Synthesis of heterocyclic compounds via nucleophilic aroylation catalyzed by imidazolidenyl carbene

Article abstract of DOI:10.1248/cpb.54.1653

Xanthones and acridones were synthesized from 3,4-difluoronitrobenzene and 2-fluorobenzaldehydes in two or three steps. The key step was nucleophilic aroylation catalyzed by imidazolidenyl carbene. The nucleophilic aroylation of 3,4-difluoronitrobenzene a

Full text of DOI:10.1248/cpb.54.1653

December 2006
Chem. Pharm. Bull. 54(12) 1653—1658 (2006)
1653
Synthesis of Heterocyclic Compounds via Nucleophilic Aroylation
Catalyzed by Imidazolidenyl Carbene
Yumiko SUZUKI,* Tomonori TOYOTA, Akira MIYASHITA, and Masayuki SATO
School of Pharmaceutical Sciences, University of Shizuoka; 52–1 Yada, Suruga-ku, Shizuoka 422–8526, Japan.
Received July 28, 2006; accepted September 6, 2006; published online September 12, 2006
Xanthones and acridones were synthesized from 3,4-difluoronitrobenzene and 2-fluorobenzaldehydes in two
or three steps. The key step was nucleophilic aroylation catalyzed by imidazolidenyl carbene. The nucleophilic
aroylation of 3,4-difluoronitrobenzene afforded 2,2ꢀ-difluoro-4-nitrobenzophenones. The cyclization of the difluo-
robenzophenones with O-nucleophile and N-nucleophile yielded 3-nitroxanthones and 3-nitroacridones, respec-
tively. Indazole, quinolino[2,3-b]quinoxaline, and thianaphtho[2,3-b]quinoxaline derivatives were also synthe-
sized via nucleophilic aroylation of 2,3-dichloroquinoxaline followed by cyclization with nucleophiles.
Key words nucleophilic aroylation; N-heterocyclic carbene; organocatalysis; xanthone; acridone
N-Heterocyclic carbenes (NHCs) are nucleophilic and ex- Results and Discussion
cellent s-donors. They readily form complexes with transi-
Among the xanthone and acridone families, there are quite
tion metals. Since 1990s, the use of NHCs as ligands has a few compounds that are reported to exhibit bioactivities
lead to significant advancements in the area of Pd-catalyzed such as antitumor, antibacteria, and antivirus.24—29) From
carbon–carbon bond-forming reactions,1) Ru-catalyzed olefin both chemical and pharmaceutical viewpoints, it would be
metathesis,2) and Rh-catalyzed hydrosilylations.3—5) NHCs significant to provide a new synthetic route to these hetero-
have also attracted significant attention as organocatalysts. cyclic compounds.
Several reactions have been catalyzed by NHCs, for e.g.,
There are two major routes to synthesize xanthones.30) The
benzoin condensation,6—11) Stetter reaction,12—14) transesteri- first one is based on the cyclization of 2-hydroxybenzophe-
fication/acylation reaction,15,16) and cyanosilylation.17—19)
nones,31—33) and the second involves the cyclodehydration of
We have previously reported NHC-catalyzed nucleophilic o-phenoxybenzoic acids.34—36) Our method is based on the
substitution on aromatic heterocyclic rings.20—22) It was con- cyclization of 2,2ꢀ-difluorobenzophenones 5 prepared by
sidered impossible to introduce aroyl groups directly into the NHC-catalyzed aroylation of 3,4-difluoronitrobenzene (3)
electron-deficient positions of aromatic rings in the conven-
tional electrophilic acylation reaction—Friedel–Crafts reac-
tion. In this NHC-catalyzed reaction, the aroyl groups (de-
rived from aromatic aldehydes) are directly introduced into
heteroarenes by nucleophilic aromatic substitution under the
catalysis of 1,3-dimethylimidazolidenyl carbene 2 that is ob-
tained from 1,3-dimethylimidazolium iodide (1) (Chart 1). In
other words, aromatic ketones can be synthesized from alde-
hydes and heterocyclic compounds by NHC catalysis in a
single step.
We have recently broadened the scope of reaction sub-
strates to include benzene rings by using fluoride ion as a
leaving group.23) Aroylation was presented as a new method
to synthesize benzophenone derivatives from fluorobenzenes
and benzaldehydes. The reaction mechanism is shown in
Chart 2.
