Synthesis of fluorinated benzophenones, xanthones, acridones, and thioxanthones by iterative nucleophilic aromatic substitution

Article abstract of DOI:10.1021/jo202062f

Fluorination of fluorophores can substantially enhance their photostability and improve spectroscopic properties. To facilitate access to fluorinated fluorophores, bis(2,4,5-trifluorophenyl)methanone was synthesized by treatment of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation of the resulting benzyl alcohol. This hexafluorobenzophenone was subjected to sequential nucleophilic aromatic substitution reactions, first at one or both of the more reactive 4,4′-fluorines, and second by cyclization through substitution of the less reactive 2,2′-fluorines, using a variety of oxygen, nitrogen, and sulfur nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated benzophenones, xanthones, acridones, and thioxanthones and provides scalable access to known and novel precursors to fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach should allow access to a wide variety of novel fluorinated fluorophores and related compounds.

Full text of DOI:10.1021/jo202062f

Article
pubs.acs.org/joc
Synthesis of Fluorinated Benzophenones, Xanthones, Acridones, and
Thioxanthones by Iterative Nucleophilic Aromatic Substitution
Zachary R. Woydziak, Liqiang Fu, and Blake R. Peterson*
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: Fluorination of fluorophores can substantially
enhance their photostability and improve spectroscopic prop-
erties. To facilitate access to fluorinated fluorophores, bis-
(2,4,5-trifluorophenyl)methanone was synthesized by treatment
of 2,4,5-trifluorobenzaldehyde with a Grignard reagent derived
from 1-bromo-2,4,5-trifluorobenzene, followed by oxidation
of the resulting benzyl alcohol. This hexafluorobenzophenone
was subjected to sequential nucleophilic aromatic substitution reactions, first at one or both of the more reactive 4,4′-fluorines,
and second by cyclization through substitution of the less reactive 2,2′-fluorines, using a variety of oxygen, nitrogen, and sulfur
nucleophiles, including hydroxide, methoxide, amines, and sulfide. This method yields symmetrical and asymmetrical fluorinated
benzophenones, xanthones, acridones, and thioxanthones and provides scalable access to known and novel precursors to
fluorinated analogues of fluorescein, rhodamine, and other derivatives. Spectroscopic studies revealed that several of these
precursors are highly fluorescent, with tunable absorption and emission spectra, depending on the substituents. This approach
should allow access to a wide variety of novel fluorinated fluorophores and related compounds.
Tokyo Green9 (3) to yield Pennsylvania Green (4)10,11 and
INTRODUCTION
Substitution of hydrogen with fluorine is extensively employed
in medicinal chemistry to alter the binding of small molecules
■
tetramethylrhodamine (5) to yield fluorinated rhodamines
(e.g., 6)12 can confer beneficial photophysical properties. How-
to biological targets and modulate metabolic reactivity.1,2 Fluorina-
ever, the synthesis and isolation of single isomers of fluorinated
fluorophores such as 5-carboxy-Oregon Green5 is challenging
and costly using existing methods.
tion can also alter the photophysical properties of compounds.3,4
Fluorination of fluorescein (1, Figure 1) at the 2′- and 7′-positions
To facilitate access to fluorinated fluorophores, we sought to
develop a practical method to synthesize diverse fluorinated
xanthone (7), acridone (8), and thioxanthone (9) precursors.
Many of these compounds are biologically active,13−25 some are
highly fluorescent,26 and the addition of Grignard reagents to
protected xanthones has been used to prepare 4-carboxy-Tokyo
Green,9 a fluorescent reporter of kinase activity,27 4-carboxy-
Penn Green,10 Tokyo Magenta,28 and other rhodamine and
fluorescein analogues.29−32 Methods for synthesis of derivatives
of 7−9 have advanced over the past decade,13,33−41 but only a
few reports27,42−44 describe derivatives with fluorine at the 2- and
7-positions and nitrogen or oxygen at carbons 3 and 6. Because
existing syntheses of fluorinated xanthones and similar com-
pounds are lengthy and low yielding, relatively little is known
about their cognate photophysical and biological properties.
RESULTS AND DISCUSSION
■
As shown in Scheme 1, we postulated that repeated SNAr reactions
of the novel benzophenone 10 might allow access to other
fluorinated benzophenones (11 and 12), as well as xanthones,
acridones, and thioxanthones (13), as precursors to more highly
conjugated fluorophores (14).45 The high selectivity observed for
Figure 1. Structures of fluorinated fluorophores and related
compounds.
yields Oregon Green (2),5 a bright fluorophore with decreased
phenol pKa (4.8 for 2 versus 6.3−6.86 for 1), improving fluo-
rescence in acidic aqueous environments and enhancing photo-
stability. Although a limited number of fluorinated fluorophores
have been reported, modification of other dyes7,8 including
Received: October 10, 2011
Published: November 23, 2011
© 2011 American Chemical Society
473
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
Scheme 1. General Synthesis of Fluorinated Benzophenones,
Xanthones, Acridones, Thioxanthones, And Derivatives
Involving Iterative Addition of Nucleophiles (Nu:) to
Bis(2,4,5-trifluorophenyl)methanone (10)
the sequential addition of multiple nucleophiles to cyanuric
chloride46 and pentafluoropyridine47 through a similar mechanism
offers precedent for this strategy. To evaluate this hypothesis, we
synthesized 10 in a two-pot process involving magnesium−
halogen exchange of inexpensive 1-bromo-2,4,5-trifluorobenzene
(15) followed by addition to 2,4,5-trifluorobenzaldehyde (16) to
generate the alcohol 17 in nearly quantitative yield (Scheme 2).
Scheme 2. Synthesis of Bis(2,4,5-trifluorophenyl)methanone
(10)
Figure 2. Structures of fluorinated benzophenones and xanthones
derived from 10.
Table 1. Reagents and Conditions for Synthesis of
Benzophenones 18−29 and Xanthones 30−39
temp time yield
product
(reactant)
entry nucleophile
solvent
(°C)
(h)
(%)
Oxidation with TEMPO-free radical and sodium hypochlorite48
produced benzophenone 10 in excellent overall yield. These reac-
tions were scalable, and multiple grams of 10 could be produced
in a single run.
Using the strategy outlined in Scheme 1, novel fluorinated
benzophenone derivatives (18−29, shown in Figure 2) were
prepared from 10 with a variety of oxygen- and nitrogen-derived
nucleophiles in good to excellent yields. As summarized in Table 1,
heating of 10 in aqueous KOH/DMSO at 80 °C efficiently sub-
stituted both fluorines at the 4,4′-positions with hydroxyl groups to
afford 18 (Table 1, entry 1). Sodium methoxide was added to 10
at room temperature in nearly quantitative yield to produce 19
(entry 2).
A wide variety of primary and secondary amines generated
similar SNAr adducts in good to excellent yields (Table 1,
entries 3−12). Piperidine and morpholine exhibited particularly
high reactivity toward 10, and dilution was necessary to prevent
formation of tri- and tetrasubstituted products. As listed in
Table 1, either monosubstituted or disubstituted fluorinated benzo-
phenones derived from ammonia, diethylamine, and piperidine
(Table 1, entries 3, 4, 6, 7 10, and 11) were obtained in >70%
yield by adjusting reaction concentrations and temperatures,
offering additional opportunities for structural diversification.
Symmetrical and asymmetrical xanthones (30−39) were
readily accessed by addition of hydroxide to fluorinated
benzophenones using the conditions listed in Table 1. Although
previous routes10,27 to 30, a valuable precursor for preparation
of fluorophores such as Pennsylvania Green, required five to
eight steps and achieved only modest overall yields, heating
benzophenone 10 with aqueous NaOH either in a sealed tube
1
2
3
4
5
6
7
8
9
KOH
DMSO/H2O
MeOH
80
26
12
12
12
12
12
12
12
3
92
99
93
75
78
85
70
93
82
91
76
81
99
99
80
85
85
95
92
90
92
95
83
18 (10)
19 (10)
20 (10)
21 (10)
22 (10)
23 (10)
24 (10)
25 (10)
26 (10)
27 (10)
28 (10)
29 (10)
30 (10)
30 (10)
31 (21)
32 (22)
33 (23)
34 (24)
35 (25)
36 (26)
37 (27)
38 (28)
39 (29)
NaOMe
NH4OH
NH4OH
DMF/KOH
HNEt2
c
DMSO/H2O
DMSO/H2O
H2O
110
35
60
a
c
b
90
HNEt2
b
26
c
H2NiPr
H2NtBu
b
60
b
46
26
26
26
12
12
3
10 piperidine
11 piperidine
12 morpholine
13 KOH
14 KOH
15 KOH
16 KOH
17 KOH
18 KOH
19 KOH
20 KOH
21 KOH
22 KOH
23 KOH
THF
THF
THF
12
3
c
H2O
200
H2O
110
48
12
12
12
12
16
12
12
12
12
c
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
150
c
150
c
170
c
150
c
150
c
150
c
170
c
150
c
170
a
b
Dimethylamine derives from decomposition of DMF. Reaction was
performed neat. Reaction performed in a sealed tube.
c
at 200 °C for 3 h or at reflux for 48 h provided 30 in nearly
quantitative yield (Table 1, entries 13 and 14). This latter method
was scalable, and multiple grams of 30 could be prepared.
Aminobenzophenones (20−29) were cleanly converted to
474
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
symmetric and asymmetric xanthones via hydroxide-mediated
SNAr reactions with DMSO as a cosolvent (Table 1, entries
15−23).
Table 2. Reagents and Conditions for Synthesis of Acridones
40−51 and Thioxanthones 52−59
temp time yield
product
(reactant)
entry nucleophile
solvent
(°C)
(h)
(%)
Cyclization with amine nucleophiles converted fluorinated
c
1
2
H2NiPr
DMF/KOH
DMF/KOH
DMF/KOH
DMF/KOH
DMF/KOH
H2NiPr
H2NBn
H2NPh
d
b
100
12
6
45
93
95
93
96
91
83
86
72
83
91
79
92
74
91
90
85
89
85
94
40 (10)
41 (10)
42 (25)
43 (21)
44 (27)
45 (28)
46 (19)
47 (19)
48 (19)
49 (46)
50 (47)
51 (48)
52 (19)
53 (19)
54 (22)
55 (23)
56 (25)
57 (26)
58 (27)
59 (29)
benzophenones to fluorinated acridones (40−48, Figure 3).
a
a
a
a
a
c
DMF/H2O
150
3
DMF/H2O
80
12
12
4
c
4
DMF/H2O
150
c
5
DMF/H2O
150
c
6
DMF/H2O
150
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
c
7
b
b
b
100
8
100
130
9
10
11
12
13
14
15
16
17
18
19
20
Cl(CH2)2Cl reflux
Cl(CH2)2Cl reflux
Cl(CH2)2Cl reflux
d
d
Na2S
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
26
90
70
70
70
70
70
70
Na2S
Na2S
Na2S
Na2S
Na2S
Na2S
Na2S
a
b
Dimethylamine derives from decomposition of DMF. Reaction was
c
d
performed neat. Reaction performed in a sealed tube. BBr3 was
employed for demethylation.
diphenylanthracene (Φ = 0.95 in EtOH) and anthracene (Φ =
0.27 in EtOH) are listed in Table 3. Absorbance and emission
spectra of 30−59 are provided in the Supporting Information.
