6474 J . Org. Chem., Vol. 62, No. 19, 1997
Sun et al.
(d, J ) 5.0, 1H), 3.83 (s, 3H), 3.81 (s, 3H); 19F-NMR φ 143.87
(dd, J ) 12, 7.0). Anal. Calcd for C8H10FNO2: C, 56.14; H,
5.89; N, 8.18. Found: C, 56.76; H, 6.04; N, 8.20.
CH2Cl2 at 20 °C under N2 was treated with BBr3 (3.0 equiv,
1.0 M in CH2Cl2) via syringe over 5 min. The reaction was
monitored by TLC and took 24-48 h to complete; an additional
0.5 equiv of BBr3 solution was sometimes necessary to drive
the reaction to completion. The reaction was carefully quenched
with water, and the resulting mixture was stirred until all
precipitate(s) dissolved. The resulting solution was extracted
with ether (2×). The extract was washed with brine (1×),
dried (MgSO4), and concd to fluorinated resorcinols. The crude
fluororesorcinols were purified by sublimation (60-100 °C at
0.3-0.5 Torr).
1-Am in o-2,4-d im eth oxy-3-flu or oben zen e (23b). Follow-
ing method C, 22b (4.66 g, 23.2 mmol) gave 3.67 g (92%) of
the title compound as a pale yellow oil: 1H-NMR (CDCl3) δ
6.52 (t, J ) 8.7, 1H), 6.40 (dd, J ) 8.8, 2.1, 1H), 3.92 (s, 3H),
3.80 (s, 3H); 19F-NMR φ 152.9 (d). Anal. Calcd for C8H10FNO2:
C, 56.14; H, 5.89; N, 8.18. Found: C, 56.14; H, 6.05; N, 8.03.
1-Am in o-3,5-d iflu or o-2,4-d im eth oxyben zen e (23c). Fol-
lowing method C, 22c (10.9 g, 49.7 mmol) gave 9.40 g (99.8%)
of the title compound as a clear, pale brown oil: 1H-NMR
(CDCl3) δ 6.25 (dd, J ) 12.1, 2.3, 1H), 3.89 (2 s, 6H), 3.7 (br s,
2H); 19F-NMR φ 135.5 (d, 1F), 146.9 (s, 1F). Anal. Calcd for
C8H9F2NO2: C, 50.80; H, 4.80; N, 7.40. Found: C, 50.61; H,
4.81; N, 7.26.
4-F lu or or esor cin ol (25a ). Following method E, 24a (52.8
g, 0.34 mol) gave 40.5 g (95%) of 25a as a colorless crystalline
solid: mp 94-96 °C; 1H-NMR (DMSO-d6) δ 8.39 (br, 1H), 8.00
(br, 1H), 6.89 (dd, J ) 10.1, 9.0, 1H), 6.48 (dd, J ) 7.3, 3.0,
1H), 6.27 (m, 1H); 19F-NMR φ 145.82 (m). Anal. Calcd for
C6H5FO2: C, 56.26; H, 3.93. Found: C, 56.23; H, 3.93.
2-F lu or or esor cin ol (25b). Following method E, 24b (0.96
g, 6.1 mmol) gave 0.75 g (95%) of 25b as a colorless crystalline
solid: mp 114-116 °C; 1H-NMR (CDCl3) δ 8.52 (br s, 2H), 6.58
(m, 1H), 6.30 (t, J ) 7.9, 2H); 19F-NMR φ 162.3 (t). Anal. Calcd
for C6H5FO2: C, 56.26; H, 3.93. Found: C, 56.05; H, 3.96.
2,4-Diflu or or esor cin ol (25c). Following method E, 24c
(0.64 g, 3.7 mmol) gave 0.49 g (90%) of 25c as a colorless
The hydrochloride salt was obtained by treating a solution
of 22c with 4 M HCl in dioxane, collecting the precipitate on
a Bu¨chner funnel, rinsing with dioxane, and drying in vacuo
to give the hydrochloride of 22c as a bone-white powder: mp
1
213-218 °C dec; H-NMR (D2O) δ 7.1 (br d, 1H), 4.05 (br s,
6H); 19F-NMR φ 131.1 (dd, 1F), 141.6 (s, 1F). Anal. Calcd for
C8H10ClF2NO2: C, 42.59; H, 4.47; N, 6.21. Found: C, 42.75;
H, 4.47; N, 6.14.