Chart 2. Reaction Mechanism of Aroylation of 4-Fluoronitrobenzene
In order to develop a new synthetic route to heterocyclic
compounds, we examined NHC-catalyzed aroylation as a
tool for the syntheses of heterocycles. In this study, we report
the syntheses of xanthones 6, acridones 7, and other hetero-
cyclic compounds via NHC-catalyzed aroylation (Chart 3).
Chart 1
Chart 3
∗ To whom correspondence should be addressed. e-mail: suzuyumi@u-shizuoka-ken.ac.jp
© 2006 Pharmaceutical Society of Japan

1654
Vol. 54, No. 12
Table 1. Nucleophilic Aroylation of 3,4-Difluoronitrobenzene (3) with Benzaldehydes 4a—f
Entry
Aldehyde
R
X
Benzophenone Yield (%)
Diketone
Yield (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
H
F
F
F
F
Cl
F
5a
5b
5c
5d
5e
5f
70
63
63
35
64
27
8a
8b
8c
8d
8e
8f
1
8
8
2
7
4-F
5-F
6-F
H
6-Cl
—
chloro-2-hydroxy-4-nitrobenzophenone (9) was obtained in
30% yield (entry 5). It is well known that fluoro substituents
are more susceptible to nucleophilic aromatic substitution
than chloro substituents. The ring closure of 2ꢀ-chloro-2,6ꢀ-
difluoro-4-nitrobenzophenone (5f) took place at 2-position
and 6ꢀ-position, and the chloro group at 2ꢀ-position remained
intact. Fluoro groups at 2- and 6ꢀ-positions were replaced by
an oxgen nucleophile to yield 1-chloro-6-nitroxanthone (6f).
The product 6d, which can be produced by the replacement
of 2ꢀ-chloro group, was not obtained.
The synthesis of acridones was also examined. There are
several routes to synthesize acridones37)—intramolecular nu-
cleophilic substitution of 2ꢀ-O-substituted 2-aminobenzophe-
nones,38) acid catalyzed cyclization of N-phenylanthranilic
acid,39) and pyrolysis or photolysis of 3-arylanthranils.40)
Analogous to xanthone synthesis, our acridone synthesis is
based on the cyclization of 2,2ꢀ-difluorobenzophenones by
Table 2. Synthesis of Xanthones
Benzophenone
Entry
Xanthone
R
X
R
Yield (%)
1
2
3
4
5
6
H
F
F
F
F
Cl
Cl
5a
5b
5c
5d
5e
5f
H
6a
6b
6c
6d
6a
6f
65
30
33
35
12a)
62
4ꢀ-F
5ꢀ-F
6ꢀ-F
H
3-F
2-F
1-F
H
6ꢀ-F
1-Cl
a) Along with 6a, compound 9 was obtained in 30% yield.
and fluorobenzaldehydes 4 (Chart 2). Two o-fluoro sub- the substitution of two o-florines with one N-nucleophile.
stituents of benzophenones 5 are replaced by an oxygen nu- The reaction between difluorobenzophenones 5a and pri-
cleophile in a reaction with aqueous alkali to afford a xan- mary amines 10a, b was carried out in refluxing 1,4-dioxane
thone structure. to obtain 2-amino-4-nitro-2ꢀ-fluorobenzophenones 11a,b in
The first step in the synthesis of xanthone is the prepara- good yields (Table 3, entries 1, 2). Acridone 7a was obtained
tion of 2,2ꢀ-difluorobenzophenones 5. The aroylation of 3,4- in 2% yield in the reaction of 10a. The reaction between ben-
difluoronitrobenzene (3) was carried out according to the zophenone 5a and amine 10c in anisole at 150 °C afforded a
method we reported previously.23) The NHC—imidazolidenyl 2-amino compound 11c in 75% yield (Table 3, entry 3). The
carbene 2—was generated in situ from the precursor 1,3-di- isolated 10a—c were heated in N,N-dimethylformamide
methylimidazolium iodide (1) and used as a catalyst. The re- (DMF) at 150 °C to obtain acridones 7a—c in 55—96%
action of 3 with benzaldehydes 4a—f, which have 2-fluoro or yields (Table 4).
