgSO4, filtered, and concentrated in vacuo. The dark
brown viscous oil was purified by silica gel flash chromatography
(20-30% acetone/toluene + 1% AcOH) to give 4b as a fluffy pink/
orange powder (84 mg, 86%): mp 78-80 °C (toluene); 1H NMR
(500 MHz, DMSO-d6, 298 K) δ 9.41 (s, 2 H), 8.98(s, 2 H), 6.75
(d, J ) 8.8 Hz, 2 H), 6.44-6.39 m, 4 H), 6.25 (d, J ) 12.5 Hz, 2
H), 5.60 (s, 1 H), 4.17 (s, 4 H), 3.64 (s, 6 H); 13C NMR (125 MHz,
DMSO-d6, 298 K) δ 171.8, 151.2, 146.3, 144.7 (d, J ) 230 Hz),
143.4 (d, J ) 13 Hz), 133.1, 129.9, 122.1 (d, J ) 62 Hz), 116.6
(d, J ) 20 Hz), 112.1, 105.1, 53.1, 52.3, 41.3; IR (thin film) 3309.9,
2954.2, 1715.1, 1612.9, 1505.4, 1435.5, 1172.0 cm-1; TLC Rf )
0.25 (30% acetone/toluene + 1% AcOH); LRMS (ESI) m/z
(relative intensity) 504 (8), 526 (100); HRMS (CI) m/z calcd for
C25H22F2NO8Na [M + Na]+ 526.1290, found 526.1302.
({4-[[4-Bis-methoxycarbonylmethylamino)phenyl]-(5-
fluoro-2,4-dihydroxyphenyl)methyl]phenyl}methoxycar-
bonylmethylamino)acetic Acid (5). Isolated from the reaction
mixture for 4b after silica gel flash chromatography as a light
brown solid (9.4 mg, 16%): mp 71-74 °C (DMSO); 1H NMR (500
MHz, DMSO-d6, 298 K) δ 9.48 (s, 1 H), 9.09 (s, 1 H), 6.80 (d, J
) 8.8 Hz, 4 H), 6.43 (d, J ) 8.8 Hz, 4 H), 6.42 (d, J ) 7.8 Hz, 1
H), 6.33 (d, J ) 12.5 Hz, 1 H), 5.40 (s, 1 H), 4.16 (s, 8 H), 3.64
(s, 12 H); 13C NMR (125 MHz, DMSO-d6, 298 K) δ 171.1, 150.5,
145.6, 144.2 (d, J ) 230 Hz), 142.8 (d, J ) 13 Hz), 132.9, 129.3,
121.8 (d, J ) 5 Hz), 116.1 (d, J ) 20 Hz), 111.5, 104.4, 52.4,
51.7, 46.5; IR (thin film) 3390.3, 3207.5, 2954.0, 1745.4, 1613.3,
1519.3, 1439.9, 1207.8, 1024.7 cm-1; TLC Rf ) 0.42 (30% acetone/
toluene + 1% AcOH); LRMS (ESI) m/z (relative intensity) 635.0
(95), 613.2 (15), 581.2 (17), 537.2 (17), 275.1 (100); HRMS (CI)
m/z calcd for C31H33F2NO10Na [M + Na]+ 635.2017, found
635.2012.
The oxidative cyclization of triarylmethane 4b with
chloranil was slow and generated a significant number
of byproducts. Unfortunately, the extent of the side
reactions increases when the reaction was heated. The
oxidative cyclization was much faster with DDQ and
proceeded to completion in less than 20 min. The extent
of the side reactions, most leading to oligomers, was
decreased when protic acids were added to the reaction
mixture. The cleanest transformations were affected in
1:1 benzene/acetic acid. Under these conditions, only two
minor byproducts were visible by LCMS, one of which
was the product of addition of DDQ (Table 2). The
dimethylamino-substituted triarylmethane 4e was very
reactive and generated a larger quantity of the undesired
byproducts, ultimately preventing purification.