Among these compounds, substituents modulated absorbance
by up to 77 nm and emission by up to 71 nm, with Stokes shifts
of >100 nm in some cases. The ability to readily access multi-
gram quantities of these precursors via iterative SNAr should
have broad utility for the synthesis of diverse fluorinated
fluorophores and related molecular probes.
Figure 3. Structures of fluorinated acridones and thioxanthone
products.
The conditions for synthesis of 40−48 are summarized in
Table 2. Heating of 10 in DMF containing KOH provided
N,N-dimethylacridone 41 in 93% yield (Table 2, entry 2).
Decomposition of DMF was responsible for generation of the
dimethylamine nucleophile. Using the same reaction con-
ditions, acridones 42−45 were synthesized from benzophe-
nones 25, 21, 27, and 28 in >90% yield. Dimethoxyacridones
46, 47, and 48, produced by heating 19 with the corresponding
amines, required subsequent treatment with NaH or heating in
higher-boiling dimethylacetamide for completion. Attempts to
demethylate 46−48 to generate 49−51 with NaSEt or Na2S
cleaved only one of the two methyl groups at 130 °C. Further
heating (170 °C) also cleaved the N-linked alkyl group of 46
and 47. However, reflux with BBr3 in 1,2-dichloroethane
provided 49−51 in high yield (Table 2).
To the best of our knowledge, 2,7-difluorinated thioxan-
thones have not been previously reported. To access these
compounds, Na2S was employed to synthesize 52−59 (Figure 3)
as summarized in Table 2. By controlling the temperature and
concentration of Na2S, dimethoxybenzophenone 19 was
converted into either 52 or 53 (Table 2, entries 13 and 14).
Additionally, diaminobenzophenones 22, 23, 25, 26, 27, and 29
reacted with Na2S at 70 °C in greater than 85% yield (Table 2,
entries 15−20).
EXPERIMENTAL SECTION
■
Optical Spectroscopy. Quantum yields (Φ) of the highly
emissive compounds 30, 31, 35, 36, 38, 40, and 42 in ethanol were
quantified by the method of Williams.49 Quantum yields for other
compounds were determined to be <0.1 by comparison. Diphenylan-
thracene (Φ = 0.95 in ethanol50) and anthracene (Φ = 0.27 in
ethanol51) were used as standards, and data from these measurements
are provided in the Supporting Information. Molar extinction coef-
ficients (ε) of 30, 31, 35, 36, 38, 40, and 42 in ethanol were deter-
mined by linear least-squares fitting of Beer’s Law plots of absorbance
versus concentration, and data from these measurements are provided
in the Supporting Information.
Synthesis. In addition to specific methods described below,
general procedures A−F were used to access structurally related
compounds.
General Procedure A. A mixture of bis(2,4,5-trifluorophenyl)-
methanone (10, 2.00 g, 6.9 mmol) and the corresponding amine
(73.3 mmol) was heated in a sealed tube. The reaction mixture was
cooled, and volatiles were removed in vacuo. If impurities were evident,
compounds were purified by column chromatography (5% EtOAc in
hexanes) to provide viscous oils that typically crystallized when washed
with hexanes.
Absorbance (18−59) and fluorescence emission spectra
(30−59) were acquired on selected compounds. Values for
λmax, molar extinction coefficient (ε), determined for
compounds with quantum yield (Φ) > 0.2, and Φ relative to
General Procedure B. A mixture of bis(2,4,5-trifluorophenyl)-
methanone (10, 1.00 g, 3.45 mmol), the corresponding amine
(10.1 mmol), and THF (10.0 mL) was stirred for 12 h at 26 °C. The
reaction mixture was concentrated in vacuo. If impurities were evident,
475
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
precipitate was filtered, washed with water (3 × 50 mL), and washed
with either diethyl ether or acetone to afford the product.
Table 3. Spectral Properties of Compounds in Ethanol
(18−51 and 53−59) or DMSO (52) (Values Not
Determined Are Indicated by −)
General Procedure E. The corresponding dimethoxyacridone
(46−48, 0.10 mmol) was dissolved in 1,2-dichloroethane (4.0 mL)
and treated with BBr3 in CH2Cl2 (0.57 mL of a 0.7 M solution,
0.40 mmol). The reaction mixture was heated to reflux for 12 h, cooled
to room temperature, and quenched with methanol (1.00 mL). The
product was concentrated and purified by column chromatography
(0−3% MeOH in CH2Cl2).
General Procedure F. A solution of diaminoxanthone (19, 22,
23, 25−27, and 29, 1.0 mmol) in DMA (5.0 mL) was vigorously
purged with Ar for 30 min followed by treatment with finely ground
Na2S (0.375 g, 5.0 mmol). The resulting yellow-orange slurry was
heated to 70 °C for 12 h with stirring. The hot reaction mixture was
poured into ice-cold water (150 mL), and the precipitate was collected
by vacuum filtration. The crude yellow solid was air-dried and further
purified by column chromatography or by washing with an organic
solvent to give the corresponding thioxanthone.
Bis(2,4,5-trifluorophenyl)methanone (10). To a solution of 17
(400 mg, 1.37 mmol) in CH2Cl2 (12 mL) were added KBr (33.2 mg,
0.28 mmol), TEMPO (11.0 mg, 0.07 mmol, 5 mol %), and saturated
aqueous NaHCO3. The biphasic mixture was vigorously stirred, and
aqueous NaOCl (6.0 mL, 0.7 M) was added. The resulting bright
orange mixture was stirred for 3 h, and the orange color dissipated.
The colorless biphasic layers were separated, the aqueous layer was
extracted with CH2Cl2 (2 × 12 mL), and the combined organic
fractions were dried over anhydrous Na2SO4 and concentrated to give
a crude yellow solid. The solid was purified elution through a plug of
silica gel (10% EtOAc in hexanes). The filtrate was concentrated to
yield 10 as a colorless solid (370 mg, 92%): mp 80−81 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.57 (qd, J = 8.8, 6.4 Hz, 2H), 6.95 (qd, J = 9.2,
6.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 184.7 (s), 156.8 (dd, J =
254.7, 9.8 Hz), 153.3 (ddd, J = 260.0, 14.5, 12.2 Hz), 147.1 (ddd, J =
248.1, 12.7, 3.1 Hz), 123.2 (d, J = 14.9 Hz), 118.8 (d, J = 20.1 Hz),
111.6−98.1 (m); IR (thin film) 3073, 1667, 1623, 1509, 1437, 1420,
1333, 1293, 1208, 1138, 889 cm−1; HRMS (ESI) m/z 291.0263 (M +
H+, C13H5F6O requires 291.0245).
abs
λmax (nm)
fluorescenc
λmax (nm)
compd
ε (M−1 cm−1
)
Φ
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
306
301
340
335
358
369
361
357
348
354
350
342
369
366
378
389
379
370
368
369
373
344
376
384
377
369
368
364
383
381
378
379
381
377
316
377
382
393
377
373
377
361
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
439
425
446
452
438
422
418
457
445
448
423
441
421
432
455
443
425
416
424
438
431
454
416
465
477
475
446
432
487
481
−
−
−
−
−
−
−
−
−
−
−
−
0.26
0.44
<0.1
<0.1
<0.1
0.41
0.31
<0.1
0.23
<0.1
0.32
<0.1
0.31
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
13300 @ 369 nm
39200 @ 366 nm
−
−
−
36200 @ 370 nm
48600 @ 368 nm
−
15300 @ 373 nm
−
36800 @ 376 nm
−
56700 @ 377 nm
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
Bis(2,4,5-trifluorophenyl)methanol (17). To a solution of
1-bromo-2,4,5-trifluorobenzene (2.34 mL, 20.0 mmol) in THF
(30 mL) at −78 °C was added i-PrMgCl (1.3 M in Et2O, 16.1 mL,
21.0 mmol), dropwise. The resulting pale yellow solution was stirred at
−78 °C for 10 min, was warmed to 4 °C, and was maintained at 4 °C
for 1 h. This solution was cooled again to −78 °C and treated with
2,4,5-trifluorobenzaldehyde (2.55 mL, 22.0 mmol). This mixture was
allowed to slowly warm to ambient temperature (23 °C). After stirring
at room temperature for 3 h, the reaction mixture was slowly quenched
with saturated aqueous NH4Cl solution (20 mL). The resulting phases
were separated, the aqueous fraction was extracted with Et2O (2 ×
30 mL), the combined organic phases were dried over anhydrous
Na2SO4, and the solution was concentrated to give a crude oil that was
purified by flash chromatography (5% EtOAc in hexanes) to provide
1
pure 17 (5.74 g, 99%): mp 81−83 °C; H NMR (CDCl3, 400 MHz)
δ 7.27 (qd, J = 10.0, 6.4 Hz, 2H), 6.95 (qd, J = 9.2, 6.4 Hz, 2H), 6.29
(d, J = 3.2 Hz, 1H), 2.46 (d, J = 3.2 Hz, 1H); 13C NMR (126 MHz,
CDCl3) δ 154.6 (ddd, J = 246.9, 9.3, 2.8 Hz), 151.5−148.5 (m),
148.4−145.2 (m), 125.4 (d, J = 15.7 Hz), 116.5−114.1 (m), 105.8 (dd,
J = 27.4, 21.1 Hz), 62.8 (s); IR (thin film) 3364, 1631, 1513, 1430,
1337, 1200, 1147, 1096 cm−1; HRMS (ESI) m/z 291.0263 (M − H,
C13H5F6O requires 291.0245).