2-chloro substituents, produced the corresponding benzophe-
In order to synthesize acridone from benzophenone 5a in a
nones 5a—f in 27—70% yields, along with the recovery of single step, the reaction of 5a with 10c was carried out in
the starting materials and diketones 8a—e (Table 1). In the DMF at 150 °C for 24 h (Chart 4). The reaction afforded 9-
reaction with 2,6-disubstituted benzaldehydes (4d, f), the benzyl-4-nitroacridone (7c) in 39% yield, but 9-methyl-4-ni-
steric hindrance caused by two ortho-substituents seems to troacridone (7a) was also produced in 35% yield. It appeared
lower the yields (entries 4, 6). Nitro group behaves as a leav- that dimethylamine derived from the DMF reacted with the
ing group in nucleophilic aromatic substitutions. The nitro starting material 5a to yield 7a. To avoid this undesired reac-
groups of major products 5a—e were substituted with ben- tion, dimethylsulfoxide (DMSO) was used as a solvent in-
zoyl groups by nucleophilic aroylation to yield 8a—e.
stead of DMF to produce only 7c in 72% yield.
Cyclization to xanthones was conducted by the treatment
When methylhydrazine was used as a nucleophile in the
of benzophenones 5a—f with 10% aqueous solution of cyclization reaction, an indazole derivative 12 was synthe-
sodium hydroxide in refluxing 1,4-dioxane (Table 2). Two sized from 5a (Chart 5). The indazole structure was formed
fluorine atoms—ortho to carbonyl group of 5a—d—were through the imine formation between 5a and hydrazine, fol-
continuously replaced by one oxygen atom to form xan- lowed by the intramolecular nucleophilic substitution of o-
thones 6a—d (entries 1—4). Benzophenone 5e has 2ꢀ-chloro fluorine by methyl-substituted nitrogen.
and 2-fluoro substituents instead of two o-fluoro groups. The
The syntheses of tetracyclic fused quinoxalines were ex-
chlorine atom was replaced and 5e was cyclized to 6a; how- amined by using the same method as that for xanthone and
ever, the yield was poor and a non-cyclized compound 2ꢀ- acridone syntheses (Chart 6). The starting material used was

December 2006
1655
Table 3. Amination of 2,2ꢀ-Difluoro-4-nitrobenzophenone (5a)
Entry
R
Amine
Solvent
Temp.
Time (h)
Product
Yield (%)
1
2
3
Methyl
Isopropyl
Benzyl
10a
10b
10c
1,4-Dioxane
1,4-Dioxane
Anisole
Reflux
Reflux
150 °C
6
3
3
11a
11b
11c
95a)
91
75
a) Along with 11a, 10-methyl-3-nitroacridone (7a) was obtained in 2% yield.
Table 4. Synthesis of Acridones
Entry
R
Time (h)
Product
Yield (%)
1
2
3
Methyl
Isopropyl
Benzyl
11a
11b
11c
12
24
24
7a
7b
7c
96
55
63
Chart 5. Synthesis of 3-(2-Fluorophenyl)-1-methyl-6-nitroindazole (12)
Chart 4
Chart 6. Synthesis of Tetracyclic Compounds via Aroylation

1656
Vol. 54, No. 12
4-Nitro-2,2ꢀ,5ꢀ-trifluorobenzophenone (5c): Colorless prisms (recrystal-
lized from n-hexane/dichloromethane). mp 76—77 °C. IR (KBr) cmꢁ1: 1664
(CO). H-NMR (CDCl3) d: 7.13 (1H, td, Jꢂ9.2, 4.6 Hz), 7.28—7.36 (1H,
m), 7.48—7.54 (1H, m), 7.86 (1H, dd, Jꢂ8.6, 6.9 Hz), 8.02 (1H, dd, Jꢂ9.6,
2.0 Hz), 8.16 (dd, Jꢂ8.6, 2.0 Hz). GC-MS (EI) m/z 281 (Mꢃ). Anal. Calcd
for C13H6F3NO3: C, 55.53; H, 2.15; N, 4.98. Found: C, 55.49; H, 2.11; N,
4.62.