TABLE 2. Oxidative Cyclization of Triarylmethanes
4b-e
product
Y
X
yield (%)
7b
7c
7d
H
OMe
H
N(CH2CO2Me)2
N(CH2CO2Me)2
H
71
70
39
Characterization of the arylxanthenones 7b-d was
complicated by their poor solubility and by slow tau-
tomerization on the NMR time scale. Even at 100 °C, the
protons at the 4 and 5 positions of the xanthenenone ring
system (which were also coupled to fluorine) were still
highly broadened. As observed by other investigators,
many of the signals corresponding to the 6-hydroxy-3H-
xanthen-3-one ring system were missing from the 13C
NMR spectra.9,14
In summary, we have shown that the condensation of
benzaldehydes with 4-fluororesorcinols in methanesulfon-
ic acid generates a triarylmethane. Since the arenes are
electron rich, retro-Friedel-Crafts fragmentations com-
pete with formation of the triarylmethane product.
Ultimately, it was shown that the yield of triarylmethane
could be improved by optimizing the concentration of
acid. The triarylmethane does not cyclize unless subjected
to an oxidant and for this purpose DDQ was shown to be
superior to chloranil. The milder, improved conditions
presented here for the synthesis of 9-arylxanthenes could
provide access to a broader range of fluorophores.
{[4-(2,7-Difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)phen-
yl]methoxycarbonylmethylamino}acetic Acid Methyl Es-
ter (7b). Triarylmethane 4b (12.4 mg, 0.025 mmol) was dis-
solved in 1 mL of AcOH and diluted with 1 mL of benzene. DDQ
(11.1 mg, 0.050 mmol) was added dropwise to 4b as a solution
in 1 mL of 1:1 AcOH/benzene. Upon addition of the first few
drops of DDQ solution, the initial light yellow solution turned
dark purple. After being stirred at room temperature for 15 min,
the reaction mixture was concentrated in vacuo. The resultant
dark brown solid (∼15 mg) was subjected to silica gel flash
chromatography on a 70 mm × 50 mm pad of silica with 10%
MeOH/CHCl3 as eluant. The crude product was dissolved in a
minimum volume of 15% MeOH/CHCl3 and further purified by
preparative RP-HPLC with gradient elution from 25 to 60%
MeCN/0.1% TFA-H2O. Pure fractions were collected and ly-
ophilized to give 7b as a dark brown powder (8.5 mg, 71%): mp
254-256 °C (H2O); 1H NMR (500 MHz, DMSO-d6, 353 K) δ 7.30
(d, J ) 8.8 Hz, 2 H), 6.94 (d, J ) 11.8 Hz, 2 H), 6.87 (d, J ) 8.8
Hz, 2 H), 6.75 (br s, 2 H), 4.32 (s, 4 H), 3.71 (s, 6 H); 13C NMR
(125 MHz, DMSO-d6, 313 K) δ 170.5, 150.7, 130.7, 119.9, 111.9,
104.9, 52.2, 51.8; 19F NMR (377 MHz, DMSO-d6, 298 K) δ -74.0;
IR (KBr) 3423.1, 2916.5, 2091.3, 1642.1, 1370.6, 1239.3 cm-1
;
TLC Rf ) 0.35 (10% MeOH/CHCl3); LRMS (ESI) m/z (relative
intensity) 484 (100); HRMS (CI) m/z calcd for C25H19F2NO7Na
[M + Na]+ 506.1027, found 506.1031.
Experimental Section
({4-[Bis-(5-fluoro-2,4-dihydroxy-phenyl)methyl]phenyl}-
methoxycarbonylmethylamino)acetic Acid Methyl Ester
(4b). To a flame-dried flask equipped with a magnetic stir bar
were added 4-fluororesorcinol (50 mg, 0.390 mmol) and [(4-
formylphenyl)methoxycarbonylmethylamino]acetic acid methyl
ester (52 mg, 0.195 mmol). The solids were dissolved in 1.5 mL
of anhydrous 1:1 Et2O/CH2Cl2. The flask was flushed with argon,
and MeSO3H (0.13 mL, 8% v/v) was added. The resulting pink/
Acknowledgment. This work was supported by
NIH R33-CA91216.
Supporting Information Available: Experimental pro-
cedures for 1c, 4c-e, 6, and 7c-d and characterization data
for all new compounds (1c, 4b-e, 5, 6, and 7b-d). This
material is available free of charge via the Internet at
(14) Sparano, B. A.; Shahi, S. P.; Koide, K. Org. Lett. 2004, 6, 1947-
1949.
JO051243I
J. Org. Chem, Vol. 70, No. 22, 2005 9053