Bis(2,5-difluoro-4-hydroxyphenyl)methanone (18). A mix-
ture of 10 (3.0 g, 10.3 mmol), aqueous KOH (10 M, 10 mL,
100 mmol), and DMSO (10 mL) was heated to 80 °C for 12 h. This
solution was transferred to a mixture of concentrated aqueous HCl
(15 mL) and ice (200 g) to generate a fine precipitate that was
collected by vacuum filtration. This colorless precipitate was washed
with cold water (3 × 100 mL) and dried overnight (16 h) under high
vacuum to provide pure 18 (2.71 g, 92%): mp 170−171 °C; 1H NMR
(400 MHz, DMSO-d6) δ 11.40 (br s, 2H), 7.45 (dd, J = 10.8, 7.0 Hz,
2H), 6.83 (dd, J = 11.6, 7.0 Hz, 2H); 13C NMR (126 MHz, DMSO-d6)
δ 184.7 (s), 157.1 (d, J = 249.8 Hz), 150.6 (t, J = 13.5 Hz), 147.4
compounds were purified by column chromatography (5% EtOAc in
hexanes) to give viscous oils that typically crystallized upon standing.
General Procedure C. A mixture of the corresponding
diaminoxanthone (21−29, 1.0 mmol), aqueous KOH (10 M, 1.5 mL,
15.0 mmol), and DMSO (1.5 mL) was heated in a sealed tube. After
the time indicated, the reaction mixtures were cooled and transferred
to ice water (150 mL). The resulting precipitate was collected by
vacuum filtration and washed with water (3 × 100 mL). If impurities
were evident, products were purified by washing with an organic
solvent or by column chromatography.
General Procedure D. The corresponding benzophenone (10,
21, 25, 27, or 28, 1.0 mmol) was dissolved in a solution of DMF
(2.0 mL, 25.9 mmol) and aqueous KOH (10 M, 2.0 mL, 20.0 mmol).
This mixture was heated in a sealed tube and at 150 °C for the time
indicated, cooled, and transferred to ice water (100 mL). The resulting
476
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
(d, J = 239.6 Hz), 117.4 (dd, J = 15.1, 4.9 Hz), 117.2 (dd, J = 21.5,
3.9 Hz), 104.9 (dd, J = 27.3, 3.0 Hz); IR (film) 3162, 3071, 2964,
1621, 1514, 1303, 1199, 1143, 789 cm−1; HRMS (ESI) m/z 285.0161
(M − H, C13H5F4O3 requires 285.0175).
Bis(4-(diethylamino)-2,5-difluorophenyl)methanone (23).
Using General Procedure A at 90 °C for 12 h, bis(2,4,5-trifluoro-
phenyl)methanone 10 (1.00 g, 3.45 mmol) and diethylamine (7.0 mL,
1
71.0 mmol) afforded 23 (1.07 g, 85%): mp 60−62 °C; H NMR
(400 MHz, CDCl3) δ 7.34 (dd, J = 12.4, 5.6 Hz, 2H), 6.54 (dd,
J = 12.8, 5.6 Hz, 2H), 4.50 (d, J = 3.6 Hz, 2H), 1.46 (s, 18H); 13C
NMR (126 MHz, CDCl3) δ 184.9 (s), 158.4 (d, J = 249.6 Hz), 148.3
(d, J = 239.2 Hz), 142.5 (s), 118.22 (dd, J = 25.9, 5.2 Hz), 116.4−
115.5 (m), 102.7 (d, J = 28.7 Hz), 46.0 (d, J = 5.7 Hz), 13.6−12.5
(m); IR (film) 2976, 2934, 1618, 1523, 1443, 1394, 1356, 1279, 1234,
1192, 1077, 779 cm−1; HRMS (ESI) m/z 397.1877 (M + H+,
C21H25F4N2O requires 397.1903).
Bis(2,5-difluoro-4-methoxyphenyl)methanone (19). A mix-
ture of 10 (2.00 g, 6.8 mmol) and methanol (28 mL) was treated with
NaOMe in methanol (5.4 M, 5.50 mL, 29.6 mmol), dropwise. This
mixture was stirred for 12 h, and water (300 mL) was added. A color-
less precipitate was collected by vacuum filtration, washed with water
(2 × 150 mL), and dried under high vacuum to provide of pure 19
(2.11 g, 99%): mp 158−160 °C; 1H NMR (400 MHz, 10% CD3OD in
CDCl3) δ 7.47 (dd, J = 10.8, 7.0 Hz, 2H), 6.70 (dd, J = 11.2, 7.0 Hz,
2H); 13C NMR (126 MHz, 10% CD3OD in CDCl3) δ 185.5 (s), 157.9
(d, J = 252.5 Hz), 152.3 (dd, J = 12.8, 10.6 Hz), 148.4 (dd, J = 244.5,
2.2 Hz), 120.4−118.0 (m), 117.1 (dd, J = 21.4, 3.7 Hz), 103.6−99.7
(m), 56.6 (s); IR (film) 3066, 2951, 1663, 1621, 1513, 1346, 1145, 794
cm−1; HRMS (ESI) m/z 337.0474 (M + Na+, C15H10F4O3Na requires
337.0464).
(4-(Diethylamino)-2,5-difluorophenyl)-(2,4,5-trifluorophenyl)-
methanone (24). Using General Procedure A at 26 °C for 12 h,
bis(2,4,5-trifluorophenyl)methanone (10, 2.60 g, 6.90 mmol) and
diethylamine (1.02 mL, 10.3 mmol) afforded 24 (1.65 g, 70%) after
column chromatography (5−10% EtOAc in hexanes): mp 74−78 °C;
1H NMR (400 MHz, CDCl3) δ 7.35−7.50 (m, 2H), 6.96 (ddd, J =
15.7, 6.2, 3.4 Hz, 1H), 6.32 (dd, J = 14.1, 7.2 Hz, 2H), 3.41 (q, J = 6.2 Hz,
2H), 1.23 (t, J = 6.2 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 184.3 (s),
162.6−156.0 (m), 155.6 (ddt, J = 252.5, 9.9, 2.5 Hz), 149.4−146.1 (m),
147.9−145.2 (m),146.6 (d, J = 239.1 Hz), 141.4 (dd, J = 15.2, 12.9 Hz),
127.2−122.7 (m), 118.4 (d, J = 4.5 Hz), 116.4 (dd, J = 21.5, 4.0 Hz),
114.9 (dd, J = 13.4, 5.5 Hz), 105.9 (dd, J = 28.4, 21.1 Hz), 103.0−99.5
(m), 46.3 (d, J = 6.3 Hz), 13.1 (d, J = 1.8 Hz); IR (film) 3067, 2980,
2938, 1650, 1607, 1528, 1511, 1424, 1392, 1329, 1280, 1131, 1076, 887,
791 cm−1; HRMS (ESI) m/z 366.0889 (M + Na+, C17H14F5NONa
requires 366.0893).
Bis(2,5-difluoro-4-(isopropylamino)phenyl)methanone
(25). Using General Procedure A, 10 (2.0 g), isopropylamine (6.00 mL,
73.3 mmol), and heating in a sealed tube at 60 °C for 3 h provided
pure 25 (2.32 g, 92%): mp 91− 92 °C; 1H NMR (400 MHz, CDCl3)
δ 7.35 (dd, J = 12.0, 5.2 Hz, 2H), 6.30 (dd, J = 12.4, 5.6 Hz, 2H), 4.32
(d, J = 5.2 Hz, 2H), 3.66 (hept, J = 6.8 Hz, 2H), 1.30 (s, J = 6.4 Hz,
12H); 13C NMR (126 MHz, CDCl3) δ 185.4 (s), 159.2 (d, J = 249.5
Hz), 146.7 (d, J = 235.7 Hz), 140.9 (dd, J = 14.0, 12.2 Hz), 115.7 (dd,
J = 21.7, 4.8 Hz), 114.8−113.2 (m), 98.4−96.9 (m), 44.2 (s), 22.6 (s);
IR (film) 3433, 3366, 2972, 2934, 1625, 1607, 1534, 1456, 1368,
1280, 1156, 907, 727 cm−1; HRMS (ESI) m/z 391.1402 (M + Na+,
C19H20F4N2ONa requires 391.1409).
Bis(4-amino-2,5-difluorophenyl)methanone (20). Bis(2,4,5-
trifluorophenyl)methanone (10, 3.00 g, 10.3 mmol) was dissolved in
DMSO (10.0 mL) and treated with concentrated aqueous NH4OH
(10.0 mL, 145 mmol). This mixture was stirred at 110 °C for 12 h
(sealed tube), followed by addition to ice water (400 mL). A yellow
precipitate was collected by vacuum filtration, washed with water (3 ×
150 mL), and dried under high vacuum for 12 h to provide pure 20
(2.73 g 93%): mp 180−182 °C; 1H NMR (400 MHz, 10% CD3OD in
CDCl3) δ 7.22 (dd, J = 11.2, 7.0 Hz, 2H), 6.37 (dd, J = 11.2, 7.0 Hz,
2H); 13C NMR (10% CD3OD in CDCl3) δ 187.7 (s), 160.1 (d, J =
250.1 Hz), 148.2 (d, J = 236.3 Hz), 142.6 (dd, J = 15.2, 12.7 Hz),
118.0 (dd, J = 21.0, 3.7 Hz), 117.2 (d, J = 13.7 Hz), 104.9−101.4 (m);
IR (film) 3343, 3087, 1627, 1599, 1523, 1459, 1362, 1314, 1371, 750
cm−1; HRMS (ESI) m/z 307.0450 (M + Na+, C13H8F4N2ONa
requires 307.0470).
(4-Amino-2,5-difluorophenyl)-(2,4,5-trifluorophenyl)-
methanone (21). Bis(2,4,5-trifluorophenyl)methanone (10, 1.00 g,
3.43 mmol) in DMSO (2.50 mL) was treated with concentrated
aqueous NH4OH (2.50 mL, 36.3 mmol). This mixture was stirred at
35 °C for 12 h, diluted with ice-cold water (100 mL), and extracted
with EtOAc (3 × 50 mL). The combined organic fractions were dried
over anhydrous Na2SO4 and concentrated in vacuo to give a crude
yellow oil that was purified by column chromatography (10% to 20%
EtOAc in hexanes) to provide pure 21 (0.738 g, 75%): mp 134−
Bis(4-(tert-butylamino)-2,5-difluorophenyl)methanone
(26). Using General Procedure A, 10 (500 mg, 1.72 mmol),
t-butylamine (7.00 mL, 71.0 mmol), and heating at 46 °C for 12 h
1
136 °C; H NMR (400 MHz, CDCl3) δ 7.39−7.60 (m, 2H), 7.00
1
afforded 26 (560 mg, 82%): mp 135−137 °C; H NMR (400 MHz,
(ddd, J = 15.6, 6.0, 3.6 Hz, 1H), 6.43 (dd, J = 11.6, 6.8 Hz, 2H), 4.45
(s, 2H); 13C NMR (126 MHz, CDCl3) δ 184.9 (s), 159.4 (d, J =
252.3 Hz), 155.9 (ddt, J = 252.5, 9.9, 2.5 Hz), 152.2 (ddd, J =
257.0, 14.5, 12.2 Hz), 147.0 (d, J = 239.1 Hz), 148.1−145.5 (m),
141.7 (dd, J = 15.2, 12.9 Hz), 127.4−123.0 (m), 119.7−117.0 (m), 116.8
(dd, J = 21.5, 4.0 Hz), 115.1 (dd, J = 13.4, 5.5 Hz), 106.1 (dd, J = 28.3,
21.1 Hz), 102.2 (dd, J = 28.8, 3.5 Hz); IR (film) 3489, 3343, 3218, 1661,
1593, 1511, 1456, 1425, 1331, 1249, 1144, 900, 787 cm−1; HRMS (ESI)
m/z 286.0276 (M − H, C13H5F5NO requires 286.0291).