2,3-dichloroquinoxaline (13). The aroylation of 13 with 4a
(1.2 eq) afforded mono-benzoylated 2-chloro-3-(2-fluoroben-
zoyl)quinoxaline (14). The 2-chloro substituent of quinoxa-
line 14 was replaced by the reaction with 40% aqueous solu-
tion of methylamine (10a) to yield a 2-methylamino deriva-
tive 15. Further, 15 was quantitively cyclized to quino-
lino[2,3-b]quinoxaline 16 by treatment with potassium car-
bonate. The reaction of 14 with thioacetic acid was carried
out in refluxing methanol for 4 h. Thianaphtho[2,3-b]quinox-
1
4-Nitro-2,2ꢀ,6ꢀ-trifluorobenzophenone (5d): Colorless needles (recrystal-
lized from n-hexane/dichloromethane). mp 101—102 °C. IR (KBr) cmꢁ1
:
1
1681 (CO). H-NMR (CDCl3) d: 7.02 (2H, td, Jꢂ8.2, 1.7 Hz), 7.52 (1H, tt,
Jꢂ8.2, 6.3 Hz), 7.98—8.05 (2H, m), 8.15 (dd, Jꢂ8.6, 2.0 Hz). 13C-NMR
aline 17 was produced in 46% yield, along with a non-cy- (CDCl3) d: 112.2 (dd, JFCꢂ21.8, 3.2 Hz), 112.7 (d, JFCꢂ28.1 Hz), 117.3 (t,
J
J
J
FCꢂ17.5 Hz), 119.5 (d, JFCꢂ4.1 Hz), 131.5 (d, JFCꢂ11.4 Hz), 132.1 (d,
FCꢂ2.1 Hz), 133.8 (t, JFCꢂ10.9 Hz), 151.2 (d, JFCꢂ8.3 Hz), 160.3 (dd,
FCꢂ255.4, 6.2 Hz), 161.0 (d, JFCꢂ295.9 Hz), 183.8. GC-MS (EI) m/z: 281
clized compound 18.
Conclusion
(Mꢃ). Anal. Calcd for C13H6F3NO3: C, 55.53; H, 2.15; N, 4.98. Found: C,
55.67; H, 1.87; N, 4.69.
We have developed a new route to synthesize xanthones
and acridones. The key step is the N-heterocyclic carbene-
catalyzed nucleophilic aroylation. The fluorine atom at 4-po-
sition of 3,4-difluoronitrobenzene (3) was replaced by 2-fluo-
robenzoyl groups to yield 2,2ꢀ-difluorobenzophenones 5.
Two o-fluorine atoms of benzophenone 5 were substituted by
O- and N-nucleophiles and cyclized to xanthones and
acridones, respectively. The cyclization of 5a with methyl-
hydrazine afforded 3-phenylindazole 12. Quinolino[2,3-
b]quinoxaline and thianaphtho[2,3-b]quinoxaline derivatives
were synthesized from 2,3-dichloroquinoxaline. To the best
of our knowledge, fluorinated xanthones, quinolino[2,3-
b]quinoxaline, and thianaphtho[2,3-b]quinoxaline were syn-
thesized for the first time using the proposed method. We be-
lieve that this method could be useful for the synthesis of
heterocyclic compounds.
2ꢀ-Chloro-2-fluoro-4-nitrobenzophenone (5e): Colorless prisms (recrys-
tallized from n-hexane/dichloromethane). mp 86—87 °C. IR (KBr) cmꢁ1
:
1
1666 (CO), 1528, 1291 (NO2). H-NMR (CDCl3) d: 7.39—7.58 (4H, m),
7.91 (1H, dd, Jꢂ8.2, 6.9 Hz), 7.99 (1H, dd, Jꢂ9.9, 2.0 Hz), 8.14 (ddd,
Jꢂ8.6, 2.3, 1.0 Hz). GC-MS (EI) m/z: 279 (Mꢃ). Anal. Calcd for
C13H7ClFNO3: C, 55.83; H, 2.52; N, 5.01. Found: C, 55.77; H, 2.41; N, 4.68.
2ꢀ-Chloro-2,6ꢀ-difluoro-4-nitrobenzophenone (5f): Slightly yellow nee-
dles (recrystallized from n-hexane/dichloromethane). mp 90—91 °C. IR
(KBr) cmꢁ1: 1675 (CO), 1534, 1347 (NO2). H-NMR (CDCl3) d: 7.12 (2H,
1
td, Jꢂ8.2, 1.0 Hz), 7.29 (1H, d, Jꢂ8.2 Hz), 7.44 (1H, td, Jꢂ8.2, 5.9 Hz),
8.00 (dd, Jꢂ10.2, 2.0 Hz), 8.07 (dd, Jꢂ8.6, 6.9 Hz), 8.15 (dd, Jꢂ8.6,
2.0 Hz). GC-MS (EI) m/z: 297 (Mꢃ). Anal. Calcd for C13H6ClF2NO3: C,
52.46; H, 2.03; N, 4.71. Found: C, 52.73; H, 2.08; N, 4.61.