1
crystalline solid: mp 99-100 °C; H-NMR (CDCl3) δ 8.99 (s,
1-Am in o-2,4-d im eth oxy-3,5,6-tr iflu or oben zen e (23d ).
Following method C, 22d (2.35 g, 9.91 mmol) gave 1.06 g (52%)
of the title compound as a pale orange solid. This solid was
dissolved in dioxane (8 mL) and treated at room temperature
with 4 M HCl in dioxane. After 5 min, the precipitate was
collected on a Bu¨chner funnel and rinsed with dioxane (10 mL)
followed by drying in vacuo over P2O5/NaOH to give 0.84 g of
the hydrochloride of 23d as an off-white powder: mp 146-
148 °C; 1H-NMR (D2O) δ 4.08 (s, 3H), 4.00 (s, 3H); 19F-NMR φ
149.6 (d, 1F), 154.0 (dd, 1F), 156.8 (d, 1F). Anal. Calcd for
C8H9F3NO2Cl: C, 39.44; H, 3.77; N, 5.75. Found: C, 39.79;
H, 3.70; N, 5.62. Free base, calcd for C8H8F3NO2: C, 46.39;
H, 3.89; N, 6.76. Found: C, 46.49; H, 3.83; N, 6.73.
Meth od D. Hyd r od ed ia zon ia tion of Am in od im eth oxy-
flu or oben zen es. A solution or mixture of the amine in water/
concd HCl (2:1, 0.3 M) was chilled in an ice-salt bath and
treated with a cold solution of sodium nitrite (1.05 equiv) in
water. The resulting solution was stirred for 15 min, and then
H3PO2 (50%, 20 equiv) was added over 5 min. The resulting
mixture was left at 4 °C overnight, stirred at 20 °C for 2 h,
and then diluted with water. The resulting mixture was
neutralized with aqueous sodium hydroxide and then extracted
with ether (2×). The extract was washed with water (1×) and
brine (1×), dried (Na2SO4), and concd in vacuo. The residue
was purified by flash column chromatography, eluting with
hexane/EtOAc (95:5).
1,3-Dim eth oxy-4-flu or oben zen e (24a). Following method
D, 23a (66.81 g, 0.39 mmol) gave 52.81 g (87%) of 24a as a
clear, colorless oil: 1H-NMR (CDCl3) δ 6.97 (dd, J ) 11.1, 9.0,
1H), 6.53 (dd, J ) 7.0, 2.9, 1H), 6.36 (dt, J ) 8.8, 3.0, 1H),
3.86 (s, 3H), 3.77 (s, 3H); 19F-NMR φ 146.0 (m). Anal. Calcd
for C8H9FO2: C, 61.53; H, 5.81. Found: C, 61.26; H, 5.94.
1,3-Dim eth oxy-2-flu or oben zen e (24b). Following method
D, 23b (1.10 g, 6.43 mmol) gave 0.96 g (96%) of 24b as a clear,
pale yellow liquid: 1H-NMR (CDCl3) δ 6.95 (dt, J ) 8.4, 2.2,
1H), 6.59 (t, J ) 7.9, 2H), 3.89 (s, 6H); 19F-NMR φ 159.2 (s).
Anal. Calcd for C8H9O2F: C, 61.53; H, 5.81. Found: C, 61.36;
H, 5.86.
1H), 8.62 (s, 1H), 6.32 (td, J ) 9.1, 2.2, 1H), 6.05 (m, 1H); 19F-
NMR φ 145.4 (m, 1F), 156.0 (m, 1F). Anal. Calcd for
C6H4F2O2: C, 49.33; H, 2.76. Found: C, 48.96; H, 2.80.
2,4,5-Tr iflu or or esor cin ol (25d ). Following method E, 24d
(0.42 g, 2.2 mmol) gave 0.36 g (100%) of 25d as a colorless
1
crystalline solid: mp 69-71 °C; H-NMR (CDCl3) δ 6.05 (m);
19F-NMR φ 144.4 (s, 1F), 162.2 (s, 1F), 169.7 (s, 1F). Anal.
Calcd for C6H3F3O2‚H2O: C, 39.58; H, 2.77. Found: C, 39.58;
H, 2.65.