CDCl3) δ 7.34 (dd, J = 12.4, 5.6 Hz, 2H), 6.54 (dd, J = 12.8, 5.6 Hz,
2H), 4.50 (d, J = 3.6 Hz, 2H), 1.46 (s, 18H); 13C NMR (126 MHz,
CDCl3) δ 184.3 (s), 157.5 (d, J = 249.0 Hz), 146.2 (d, J = 235.6 Hz),
139.2 (s), 114.2 (d, J = 4.5 Hz), 113.4−112.4 (m), 99.5−97.6 (m),
50.3 (s), 28.3 (s); IR (film) 3436, 2979, 1626, 1534, 1462, 1371, 1288,
1211, 796 cm−1; HRMS (ESI) m/z 397.1877 (M + H+, C21H25F4N2O
requires 397.1903).
Bis(2,5-difluoro-4-(piperidin-1-yl)phenyl)methanone (27).
Using General Procedure B, 10 (1.00 g, 3.45 mmol), piperidine
(1.0 mL, 10.1 mmol), and THF (6.00 mL), and a reaction time of 12 h
Bis(4-(dimethylamino)-2,5-difluorophenyl)methanone
(22). Bis(2,4,5-trifluorophenyl)methanone (10, 291 mg, 1.00 mmol)
was dissolved in DMF (2.00 mL, 25.9 mmol), treated with aqueous
KOH (10 M, 2.00 mL, 20.0 mmol), and stirred at 60 °C for 12 h. This
mixture was cooled to room temperature (23 °C), transferred to ice
water (50 mL), extracted with EtOAc (3 × 20 mL), and the combined
organic fractions were washed with water (2 × 30 mL). The organic
layer was dried over anhydrous Na2SO4, concentrated in vacuo, and
purified by flash chromatography (5−10% EtOAc in hexanes) to
provide pure 22 (265 mg, 78%) as a yellow solid: mp 120−121 °C; 1H
NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 14.1, 7.0 Hz, 2H), 6.39 (dd,
J = 12.8, 7.0 Hz, 2H), 3.01 (s, 12H); 13C NMR (126 MHz, CDCl3) δ
185.2 (s), 158.2 (d, J = 249.8 Hz), 148.9 (d, J = 240.7 Hz), 144.7 (s),
120.4−116.9 (m), 117.1−115.6 (m), 106.9−99.3 (m), 42.1 (d, J = 6.1
Hz); IR (film) 2954, 2807, 1619, 1526, 1446, 1359, 1121, 782 cm−1;
HRMS (ESI) m/z 341.1259 (M + H+, C17H17F4N2O requires
341.1277).
1
afforded 27 (1.28 g, 91%): mp 141−143 °C; H NMR (400 MHz,
CDCl3) δ 7.33 (dd, J = 13.3, 6.4 Hz, 2H), 6.53 (dd, J = 12.4, 5.5 Hz,
2H), 3.17 (t, J = 5.2 Hz, 8H), 1.72 (p, J = 5.7 Hz, 8H), 1.61 (p, J = 5.4
Hz, 4H); 13C NMR (126 MHz, CDCl3) δ 185.6 (s), 158.0 (d, J =
251.1 Hz), 150.4 (dd, J = 242.6, 1.6 Hz), 145.7 (s), 119.5−117.9 (m),
118.3−116.5 (m), 105.1 (s), 51.0 (d, J = 5.0 Hz), 25.8 (s), 24.1 (s); IR
(film) 2937, 2854, 2821, 1614, 1508, 1437, 1385, 1255, 1164, 1123,
782 cm−1; HRMS (ESI) m/z 421.1877 (M + H+, C23H25F4N2O
requires 421.1903).
(2,5-Difluoro-4-(piperidin-1-yl)phenyl)(2,4,5-trifluorophenyl)-
methanone (28). Using General Procedure B, 10 (640 mg, 2.20
mmol), piperidine (0.24 mL, 2.40 mmol), THF (10 mL), and a
1
reaction time of 3 h afforded 28 (600 mg, 76%): mp 71−73 °C; H
NMR (400 MHz, CDCl3) δ 7.35−7.52 (m, 2H), 6.96 (ddd, J = 15.7,
6.1, 3.5 Hz, 1H), 6.50 (dd, J = 13.1, 7.0 Hz, 1H), 3.24 (t, J = 5.2 Hz,
4H), 1.71 (p, J = 5.4 Hz, 8H), 1.65 (p, J = 5.2 Hz, 4H); 13C NMR
477
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
(125 MHz, CDCl3) δ 184.8 (s), 159.0 (d, J = 315.0 Hz), 154.2 (dd,
J = 163.8, 12.5 Hz), 150.3 (dd, J = 312.5, 12.3 Hz), 149.5 (d, J = 225.3
Hz), 146.9 (dd, J = 325.3, 9.8 Hz), 146.5−146.8 (m), 122.2−122.7
(m), 118.3 (d, J = 23.7 Hz), 117.4 (dd, J = 31.6, 5.1 Hz), 116.0−116.5
(m), 106.1 (dd, J = 35.5, 26.4 Hz), 104.9 (dd, J = 35.3, 5.0 Hz), 50.8
(s), 25.7 (s), 24.1 (s); IR (film) 3070, 2940, 2856, 1665, 1614, 1509,
1438, 1256, 1126, 878, 758 cm−1; HRMS (ESI) m/z 356.1067
(M + H+, C18H15F5NO requires 356.1074).
104.6 (d, J = 2.6 Hz), 102.4 (s), 45.7 (d, J = 5.9 Hz), 12.8 (s); IR
(film) 3069, 2975, 2733, 1618, 1578, 1475, 1398, 1275, 1213, 1080,
775 cm−1; HRMS (ESI) m/z 318.0916 (M − H, C17H14F2NO3
requires 318.0942).
2,7-Difluoro-3,6-bis(isopropylamino)-9H-xanthen-9-one
(35). Using General Procedure C, 25 (2.50 g, 6.79 mmol), and
heating at 150 °C for 16 h afforded 35 (2.15 g, 92%): mp 238−239 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 12.0 Hz, 2H), 6.64 (d,
Bis(2,5-difluoro-4-morpholinophenyl)methanone (29).
Using General Procedure B, 10 (1.00 g, 3.45 mmol), morpholine
(0.75 mL, 8.62 mmol), THF (8 mL), and a reaction time of 12 h
J = 7.2 Hz, 2H), 6.45 (dd, J = 2, 8.0 Hz, 2H), 3.76 (hept, J = 6.4 Hz,
2H), 1.22 (d, J = 6.4 Hz, 12H); 13C NMR (126 MHz, DMSO-d6) δ
172.3 (s), 154.2 (s), 147.7 (d, J = 129.2 Hz), 142.0 (s), 141.8 (s),
110.8−106.0 (m), 96.9 (d, J = 3.8 Hz), 43.5 (s), 21.7 (s); IR (film)
3435, 2392, 3968, 2837, 1645, 1610, 1531, 1461, 1296, 1016 cm−1;
HRMS (ESI) m/z 347.1592 (M + H+, C19H21F2N2O2 requires
347.1571).
3,6-Bis(tert-butylamino)-2,7-difluoro-9H-xanthen-9-one
(36). Using General Procedure C, 26 (1.00 g, 2.52 mmol), and
heating at 150 °C for 12 h afforded 36 (848 mg, 90%): mp 289−291 °C;
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 12.0 Hz, 2H), 6.75 (d, J =
1
afforded 29 (1.18 g, 81%): mp 189−191 °C; H NMR (400 MHz,
CDCl3) δ 7.37 (dd, J = 6.7, 5.6 Hz, 2H), 6.54 (dd, J = 12.0, 5.2 Hz,
2H), 3.86 (t, J = 4.6 Hz, 8H), 3.21 (t, J = 4.6 Hz, 8H); 13C NMR (125
MHz, CDCl3) δ 185.3 (s), 158.0 (d, J = 314.7 Hz), 150.5 (d, J = 305.0
Hz), 144.7 (d, J = 12.1 Hz), 119.2−119.8 (m), 117.7 (d, J = 30.6 Hz),
105.1 (d, J = 34.4 Hz), 66.6 (s), 49.9 (s); IR (film) 2960, 2916, 2861,
1620, 1509, 1267, 1170, 1115, 782 cm−1; HRMS (ESI) m/z 447.1300
(M + Na+, C21H20F4N2O3Na requires 447.1308).
2,7-Difluoro-3,6-dihydroxyxanthen-9-one (30). A mixture of
10 (4.46 g, 15.4 mmol) and aqueous KOH (10 M, 30 mL, 0.300 mol)
was heated to reflux for 48 h. During this time, 10 slowly dissolved to
give a bright yellow-orange solution. This hot solution was poured
onto acidic ice (20 mL of 12 M HCl and 200 g of ice) and was allowed
to stand for 3 h. The resulting colorless slurry was filtered via vacuum,
and the filtrate was washed with cool water (3 × 100 mL), ethanol
(2 × 50 mL), and dried under high vacuum to yield pure colorless
difluoroxanthone 30 (3.91 g, 96%). Xanthone 30 had spectral
properties identical to those previously reported.27
6.7 Hz, 2H), 4.60 (d, J = 4.9 Hz, 2H), 1.48 (s, 18H); 13C NMR (126
MHz, CDCl3) δ 174.3 (s), 154.1 (s), 148.8 (d, J = 239.0 Hz), 140.8 (d,
J = 13.0 Hz), 110.1 (d, J = 6.7 Hz), 109.4 (d, J = 21.7 Hz), 99.1 (d, J =
2.2 Hz), 51.4 (s), 29.2 (s); IR (film) 3451, 2972, 1623, 1527, 1491,
1294, 1217, 887, 821 cm−1; HRMS (ESI) m/z 375.1897 (M + H+,
C21H25F2N2O2 requires 375.1884).