1,4-Bis(2-fluorobenzoyl)-2-fluorobenzene (8a): Yellow prisms (recrystal-
lized from acetone/n-hexane). mp 132.5—134 °C. IR (KBr) cmꢁ1: 1651
(CO). 1H-NMR (CDCl3) d: 7.10—7.23 (2H, m), 7.26—7.34 (2H, m), 7.55—
7.70 (5H, m), 7.74—7.81 (2H, m). GC-MS (EI) m/z: 340 (Mꢃ). Anal. Calcd
for C20H11F3O2: C, 70.59; H, 3.20. Found: C, 70.48; H, 3.01.
1,4-Bis(2,4-difluorobenzoyl)-2-fluorobenzene (8b): Colorless prisms (re-
Experimental
crystallized from n-hexane/dichloromethane). mp 120—122 °C. IR (KBr)
1
General Melting points are determined using the Yazawa micromelting cmꢁ1: 1653 (CO). H-NMR (CDCl3) d: 6.84—7.09 (4H, m), 7.56 (1H, td,
point apparatus without correction. The H-NMR (270 MHz) and 13C-NMR Jꢂ10.2, 1.3 Hz), 7.63—7.72 (2H, m), 7.76 (dd, Jꢂ7.8, 4.6 Hz), 7.84 (td,
(67.8 MHz) spectra were recorded using the JEOL JNM-GSX270 NMR
spectrometer. The IR spectra were recorded using the Jasco IR-700 infrared 63.84; H, 2.41. Found: C, 63.84; H, 2.13.
1
Jꢂ8.6, 6.3 Hz). GC-MS (EI) m/z: 376 (Mꢃ). Anal. Calcd for C20H9F5O2: C,
spectrophotometer and the Jasco A-102 infrared spectrophotometer. The
1,4-Bis(2,5-difluorobenzoyl)-2-fluorobenzene (8c): Colorless prisms (re-
GC-MS (EI) spectra were recorded using the JEOL JMS AX505W mass crystallized from n-hexane/dichloromethane). mp 148—150 °C. IR (KBr)
1
spectrometer. The MS (FAB) spectra were recorded using the JEOL JMS- cmꢁ1: 1667 (CO). H-NMR (CDCl3) d: 7.12 (1H, td, Jꢂ8.9, 4.9 Hz), 7.20
SX102 mass spectrometer and m-nitrobenzyl alcohol as the matrix. Column
chromatography was performed using Merck silica gel 60 and silica gel 60
N (spherical, neutral; Kanto Chemical Co., Inc.).
(1H, ddd, Jꢂ8.9, 4.3, 0.7 Hz), 7.24—7.35 (3H, m), 7.48 (1H, ddd, Jꢂ7.9,
5.6, 3.3 Hz), 7.59 (1H, dt, Jꢂ10.2, 1.3 Hz), 7.68 (1H, dt, Jꢂ7.98, 1.3 Hz),
7.79 (1H, dd, Jꢂ7.9, 6.6 Hz). GC-MS (EI) m/z: 376 (Mꢃ). Anal. Calcd for
General Procedure Synthesis of Benzophenone Under an argon atmo- C20H9F5O2: C, 63.84; H, 2.41. Found: C, 63.62; H, 2.20.