5-F lu or or esor cin ol. Following method E, 3,5-dimethoxy-
fluorobenzene (5.0 g, 32.0 mmol) gave 3.69 g (92%) of 5-fluo-
roresorcinol as a colorless crystalline solid: mp 134-135.5 °C;
1H-NMR (DMSO-d6) δ 9.60 (s, 2H), 6.05 (s, 1H), 5.97 (d, 2H);
19F-NMR φ 108.26 (t, J ) 11.1). Anal. Calcd for C6H5FO2: C,
56.26; H, 3.93. Found: C, 56.33; H, 3.98.
Meth od F . P r ep a r a tion of F lu or escein s. Trimellitic
anhydride (26), phthalic anhydride (27), or tetrafluorophthalic
anhydride (28) (1 equiv) was added to a solution of the
appropriate fluorinated resorcinol (2 equiv) in methanesulfonic
acid (1 M). The resulting mixture was heated under dry
nitrogen at 80-85 °C for 36-48 h. The cooled mixture was
poured into 7 volumes of ice water followed by filtration. The
filtrand, containing the fluorinated fluorescein, was dried at
60 °C in vacuo to constant weight.
Meth od G. P u r ifica tion of F lu or escein s. The dried
fluorescein was converted to the diacetate by dissolution in
acetic anhydride and pyridine and heating briefly, and the
resulting solution was subjected to aqueous workup and
recrystallization from absolute ethanol. The diacetate was
dissolved in THF/MeOH (1:1) to yield a 5% (w/v) solution and
stirred with NH4OH (10 equiv) for 2 h. The reaction mixture
was poured into 5 volumes of cold water, acidified to pH 2 with
10% HCl, and concd in vacuo to remove THF/MeOH. The solid
was collected by filtration, washed with cold water, and dried
in vacuo at 60 °C to constant weight (Scheme 4).
Meth od H. P u r ifica tion of F lu or escein s. Similar to
method G except that the recrystallization step was replaced
with silica gel flash column chromatography eluting with
CHCl3/MeOH (95:5).
5(6)-Ca r boxy-2′,7′-d iflu or oflu or escein (14a ,b). Follow-
ing method F, 25a (10.0 g, 78.0 mmol) and 26 (7.60 g, 39.6
mmol) gave 14.80 g (92%) of the title compound as an orange
powder.
1,3-Dim et h oxy-2,4-d iflu or ob en zen e (24c). Following
method D, 23c (0.566 g, 2.99 mmol) gave 0.38 g (73%) of 24c
as a clear, colorless liquid: 1H-NMR (CDCl3) δ 6.80 (td, J )
9.6, 2.5, 1H), 6.58 (m, 1H), 4.00 (s, 3H), 3.87 (s, 3H); 19F-NMR
φ 138.8 (d, 1F), 150. 1 (d, 1F). Anal. Calcd for C8H8F2O2: C,
55.19; H, 4.63. Found: C, 54.76; H, 4.63.
1,3-Dim eth oxy-2,4,5-tr iflu or oben zen e (24d ). Following
method D, 23d (0.70 g, 2.9 mmol) gave 0.44 g (80%) of 24d as
a clear, colorless oil: 1H-NMR (CDCl3) δ 6.51 (m, 1H), 4.07 (s,
3H), 3.83 (s, 3H); 19F-NMR φ 141.9 (dd, 1F), 156.7 (t, 1F), 163.4
(dd, 1F). Anal. Calcd for C8H7F3O2: C, 50.01; H, 3.67.
Found: C, 49.63; H, 3.69.
Isola tion of 14bAc2. The solid thus obtained in the above
preparation was heated with Ac2O (35.0 g, 340 mmol) and
pyridine (6.09 g, 77 mmol) for 5 min at 80 °C. The solution
was cooled down and then placed in a freezer for 16 h. The
precipitate was collected, washed with Ac2O (2 × 5 mL) and
ether (2 × 10 mL), and pumped in a desiccator with P2O5 for
12 h to yield 6.25 g (34%) of 6-carboxy-2′,7′-difluorofluorescein
diacetate, pyridinium salt: 1H-NMR (CDCl3) δ 8.67 (m, 2H),
Meth od E. Dem eth yla tion of Dim eth oxyflu or oben -
zen e. A solution of the dimethoxyfluorobenzene in anhydrous