2,7-Difluoro-3,6-di(piperidin-1-yl)-9H-xanthen-9-one (37).
Using General Procedure C, 27 (840 mg, 2.00 mmol), and heating
1
to 170 °C for 12 h afforded 37 (733 mg, 92%): mp 200−201 °C; H
NMR (400 MHz, 10% CD3OD in CDCl3) δ 7.45 (d, J = 13.2 Hz, 2H),
6.58 (d, J = 6.8 Hz, 2H), 2.99 (t, J = 4.8 Hz, 8H), 1.49 (p, J = 4.8 Hz,
8H), 1.41 (hept, J = 4.8 Hz, 4H); 13C NMR (125 MHz, 10% CD3OD
in CDCl3) δ 175.2 (s), 153.9 (s), 151.9 (d, J = 252.0 Hz), 147.3 (d, J =
10.1 Hz), 113.5 (d, J = 6.3 Hz), 111.0 (d, J = 23.9 Hz), 105.4 (d, J =
3.8 Hz), 51.1 (d, J = 5.0 Hz), 25.6 (s), 24.0 (s); IR (film) 2931, 1619,
1461, 1234, 1130, 776 cm−1; HRMS (ESI) m/z 421.1714 (M + Na+,
C23H24F2N2O2Na requires 421.1704).
3-Amino-2,7-difluoro-6-hydroxy-9H-xanthen-9-one (31).
Using General Procedure C, 21 (1.17 g, 4.07 mmol), and heating at
1
150 °C for 12 h afforded 31 (726 mg, 80%): mp 247−250 °C; H
NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 10.9 Hz, 1H), 7.56 (d, J =
11.3 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 6.55
(s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 172.7 (s), 154.0 (s), 152.8
(s), 151.3 (d, J = 14.8 Hz), 149.2 (d, J = 85.9 Hz), 147.2 (d, J = 83.7
Hz), 144.1 (d, J = 15.9 Hz), 112.8 (d, J = 5.5 Hz), 110.9 (d, J = 19.9
Hz), 109.7 (d, J = 19.8 Hz), 109.0−108.2 (m), 104.7 (d, J = 2.5 Hz),
100.1 (d, J = 4.5 Hz); IR (film) 3369, 3221, 2986, 1614, 1481, 1288,
773 cm−1; HRMS (ESI) m/z 262.0291 (M − H, C13H6F2NO3 requires
262.0316).
2,7-Difluoro-3-hydroxy-6-(piperidin-1-yl)-9H-xanthen-9-one
(38). Using General Procedure C, 28 (710 mg, 2.01 mmol), and
heating at 150 °C for 12 h afforded 38 (630 mg, 95%): mp 230−231 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 2H), 7.73 (d, J = 10.8 Hz,
1H), 7.64 (d, J = 13.3 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 7.01 (d,
J = 6.9 Hz, 1H), 3.21 (t, J = 5.4 Hz, 1H), 1.65 (p, J = 5.2 Hz, 1H), 1.58
(p, J = 5.4 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 172.9 (s),
152.6 (d, J = 161.3 Hz), 155.0 (d, J = 155.0 Hz), 152.1 (s), 150.1 (s),
149.7 (s), 147.7 (s), 146.5 (d, J = 10.1 Hz), 113.1−112.5 (m), 111.0
(d, J = 20.2 Hz), 110.7 (d, J = 23.5 Hz), 105.9 (s), 104.6 (s), 50.5 (d,
J = 5.0 Hz), 25.3 (s), 23.6 (s); IR (film) 3126, 2936, 1625, 1587, 1484,
1296, 1090, 832, 778 cm−1; HRMS (ESI) m/z 330.0925 (M − H,
C18H14F2NO3 requires 330.0942).
3,6-Bis(dimethylamino)-2,7-difluoro-9H-xanthen-9-one
(32). Using General Procedure C, 22 (2.00 g, 5.05 mmol), and
heating to 150 °C for 12 h afforded 32 (1.61 g, 85%): mp 211−213 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 14.0 Hz, 2H), 6.76 (d,
J = 7.6 Hz, 2H), 3.03 (s, 12H); 13C NMR (126 MHz, DMSO-d6) δ
172.4 (s), 153.2 (s), 150.7 (s), 149.5−144.7 (m), 111.4 (d, J =
6.7 Hz), 110.8 (d, J = 23.7 Hz), 103.1 (d, J = 4.1 Hz), 41.8 (d, J =
6.0 Hz); IR (film) 3450, 2922, 2850, 2798, 1615, 15221, 1447, 1371,
1332, 1257, 1132, 777 cm−1; HRMS (ESI) m/z 341.1087 (M + Na+,
C17H16F2N2O2Na requires 341.1078).
2,7-Difluoro-3,6-dimorpholino-9H-xanthen-9-one (39).
Using General Procedure C, 29 (1.00 g, 2.36 mmol), and heating at
1
3,6-Bis(diethylamino)-2,7-difluoro-9H-xanthen-9-one (33).
Using General Procedure C, 23 (1.50 g, 3.78 mmol), and heating at
170 °C for 12 h afforded 33 (1.20 g, 85%): mp 108−109 °C; 1H NMR
(400 MHz, CDCl3) δ 7.77 (d, J = 14.4 Hz, 2H), 6.31 (d, J = 7.3 Hz,
2H), 3.42 (q, J = 7.0 Hz, 8H), 1.23 (t, J = 7.0 Hz, 2H); 13C NMR (126
MHz, CDCl3) δ 173.0 (s), 152.9 (s), 148.9 (d, J = 219.2 Hz), 142.5
(d, J = 10.5 Hz), 111.1(d, J = 24.9 Hz), 110.8 (d, J = 7.1 Hz), 101.5
(s), 45.1 (d, J = 5.9 Hz), 11.9 (d, J = 1.5 Hz); IR (film) 2976, 2934,
1615, 1519, 1457, 1274, 1246, 1071, 773 cm−1; HRMS (ESI) m/z
375.1857 (M + H+, C21H25F2N2O2 requires 375.1884).
170 °C for 12 h afforded 39 (787 mg, 83%): mp 236−237 °C; H
NMR (400 MHz, CDCl3) δ 7.83 (d, J = 13.0 Hz, 2H), 6.80 (d, J =
6.8 Hz, 2H), 3.90 (t, J = 5.0 Hz, 8H), 3.26 (t, J = 5.0 Hz, 8H); 13C
NMR (125 MHz, CDCl3) δ 13C NMR (126 MHz, CDCl3) δ 174.4
(s), 153.6 (s), 151.9 (d, J = 245.9 Hz), 146.1 (d, J = 10.6 Hz), 114.9
(d, J = 7.2 Hz), 112.0 (d, J = 23.5 Hz), 105.5 (d, J = 3.0 Hz), 66.6 (s),
50.1 (d, J = 4.8 Hz); IR (film) 2921, 2863, 1619, 1473, 1259, 1198,
1123, 1030, 900, 777 cm−1; HRMS (ESI) m/z 403.1490 (M + H+,
C21H21F2N2O4 requires 403.1469).
2,7-Difluoro-10-isopropyl-3,6-bis(isopropylamino)acridin-9-
(10H)-one (40). Bis(2,4,5-trifluorophenyl)methanone 10 (291 mg,
1.00 mmol) was dissolved in isopropylamine (3.00 mL, 36.7 mmol)
and transferred to a sealed tube. The reaction was stirred at 100 °C for
12 h, and all volatiles were removed under reduced pressure. The
residual oil was purified by flash chromatography to yield 40 (170 mg,
45%) as a white solid: mp 160−162 °C; 1H NMR (400 MHz, CDCl3)
δ 7.98 (d, J = 12.0 Hz, 2H), 6.56 (d, J = 8.0 Hz, 2H), 5.01 (hept, J =
7.0 Hz, 1H), 4.34 (br s, 2H), 3.75 (hept, J = 5.92 Hz, 2H), 1.75 (d, J =
7.0 Hz, 6H), 1.33 (d, J = 7.0 Hz, 12H); 13C NMR (126 MHz, CDCl3)
3-(Diethylamino)-2,7-difluoro-6-hydroxy-9H-xanthen-9-one
(34). Using General Procedure C, 24 (1.00 g, 2.92 mmol), and
heating at 150 °C for 12 h afforded 34 (884 mg, 95%): mp 299−300 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.41 (br s, 1 H), 7.71 (d, J = 10.8
Hz, 1H), 7.59 (d, J = 12.8 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.80 (d,
J = 7.3 Hz, 1H), 3.43 (q, J = 6.5 Hz, 4H), 1.17 (t, J = 6.5 Hz, 6H); 13
C
NMR (126 MHz, DMSO-d6) δ 172.6 (s), 153.6 (s), 152.9 (s), 151.6
(s), 151.5 (s), 149.9 (d, J = 84.3 Hz), 148.0 (d, J = 84.6 Hz), 143.3 (d,
J = 10.1 Hz), 112.8 (d, J = 5.4 Hz), 111.8−110.31 (m), 110.3 (s),
478
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
δ 173.9 (s), 146.5 (d, J = 238.3 Hz), 140.1 (s), 138.9 (d, J = 13.7 Hz),
112.4 (d, J = 5.8 Hz), 109.7 (d, J = 19.5 Hz), 95.4 (s), 50.8 (s), 43.0
(s), 21.6 (s), 20.5 (s); IR (film) 3437, 3304, 2970, 2934, 1622, 1599,
1498, 1281 cm−1; HRMS (ESI) m/z 388.2204 (M + H+, C22H28F2N3O
requires 388.2200).
2,7-Difluoro-10-isopropyl-3,6-dimethoxyacridin-9(10H)-one
(46). A solution of 19 (100 mg, 0.32 mmol) in isopropylamine (3.00
mL, 36.6 mmol) was heated to 100 °C in a sealed tube for 12 h. This
mixture was cooled and residual isopropylamine removed in vacuo.