sphere, 60% sodium hydride in oil (160 mg, 4 mmol) was added to a mixture
of 3,4-difluoronitrobenzene (3) (477 mg, 3 mmol), and benzaldehyde 4a—f
(3.6 mmol), 1,3-dimethylimidazolium iodide (1) (224 mg, 1 mmol) in DMF
(20 ml). The mixture was stirred at 0 °C for 1 h and poured into ice-water. dd, Jꢂ8.6, 7.6 Hz), 7.42—7.57 (2H, m), 7.62 (1H, dd, Jꢂ10.9, 1.6 Hz), 7.71
The products were extracted with ethyl acetate. The organic layer was (1H, dt, Jꢂ8.2, 0.5 Hz), 7.94 (1H, dd, Jꢂ8.2, 6.9 Hz). GC-MS (EI) m/z: 376
1,4-Bis(2,6-difluorobenzoyl)-2-fluorobenzene (8d): Colorless prisms (re-
crystallized from n-hexane/dichloromethane). mp 153—154 °C. IR (KBr)
1
cmꢁ1: 1665 (CO). H-NMR (CDCl3) d: 7.00 (2H, t, Jꢂ8.6 Hz), 7.04 (2H,
washed with water and brine, dried over Na2SO4, and concentrated. The
(Mꢃ). Anal. Calcd for C20H9F5O2: C, 63.84; H, 2.41. Found: C, 63.68; H,
residue was purified by silica gel column chromatography (n-hexane/ethyl 2.28.
acetate) to obtain benzophenone 5a—f and diketone 8a—e.
1,4-Bis(2-chlorobenzoyl)-2-fluorobenzene (8e): Colorless prisms (recrys-
2,2ꢀ-Difluoro-4-nitrobenzophenone (5a): Colorless prisms (recrystallized tallized from n-hexane/dichloromethane). mp 102—103 °C. IR (KBr) cmꢁ1
:
from dichloromethane/n-hexane). mp 93 °C. IR (KBr) cmꢁ1: 1654 (CO),
1654 (CO). H-NMR (CDCl3) d: 7.36—7.56 (9H, m), 7.63 (1H, dd, Jꢂ7.9,
1
1526, 1297 (NO2). 1H-NMR (CDCl3) d: 7.14 (1H, ddd, Jꢂ10.7, 8.3, 0.9 Hz), 1.7 Hz), 7.81 (1H, dd, Jꢂ8.6, 6.9 Hz). GC-MS (EI) m/z: 372 (Mꢃ). Anal.
7.33 (1H, td, Jꢂ7.6, 0.9 Hz), 7.59—7.67 (1H, m), 7.87—7.79 (2H, m), 8.00 Calcd for C20H11Cl2FO2: C, 64.37; H, 2.97. Found: C, 64.20; H, 2.90.
(1H, dd, Jꢂ9.6, 2.3 Hz), 8.15 (1H, dd, Jꢂ8.4, 2.3 Hz). 13C-NMR (CDCl3) d:
112.2 (d, JFCꢂ27.0 Hz), 116.5 (d, JFCꢂ21.8 Hz), 119.5 (d, JFCꢂ4.2 Hz),
General Procedure for the Synthesis of Xanthone Benzophenone
5a—f (1 mmol) was dissolved in 1,4-dioxane (30 ml) and 10% aqueous solu-
124.8 (d,
J
J
J
FCꢂ3.1 Hz), 125.9 (d,
FCꢂ3.1 Hz), 133.5 (d, JFCꢂ13.5 Hz), 135.7 (d, JFCꢂ9.3 Hz), 150.5 (d, refluxed for 12 h, cooled, and neutralized with 10% hydrochloric acid. The
FCꢂ8.3 Hz), 160.1 (d, JFCꢂ259.5 Hz), 161.6 (d, JFCꢂ256.4 Hz), 187.8. GC- products were extracted with ethyl acetate. The organic layer was washed
JFCꢂ11.4 Hz), 131.0, 131.4 (d, tion of sodium hydroxide (5 ml) was added to the solution. The mixture was
MS (EI) m/z: 263 (Mꢃ). Anal. Calcd for C13H7F2NO3: C, 59.32; H, 2.68; N, with water and brine, dried over Na2SO4, and concentrated. The residue was
5.32. Found: C, 59.31; H, 2.46; N, 5.30.
purified by silica gel column chromatography (n-hexane/ethyl acetate) to ob-
4-Nitro-2,2ꢀ,4ꢀ-trifluorobenzophenone (5b): Slightly yellow prisms (re- tain xanthone 6a—e.