The resulting crude yellow oil was dissolved in THF (7.00 mL),
treated with NaH (60%, 77.0 mg, 1.92 mmol), and heated to 60 °C for
12 h. The reaction mixture was cooled in an ice bath and carefully
neutralized with saturated aqueous NaHCO3 (20 mL). Extraction with
THF (3 × 20 mL), drying of the combined organic fractions over
anhydrous Na2SO4, and removal of solvent in vacuo provided a crude
yellow oil that was purified by column chromatography (CH2Cl2) to
provide dimethoxyacridone 46 (88.4 mg, 83%): mp 158−159 °C;
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 11.2 Hz, 2H), 7.04 (d, J =
6.8 Hz, 2H), 5.09 (p, J = 7.2 Hz, 1H), 4.06 (s, 6H), 1.83 (d, J = 7.2 Hz,
6H); 13C NMR (126 MHz, CDCl3) δ 175.3 (s), 152.1 (d, J = 12.9
Hz), 148.5 (d, J = 245.9 Hz), 140.2 (s), 117.0 (d, J = 5.4 Hz), 112.8 (d,
J = 18.9 Hz), 100.1 (s), 56.4 (s), 52.4 (s), 21.4 (s); IR (film) 2924,
2851, 1736, 1626, 1603, 1488, 1263, 1091, 796 cm−1; HRMS (ESI) m/z
334.1255 (M + H+, C18H18F2NO3 requires 334.1255).
10-Benzyl-2,7-difluoro-3,6-dimethoxyacridin-9(10H)-one
(47). A solution of 19 (1.50 g, 4.78 mmol) in benzylamine (8.00 mL,
73.3 mmol) was heated to 100 °C for 12 h. This mixture was cooled
and residual benzylamine removed by vacuum distillation (36 °C,
1 mmHg). The resulting crude yellow oil was dissolved in THF
(30 mL), treated with NaH (60%, 574 mg, 14.4 mmol), and heated to
60 °C for 12 h. The reaction mixture was cooled in an ice bath and
carefully neutralized with saturated aqueous NaHCO3 (20 mL). The
resulting biphasic mixture was extracted with THF (3 × 20 mL), and
the combined organic fractions were dried over anhydrous Na2SO4
and concentrated to give a crude yellow oil that was purified by
column chromatography (CH2Cl2) to provide dimethoxyacridone 47
(1.56 g, 86%): mp 205−206 °C; 1H NMR (400 MHz, CDCl3) δ 8.00
(d, J = 11.2 Hz, 2H), 7.45−7.30 (m, 3H), 7.22 (d, J = 6.8 Hz, 2H),
6.93 (d, J = 6.8 Hz, 2H), 5.70 (s, 2H), 4.82 (s, 6H); 13C NMR
(126 MHz, CDCl3) δ 174.9 (s), 153.0 (d, J = 13.0 Hz), 148.7 (d, J =
246.0 Hz), 140.1 (s), 135.1 (s), 129.5 (s), 128.22 (s), 125.6 (s), 115.6
(d, J = 5.4 Hz), 112.5 (d, J = 19.1 Hz), 98.5 (s), 56.21 (s), 51.6 (s); IR
(film) 2989, 2938, 1607, 1498, 1273, 1042 cm−1; HRMS (ESI) m/z
382.1278 (M + H+, C22H18F2NO3 requires 382.1255).
2,7-Difluoro-3,6-dimethoxy-10-phenylacridin-9(10H)-one
(48). A solution of 19 (100 mg, 0.320 mmol) in aniline (2.00 mL,
21.9 mmol) was heated to 130 °C for 12 h in a sealed tube. The
reaction mixture was cooled, and the residual aniline was removed by
vacuum distillation (40 °C, 1 mmHg). The resulting crude yellow oil
was dissolved in DMA (3.5 mL) and heated at 170 °C for 12 h. The
reaction mixture was cooled, diluted with water (30 mL), and
extracted with THF (3 × 20 mL). The combined organic fractions
were dried over anhydrous Na2SO4 and concentrated to give a crude
yellow oil that was purified by column chromatography (CH2Cl2) to
provide dimethoxyacridone 48 (84.5 mg, 72%): mp 256−257 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 11.6 Hz, 2H), 7.74−
7.87 (m, 3H), 7.59 (d, J = 7.2 Hz, 2H), 6.17 (d, J = 7.2 Hz, 2H), 3.62
(s, 6H); 13C NMR (126 MHz, DMSO-d6) δ 173.5 (s), 151.8 (d, J =
13.1 Hz), 148.0 (d, J = 244.2 Hz), 140.7 (s), 138.0 (s), 131.4 (s),
130.3 (s), 129.6 (s), 113.9 (d, J = 5.1 Hz), 111.0 (d, J = 18.7 Hz),
100.1 (s), 55.8 (s); IR (film) 3057, 2939, 1612, 1580, 1479, 1306,
1256, 1084, 823, 701 cm−1; HRMS (ESI) m/z 368.1098 (M + H+,
C21H16F2NO3 requires 368.1098).
2,7-Difluoro-3,6-dihydroxy-10-isopropylacridin-9(10H)-one
(49). Using General Procedure E, 46 (20.0 mg, 0.0601 mmol)
afforded dihydroxylacridone 49 (15.2 mg, 83%): mp 172−173 °C;
1H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 11.6 Hz, 2H), 7.29 (d,
J = 7.2 Hz, 2H), 5.18 (p, J = 7.2 Hz, 2H), 1.75 (d, J = 7.2 Hz, 2H);
13C NMR (126 MHz, CD3OD) δ 177.2 (s), 152.4 (d, J = 15.4 Hz),
149.6 (d, J = 242.1 Hz), 142.1 (s), 116.7 (d, J = 5.1 Hz), 112.8 (d,
J = 19.2 Hz), 105.2 (s), 53.6 (s), 20.9 (s); IR (film) 3357, 3075,
2977, 1701, 1627, 1542, 1490, 1448, 1406, 1277, 1199, 889, 770 cm−1;
HRMS (ESI) m/z 304.0765 (M − H, C16H12F2NO3 requires 304.0785).
10-Benzyl-2,7-difluoro-3,6-dihydroxyacridin-9(10H)-one
(50). Using General Procedure E, 47 (20.0 mg, 0.0526 mmol)
3,6-Bis(dimethylamino)-2,7-difluoro-10-methylacridin-9-
(10H)-one (41). Using General Procedure D, 10 (291 mg, 1.00
mmol), a reaction time of 6 h, purification by washing with acetone,
and removal of solvent in vacuo afforded 41 (307 mg, 93%): mp 200−
1
203 °C; H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 14.2 Hz, 2H),
6.51 (d, J = 6.5 Hz, 2H), 3.73 (s, 3H), 3.06 (s, 12H); 13C NMR (126
MHz, DMSO-d6) δ 172.8 (s), 149.3 (d, J = 241.6 Hz), 144.9 (d, J =
10.3 Hz), 140.4 (s), 113.5 (s), 111.3 (d, J = 22.3 Hz), 102.2 (d, J =
3.3 Hz), 42.0 (d, J = 5.5 Hz), 34.2 (s); IR (film) 2916, 1602, 1329,
1267, 750 cm−1; HRMS (ESI) m/z 332.1548 (M + H+, C18H20F2N3O
requires 332.1574).
2,7-Difluoro-3,6-bis(isopropylamino)-10-methylacridin-9-
(10H)-one (42). Using General Procedure D, 25 (1.70 g, 4.62
mmol), heating to 80 °C for 12 h, and purification by washing with
ether and removal of solvent in vacuo afforded 42 (1.58 g, 95%) mp
232−233 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 12.2 Hz,
2H), 6.33 (d, J = 6.8 Hz, 2H), 4.33 (d, J = 4.0 Hz, 2H), 3.73 (hept, J =
6.6 Hz, 2H), 3.69 (s, 3H), 1.31 (d, J = 6.3 Hz, 2H); 13C NMR (126
MHz, DMSO-d6) δ 172.5 (s), 146.9 (d, J = 244.4 Hz), 141.3 (s), 140.8
(d, J = 13.9 Hz), 110.4 (d, J = 5.1 Hz), 109.3 (d, J = 18.9 Hz), 94.9 (d,
J = 3.1 Hz), 43.1 (s), 34.3 (s), 21.9 (s); IR (film) 3405, 3302, 2970,
1623, 1596, 1505, 1284, 1034, 800 cm−1; HRMS (ESI) m/z 360.1866
(M + H+, C20H24F2N3O requires 360.1887).
3-Amino-6-(dimethylamino)-2,7-difluoro-10-methylacridin-
9(10H)-one (43). Using General Procedure D, 21 (300 mg, 1.05
mmol), a reaction time of 12 h, and purification by washing with ether
and removal of solvent in vacuo afforded 43 (295 mg, 93%): mp 263−
264 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 14.3 Hz, 1H),
7.71 (d, J = 11.7 Hz, 1H), 6.89 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 7.6 Hz,
1H), 6.24 (s, 2H), 3.75 (s, 3H), 3.03 (s, 6H); 13C NMR (101 MHz,
DMSO-d6) δ 173.3 (s), 149.8 (d, J = 200.6 Hz), 147.4 (d, J = 250.7
Hz), 145.1 (d, J = 10.3 Hz), 143.3 (s), 143.1 (s), 141.5 (s), 140.5 (s),
113.9 (d, J = 6.3 Hz), 111.8 (d, J = 22.3 Hz), 110.6 (d, J = 18.6 Hz),
102.5 (d, J = 3.3 Hz), 99.0 (d, J = 3.9 Hz), 42.5 (s), 34.4 (s); IR (film)
3322, 3176, 1619, 1493, 1309, 1256, 1026, 902, 777 cm−1; HRMS
(ESI) m/z 304.1260 (M + H+, C16H16F2N3O requires 304.1261).
2,7-Difluoro-10-methyl-3,6-di(piperidin-1-yl)acridin-9(10H)-
one (44). Using General Procedure D, 27 (1.50 g, 3.58 mmol), a
reaction time of 4 h, and purification by washing the product with
ether and removal of solvent in vacuo afforded 44 (1.37 g, 93%): mp
1
243−244 °C; H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 12.1 Hz,
2H), 6.69 (d, J = 6.9 Hz, 2H), 3.74 (s, 3H), 3.21 (t, J = 5.2 Hz, 8H),
1.79 (p, J = 5.2 Hz, 8H), 1.64 (hept, J = 5.2 Hz, 4H); 13C NMR
(126 MHz, CDCl3) δ 174.9 (s), 151.1 (d, J = 245.7 Hz), 146.5 (d, J =
10.4 Hz), 140.3 (s), 115.9 (d, J = 6.7 Hz), 112.6 (d, J = 22.5 Hz),
102.9 (d, J = 2.7 Hz), 51.5 (d, J = 4.5 Hz), 34.2 (s), 26.0 (s), 24.2 (s);
IR (film) 2938, 2846, 1624, 1597, 1494, 1274, 1225, 1145, 783 cm−1;
HRMS (ESI) m/z 412.2196 (M + H+, C24H28F2N3O requires
412.2200).
3-(Dimethylamino)-2,7-difluoro-10-methyl-6-(piperidin-1-yl)-
acridin-9(10H)-one (45). Using General Procedure D, 28 (355 mg,
1.00 mmol), a reaction time of 12 h, and purification by washing with
ether and removal of solvent in vacuo afforded 45 (338 mg, 91%): mp
1
227−229 °C; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 12.6 Hz,
1H), 7.96 (d, J = 14.2 Hz, 1H), 6.65 (d, J = 6.9 Hz, 1H), 6.43 (d, J =
7.2 Hz, 1H), 3.67 (s, 3H), 3.19 (t, J = 5.2 Hz, 4H), 3.05 (s, 6H), 1.78
(p, J = 5.4 Hz, 4H), 1.65 (p, J = 5.4 Hz, 2H); 13C NMR (126 MHz,
DMSO-d6) δ 173.6 (s), 151.3 (d, J = 138.6 Hz), 149.5 (d, J = 127.8 Hz),
146.1 (d, J = 10.4 Hz), 145.5 (d, J = 10.0 Hz), 141.1 (s), 141.0 (s),
115.5 (s), 114.2 (s), 111.9 (d, J = 22.5 Hz), 111.7 (d, J = 22.6 Hz),
104.7 (d, J = 2.6 Hz), 102.4 (d, J = 3.4 Hz), 51.5 (d, J = 4.7 Hz), 42.5
(d, J = 5.8 Hz), 34.7 (s), 26.0 (s), 24.2 (s); IR (film) 2836, 1626, 1601,
1503, 1280, 1011, 895 cm−1; HRMS (ESI) m/z 372.1889 (M + H+,
C21H24F2N3O requires 372.1887).
479
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
afforded dihydroxyacridone 50 (17.0 mg, 91%): mp 247−249 °C;
1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 11.2 Hz, 2H), 7.25−
7.45 (m, 3H), 7.18 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 5.53
(s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 173.6 (s), 151.2 (s), 147.8
(d, J = 241.4 Hz), 140.3 (s), 135.6 (s), 129.0 (s), 127.4 (s), 125.7 (s),
113.8 (s), 111.6 (d, J = 18.9 Hz), 102.8 (s), 50.3 (s); IR (film) 3369,
3050, 3007, 1629, 1574, 1490, 1276, 750 cm−1; HRMS (ESI) m/z
352.0776 (M − H, C20H12F2NO3 requires 352.0785).
2,7-Difluoro-3,6-dihydroxy-10-phenylacridin-9(10H)-one
(51). Using General Procedure E, 48 (20.0 mg, 0.0545 mmol)
afforded dihydroxylacridone 51 (14.6 mg, 79%): mp 257−259 °C;
1H NMR (400 MHz, CD3OD) δ 8.10 (d, J = 11.2 Hz, 2H), 7.75−7.90
(m, 3H), 7.49 (d, J = 6.8 Hz, 2H), 6.36 (d, J = 7.2 Hz, 2H); 13C NMR
(126 MHz, CD3OD) δ 174.4 (s), 154.1 (d, J = 15.5 Hz), 150.7 (d, J =
245.7 Hz), 143.3 (s), 140.1 (s), 132.6 (s), 131.6 (s), 130.6 (s), 113.6
(d, J = 6.2 Hz), 112.0 (d, J = 20.4 Hz), 104.8 (d, J = 2.4 Hz); IR (film)
3369, 3064, 2924, 1727, 1624, 1547, 1489, 1395, 1268, 1193, 893
cm−1; HRMS (ESI) m/z 338.0609 (M − H, C19H10F2NO3 requires
338.0629).
2,7-Difluoro-3,6-dimethoxy-9H-thioxanthen-9-one (52).
Using General Procedure F, 19 (3.15 g, 10.0 mmol), 26 °C, and
purification by washing with water (3 × 100 mL), methanol (3 ×
50 mL), acetone (3 × 50 mL), and removal of solvent in vacuo
afforded 52 (2.74 g, 92%): mp >300 °C; 1H NMR (400 MHz, DMSO-d6)
δ 8.13 (d, J = 12.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 4.032
(s, 2H); IR (film) 3047, 2967, 1603, 1419, 1346, 1263, 1046, 894, 771
cm−1; HRMS (ESI) m/z 309.0407 (M + H+, C15H11F2O3S requires
309.0397).
2,7-Difluoro-3,6-dihydroxy-9H-thioxanthen-9-one (53).
Using General Procedure F, 19 (1.58 g, 5.00 mmol), heating to
90 °C, and purification by column chromatography (1−3% MeOH
in CH2Cl2) afforded 53 (1.04 g, 74%): mp >300 °C; 1H NMR
(400 MHz, DMSO-d6) δ 8.03 (d, J = 12.0 Hz, 2H), 7.17 (d, J = 8.0 Hz,
2H), 3.42 (br s, 2H); 13C NMR (126 MHz, DMSO) δ 175.7 (s), 150.5
(d, J = 243.2 Hz), 150.2 (d, J = 14.1 Hz), 133.4 (d, J = 1.9 Hz), 120.1
(d, J = 5.0 Hz), 115.3 (d, J = 19.5 Hz), 112.7 (d, J = 2.7 Hz); IR (film)
3393, 3064, 1617, 1553, 1502, 1413, 1391, 1303, 1287, 1182, 1114,
903 cm−1; HRMS (ESI) m/z 278.9924 (M − H, C13H5F2O3S requires
278.9927).
1026, 774 cm−1; HRMS (ESI) m/z 363.1338 (M + H+, C19H21-
F2N2OS requires 363.1343).
3,6-Bis(tert-butylamino)-2,7-difluoro-9H-thioxanthen-9-one
(57). Using General Procedure F, 26 (300 mg, 0.762 mmol), and
purification by column chromatography (10−20% EtOAc in hexanes)
1
afforded 57 (263 mg, 89%): mp 199−201 °C; H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 13.2 Hz, 2H), 6.33 (d, J = 7.8 Hz, 2H), 4.57
(d, J = 4.6 Hz, 2H), 1.47 (s, 18H), 1.31 (d, J = 6.3 Hz, 2H); 13C NMR
(126 MHz, CDCl3) δ 176.9 (s), 150.9 (d, J = 241.0 Hz), 139.2 (d, J =
12.2 Hz), 135.6−132.8 (m), 118.0 (d, J = 6.1 Hz), 113.6 (d, J = 21.3
Hz), 106.6 (s), 51.4 (s), 29.3 (s); IR (film) 3437, 2978, 1598, 1514,
1420, 1364, 1202 cm−1; HRMS (ESI) m/z 391.1649 (M + H+,
C21H25F2N2OS requires 391.1656).
2,7-Difluoro-3,6-di(piperidin-1-yl)-9H-thioxanthen-9-one
(58). Using General Procedure F, 27 (400 mg, 1.00 mmol), and
purification by column chromatography (10−20% EtOAc in hexanes)
1
afforded 58 (352 mg, 85%): mp 205−206 °C; H NMR (400 MHz,
CDCl3) δ 8.15 (d, J = 14.3 Hz, 2H), 6.87 (d, J = 7.7 Hz, 2H), 3.23 (t,
J = 5.2 Hz, 8H), 1.75 (p, J = 5.2 Hz, 8H), 1.63 (hept, J = 5.2 Hz, 4H);
13C NMR (126 MHz, CDCl3) δ 177.1 (s), 153.9 (d, J = 238.1 Hz),
145.1 (d, J = 10.0 Hz), 133.9 (s), 122.0 (d, J = 6.5 Hz), 115.8 (d, J =
23.2 Hz), 113.3 (d, J = 3.0 Hz), 51.2 (d, J = 4.8 Hz), 25.8 (s), 24.2 (s);
IR (film) νmax 2936, 2852, 1624, 1597, 1497, 1420, 1350, 1269, 1252,
1240, 1115, 750 cm−1; HRMS (ESI) m/z 415.1650 (M + H+,
C23H25F2N2OS requires 415.1656).
2,7-Difluoro-3,6-dimorpholino-9H-thioxanthen-9-one (59).
Using General Procedure F, 29 (213 mg, 0.500 mmol), and purifi-
cation by column chromatography (15−30% EtOAc in hexanes)
1
afforded 59 (195 mg, 94%): mp 275−276 °C; H NMR (400 MHz,
CDCl3) δ 8.16 (d, J = 14.2 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 3.90 (t,
J = 4.7 Hz, 8H), 3.26 (t, J = 4.7 Hz, 8H); 13C NMR (126 MHz,
CDCl3) δ 176.0 (s), 152.9 (d, J = 258.3 Hz), 143.1 (d, J = 9.9 Hz),
132.8 (d, J = 2.0 Hz), 122.0 (d, J = 6.7 Hz), 115.1 (d, J = 23.1 Hz),
112.1 (d, J = 2.8 Hz), 65.6 (s), 49.1 (d, J = 4.7 Hz); IR (film) 2990,
2923, 2887, 1602, 1499, 1426, 1271, 1122, 1006 cm−1; HRMS (ESI)
m/z 441.1056 (M + Na+, C21H20F2N2O3SNa requires 441.1060).
ASSOCIATED CONTENT
■
S
* Supporting Information
3,6-Bis(dimethylamino)-2,7-difluoro-9H-thioxanthen-9-one
(54). Using General Procedure F, 22 (150 mg, 0.440 mmol), and
purification by column chromatography (10−20% EtOAc in hexanes)
Methods and data used to determine quantum yields and molar
extinction coefficients, and absorption, fluorescence emission,
1H NMR, and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
afforded 54 (134 mg, 91%): mp 218−220 °C; H NMR (400 MHz,
CDCl3) δ 8.08 (d, J = 15.1 Hz, 2H), 6.63 (d, J = 8.0 Hz, 2H), 3.02
(s, 12H); 13C NMR (126 MHz, CDCl3) δ 175.8 (s), 151.4 (d, J =
246.1 Hz), 142.7 (d, J = 10.0 Hz), 132.9 (s), 119.5 (d, J = 6.3 Hz),
114.8 (d, J = 23.5 Hz), 110.0 (d, J = 3.7 Hz), 41.1 (d, J = 6.0 Hz); IR
(film) 2907, 2898, 2853, 1682, 1601, 1583, 1354, 1256, 1116, 722
cm−1; HRMS (ESI) m/z 335.1042 (M + H+, C17H17F2N2OS requires
335.1030).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: brpeters@ku.edu.