crystallized from n-hexane/dichloromethane). mp 84—85 °C. IR (KBr)
3-Nitroxanthone (6a)41)
:
Yellow needles (recrystallized from n-
1
cmꢁ1: 1652 (CO), 1530, 1290 (NO2). H-NMR (CDCl3) d: 6.90 (1H, ddd, hexane/acetone). mp 173.5—174.5 °C. IR (KBr) cmꢁ1: 1664 (CO), 1514,
Jꢂ10.9, 8.6, 2.3 Hz), 7.06 (1H, dddd, Jꢂ8.6, 7.6, 2.3, 1.0 Hz), 7.83 (1H, dd, 1343 (NO2). 1H-NMR (CDCl3) d: 7.47 (1H, td, Jꢂ8.8, 1.5 Hz), 7.57 (1H, d,
Jꢂ8.6, 6.9 Hz), 7.89 (1H, td, Jꢂ8.6, 6.3 Hz), 8.01 (1H, dd, Jꢂ9.6, 2.0 Hz),
8.16 (ddd, Jꢂ8.6, 2.0, 0.7 Hz). GC-MS (EI) m/z: 281 (Mꢃ). Anal. Calcd for 8.36 (1H, dd, Jꢂ7.5, 1.5 Hz), 8.41 ( 1H, d, Jꢂ2.0 Hz), 8.53 (1H, d, J ꢂ
C13H6F3NO3: C, 55.53; H, 2.15; N, 4.98. Found: C, 55.39; H, 2.26; N, 4.91.
8.8 Hz). 13C-NMR (CDCl3) d: 111.0, 115.0, 115.1, 122.6, 123.0, 125.5,
Jꢂ8.8 Hz), 7.82 (1H, ddd, Jꢂ8.5, 7.5, 2.0 Hz), 8.19 (1H, dd, Jꢂ8.8, 2.0 Hz),

December 2006
1657
128.0, 130.0, 134.9, 142.5, 143.0, 150.9, 177.2. GC-MS (EI) m/z: 241 (Mꢃ).
Anal. Calcd for C13H7NO4: C, 64.74; H, 2.93; N, 5.81. Found: C, 64.78; H,
2.81; N, 5.60.
3-Fluoro-6-nitroxanthone (6b): Colorless needles (recrystallized from n-
hexane/dichloromethane). mp 218 °C. IR (KBr) cmꢁ1: 1662 (CO), 1533,
1346 (NO2). 1H-NMR (CDCl3) d: 7.16—7.28 (2H, m), 8.21 (1H, dd, Jꢂ8.6,
2.0 Hz), 8.36—8.41 (2H, m), 8.51 (1H, d, Jꢂ8.6 Hz). GC-MS (EI) m/z: 259
(Mꢃ). Anal. Calcd for C13H6FNO4: C, 60.24; H, 2.33; N, 5.40. Found: C,
60.15; H, 1.94; N, 5.18.
2-Fluoro-6-nitroxanthone (6c): Slightly yellow needles (recrystallized
from n-hexane/dichloromethane). mp 200—201 °C. IR (KBr) cmꢁ1: 1667
(CO), 1528, 1345 (NO2). 1H-NMR (CDCl3) d: 7.51—7.63 (2H, m), 7.99
(1H, ddd, Jꢂ7.9, 2.8, 0.7 Hz), 8.20 (1H, dd, Jꢂ8.6, 2.3 Hz), 8.41 (1H, d,
Jꢂ2.3 Hz), 8.51 (1H, d, Jꢂ8.6 Hz). GC-MS (EI) m/z: 259 (Mꢃ). Anal. Calcd
for C13H6FNO4: C, 60.24; H, 2.33; N, 5.40. Found: C, 60.10; H, 2.15; N,
5.08.
acetate) to obtain 11c (264 mg, 75%). Recrystallization of the crude product
from n-hexane/dichloromethane yielded crystals of 11c as orange plates. mp
133—134 °C. IR (KBr) cmꢁ1: 3320 (NH), 1629 (CO), 1526, 1348 (NO2).
1H-NMR (CDCl3) d: 4.57 (2H, d, Jꢂ5.6 Hz), 7.17 (1H, t, Jꢂ8.9 Hz), 7.25—
7.57 (10H, m), 7.59 (1H, d, Jꢂ2.0 Hz), 9.32 (1H, bs). GC-MS (EI) m/z: 350
(Mꢃ). Anal. Calcd for C20H15FN2O3: C, 68.57; H, 4.32; N, 8.00. Found: C,
68.44; H, 4.46; N, 7.88.