3,6-Bis(diethylamino)-2,7-difluoro-9H-thioxanthen-9-one
(55). Using General Procedure F, 23 (1.10 g, 2.77 mmol), and
purification by column chromatography (10−20% EtOAc in hexanes)
ACKNOWLEDGMENTS
■
1
We thank the NIH (R01 CA83831 and RC1 GM091086) for
financial support. Z.W. thanks the NIH for an IRACDA
postdoctoral fellowship.
afforded 55 (973 mg, 90%): mp 145−147 °C; H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 15.6 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 3.40
(q, J = 7.0 Hz, 8H), 1.21 (t, J = 7.0 Hz, 12H); 13C NMR (101 MHz,
CDCl3) δ 176.7 (s), 152.1 (d, J = 312.5 Hz), 141.8 (d, J = 9.9 Hz),
134.0 (d, J = 1.5 Hz), 119.7 (s), 116.3 (d, J = 24.3 Hz), 110.6 (s), 46.0
(d, J = 5.8 Hz), 13.0 (d, J = 1.5 Hz); IR (film) 2972, 2931, 2872, 1590,
1504, 1426, 1352, 1264, 1238, 1071, 901, 790 cm−1; HRMS (ESI) m/z
391.1662 (M + H+, C21H25F2N2OS requires 391.1656).
REFERENCES
■
(1) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−1886.
(2) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359−4369.
(3) Lavis, L. D.; Raines, R. T. ACS Chem. Biol. 2008, 3, 142−155.
(4) Funabiki, K.; Sugiyama, N.; Iida, H.; Jin, J.-Y.; Yoshida, T.; Kato,
Y.; Minoura, H.; Matsui, M. J. Fluorine Chem. 2006, 127, 257−262.
(5) Sun, W. C.; Gee, K. R.; Klaubert, D. H.; Haugland, R. P. J. Org.
Chem. 1997, 62, 6469−6475.
(6) Lavis, L. D.; Rutkoski, T. J.; Raines, R. T. Anal. Chem. 2007, 79,
6775−6782.
(7) Liu, J. X.; Diwu, Z. J.; Leung, W. Y. Bioorg. Med. Chem. Lett. 2001,
11, 2903−2905.
2,7-Difluoro-3,6-bis(isopropylamino)-9H-thioxanthen-9-one
(56). Using General Procedure F, 25 (1.00 g, 2.71 mmol), and puri-
fication by column chromatography (CH2Cl) afforded 56 (834 mg,
1
85%): mp 164−165 °C; H NMR (400 MHz, CDCl3) δ 8.14 (d,
J = 12.8 Hz, 2H), 6.59 (d, J = 7.6 Hz, 2H), 4.41 (br s, 2H), 3.74 (hept,
J = 6.4 Hz, 2H), 1.33 (d, J = 6.4 Hz, 12H); 13C NMR (126 MHz,
CDCl3) 176.9 (s), 150.4 (d, J = 225.5 Hz), 139.3 (d, J = 41.6 Hz),
134.8 (s), 118.2 (s), 113.8 (d, J = 18.9 Hz), 104.9 (s), 44.0 (s), 22.6
(s); IR (film) 3435, 3322, 2969, 1610, 1592, 1515, 1426, 1287, 1326,
480
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481

The Journal of Organic Chemistry
Article
(8) Spagnuolo, C. C.; Massad, W.; Miskoski, S.; Menendez, G. O.;
Garcia, N. A.; Jares-Erijman, E. A. Photochem. Photobiol. 2009, 85,
1082−1088.
(39) Gibson, S. L.; Holt, J. J.; Ye, M.; Donnelly, D. J.; Ohulchanskyy,
T. Y.; You, Y.; Detty, M. R. Bioorg. Med. Chem. 2005, 13, 6394−6403.
(40) Ahn, Y. H.; Lee, J. S.; Chang, Y. T. J. Am. Chem. Soc. 2007, 129,
4510−4501.
(9) Urano, Y.; Kamiya, M.; Kanda, K.; Ueno, T.; Hirose, K.; Nagano,
T. J. Am. Chem. Soc. 2005, 127, 4888−4894.
(41) Wu, L.; Burgess, K. J. Org. Chem. 2008, 73, 8711−8718.
(42) Lubenets, E. G.; Gerasimova, T. N.; Fokin, E. P. Zh. Org. Khim.
1971, 7, 805−812.
(10) Mottram, L. F.; Boonyarattanakalin, S.; Kovel, R. E.; Peterson,
B. R. Org. Lett. 2006, 8, 581−584.
(11) Mottram, L. F.; Maddox, E.; Schwab, M.; Beaufils, F.; Peterson,
B. R. Org. Lett. 2007, 9, 3741−3744.
(43) Eggins, B. R. Tetrahedron 1975, 31, 1191−1194.
(44) Dmitrieva, L. L.; Babushkin, V. A.; Kurov, G. N.; Nechvold,
G. V.; Smirnov, V. I. Zh. Prikl. Khim. 1993, 66, 610−614.
(45) Wu, L.; Burgess, K. Org. Lett. 2008, 10, 1779−1782.
(46) Simanek, E. E.; Chouai, A. J. Org. Chem. 2008, 73, 2357−2366.
(47) Cartwright, M. W.; Convery, L.; Kraynck, T.; Sandford, G.;
Yufit, D. S.; Howard, J. A. K.; Christopher, J. A.; Miller, D. D.
Tetrahedron 2010, 66, 519−529.
(12) Mitronova, G. Y.; Belov, V. N.; Bossi, M. L.; Wurm, C. A.;
Meyer, L.; Medda, R.; Moneron, G.; Bretschneider, S.; Eggeling, C.;
Jakobs, S.; Hell, S. W. Chem.Eur. J. 2010, 16, 4477−4488.
(13) Pinto, M. M.; Sousa, M. E.; Nascimento, M. S. Curr. Med. Chem.
2005, 12, 2517−2538.
(14) Watterson, S. H.; Chen, P.; Zhao, Y.; Gu, H. H.; Dhar, T. G.;
Xiao, Z.; Ballentine, S. K.; Shen, Z.; Fleener, C. A.; Rouleau, K. A.;
Obermeier, M.; Yang, Z.; McIntyre, K. W.; Shuster, D. J.; Witmer, M.;
Dambach, D.; Chao, S.; Mathur, A.; Chen, B. C.; Barrish, J. C.; Robl,
J. A.; Townsend, R.; Iwanowicz, E. J. J. Med. Chem. 2007, 50, 3730−
3742.
(15) Matsumoto, K.; Akao, Y.; Yi, H.; Ohguchi, K.; Ito, T.; Tanaka,
T.; Kobayashi, E.; Iinuma, M.; Nozawa, Y. Bioorg. Med. Chem. 2004,
12, 5799−5806.
(16) Schwaebe, M. K.; Moran, T. J.; Whitten, J. P. Tetrahedron Lett.
2005, 827−829.
(17) Pouli, N.; Marakos, P. Anticancer Agents Med. Chem. 2009, 9,
77−98.
(48) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Am. Chem. Soc.
1987, 52, 2559−2562.
(49) Williams, A. T.; Winfield, S. A. Analyst 1983, 108, 1067−1071.
(50) Morris, J. V.; Mahaney, M. A.; Huber, J. R. J. Phys. Chem. 1976,
80, 969−974.
(51) Dawson, W. R.; Windsor, M. W. J. Phys. Chem. 1968, 72, 3251−
3260.
(18) Matsumoto, K.; Akao, Y.; Ohguchi, K.; Ito, T.; Tanaka, T.;
Iinuma, M.; Nozawa, Y. Bioorg. Med. Chem. 2005, 13, 6064−6069.
(19) Na, Y. J. Pharm. Pharmacol. 2009, 61, 707−712.
(20) Pedro, M.; Cerqueira, F.; Sousa, M. E.; Nascimento, M. S.;
Pinto, M. Bioorg. Med. Chem. 2002, 10, 3725−3730.
(21) Dodean, R. A.; Kelly, J. X.; Peyton, D.; Gard, G. L.; Riscoe,
M. K.; Winter, R. W. Bioorg. Med. Chem. 2008, 16, 1174−1183.
(22) Riscoe, M.; Kelly, J. X.; Winter, R. Curr. Med. Chem. 2005, 12,
2539−2549.
(23) Poondru, S.; Zhou, S.; Rake, J.; Shackleton, G.; Corbett, T. H.;
Parchment, R. E.; Jasti, B. R. J. Chromatogr., B 2001, 759, 175−178.
(24) Corbett, T. H.; Valeriote, F. A.; Demchik, L.; Lowichik, N.;
Polin, L.; Panchapor, C.; Pugh, S.; White, K.; Kushner, J.; Rake, J.;
Wentland, M.; Golakoti, T.; Hetzel, C.; Ogino, J.; Patterson, G.;
Moore, R. Invest. New Drugs 1997, 15, 207−218.
(25) Manfroni, G.; Paeshuyse, J.; Massari, S.; Zanoli, S.; Gatto, B.;
Maga, G.; Tabarrini, O.; Cecchetti, V.; Fravolini, A.; Neyts, J. J. Med.
Chem. 2009, 52, 3354−3365.
(26) Li, J.; Hu, M.; Yao, S. Q. Org. Lett. 2009, 11, 3008−3011.
(27) Chen, C. A.; Yeh, R. H.; Lawrence, D. S. J. Am. Chem. Soc. 2002,
124, 3840−3841.
(28) Egawa, T.; Koide, Y.; Hanaoka, K.; Komatsu, T.; Terai, T.;
Nagano, T. Chem Commun. 2011, 47, 4162−4164.
(29) Li, J.; Yao, S. Q. Org. Lett. 2009, 11, 405−408.
(30) Gannon, M. K.; Detty, M. R. J. Org. Chem. 2007, 72, 2647−
2650.
(31) Calitree, B. D.; Detty, M. R. Synlett 2010, 89−92.
(32) Lim, S. H.; Wu, L.; Burgess, K.; Lee, H. B. Anticancer Drugs
2009, 20, 461−468.
(33) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273−4275.
(34) MacNeil, S. L.; Wilson, B. J.; Snieckus, V. Org. Lett. 2006, 8,
1133−1136.
(35) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117−
3119.
(36) Johnson, M. M.; Naidoo, J. M.; Fernandes, M. A.; Mmutlane,
E. M.; van Otterlo, W. A.; de Koning, C. B. J. Org. Chem. 2010, 75,
8701−8714.
(37) Gong, J.; Xie, F.; Chen, H.; Hu, Y. Org. Lett. 2010, 12, 3848−
3851.
(38) Zhao, L.; Xie, F.; Cheng, G.; Hu, Y. Angew. Chem., Int. Ed. 2009,
48, 6520−6523.
481
dx.doi.org/10.1021/jo202062f | J. Org. Chem. 2012, 77, 473−481