General Procedure for the Synthesis of Acridone A solution of 2-
aminobenzophenone 11a—c (1 mmol) in DMF (10 ml) was stirred at 150 °C
for 12 or 24 h and then cooled. Water was added to the solution. The prod-
ucts were extracted with ethyl acetate. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated. The residue was puri-
fied by silica gel column chromatography (n-hexane/ethyl acetate) to obtain
acridone 7a—c.
10-Methyl-3-nitroacridone (7a): Orange needles (recrystallized from n-
hexane/acetone). mp 209—212 °C (lit.42) 219—220 °C). IR (KBr) cmꢁ1
:
1670 (CO), 1522, 1351 (NO2). 1H-NMR (CDCl3) d: 4.01 (3H, s), 7.39 (1H,
dd, Jꢂ7.8, 6.8 Hz), 7.61 (1H, d, Jꢂ8.8 Hz), 7.82 (1H, ddd, Jꢂ8.8, 6.8,
1.5 Hz), 8.05 (1H, dd, Jꢂ8.3, 2.0 Hz), 8.48 (1H, d, Jꢂ2.0 Hz), 8.56 (1H, dd,
Jꢂ7.8, 1.5 Hz), 8.70 (1H, d, Jꢂ8.3 Hz). FAB-MS m/z: 255 (Mꢃ). Anal.
Calcd for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C, 66.22; H,
3.92; N, 10.88.
1-Fluoro-6-nitroxanthone (6d): Slightly yellow needles (recrystallized
from n-hexane/dichloromethane). mp 208—209 °C. IR (KBr) cmꢁ1: 1670
1
(CO), 1523, 1347 (NO2). H-NMR (CDCl3) d: 7.13 (1H, ddd, Jꢂ10.4, 8.6,
1.0 Hz), 7.38 (1H, dt, Jꢂ8.6, 1.0 Hz), 7.75 (1H, td, Jꢂ8.6, 5.6 Hz), 8.19 (1H,
dd, Jꢂ8.6, 2.0 Hz), 8.36 (1H, d, Jꢂ2.0 Hz), 8.50 (1H, d, Jꢂ8.6 Hz). GC-MS
(EI) m/z: 259 (Mꢃ). Anal. Calcd for C13H6FNO4: C, 60.24; H, 2.33; N, 5.40.
Found: C, 60.10; H, 2.23; N, 5.01.
10-Isopropyl-3-nitroacridone (7b): Orange needles (recrystallized from n-
hexane/acetone). mp 246—248 °C. IR (KBr) cmꢁ1: 1639 (CO). 1H-NMR
(CDCl3) d: 1.86 (6H, d, Jꢂ7.3 Hz), 5.23 (1H, septet, Jꢂ7.3 Hz), 7.35 (1H,
ddd, Jꢂ7.9, 6.6, 1.3 Hz), 7.68—7.79 (2H, m), 8.02 (1H, dd, Jꢂ8.9, 2.0 Hz),
8.51 (1H, ddd, Jꢂ7.9, 1.3, 0.6 Hz), 8.59 (1H, d, Jꢂ2.0 Hz), 8.65 (1H, d,
Jꢂ8.9 Hz). Anal. Calcd for C16H14N2O3: C, 68.08; H, 5.00; N, 9.92. Found:
C, 68.01; H, 4.64; N, 9.79.
1-Chloro-6-nitroxanthone (6f): Colorless needles (recrystallized from n-
hexane/dichloromethane). mp 212—213 °C (lit.34,42) 214—216 °C). IR (KBr)
1
cmꢁ1: 1667 (CO), 1525, 1346 (NO2). H-NMR (CDCl3) d: 7.46 (1H, dd,
Jꢂ7.9, 1.3 Hz), 7.49 (1H, dd, Jꢂ8.6, 1.0 Hz), 7.66 (1H, dd, Jꢂ8.6, 7.9 Hz),
8.18 (1H, dd, Jꢂ8.6, 2.0 Hz), 8.34 (1H, d, Jꢂ2.0 Hz), 8.48 (1H, d,
Jꢂ8.2 Hz). GC-MS (EI) m/z: 275 (Mꢃ). Anal. Calcd for C13H6ClNO4: C,
56.65; H, 2.19; N, 5.08. Found: C, 56.79; H, 2.03; N, 4.79.
10-Benzyl-3-nitroacridone (7c)43): Orange needles (recrystallized from n-
hexane/dichloromethane). mp 201 °C. IR (KBr) cmꢁ1: 1640 (CO). 1H-NMR
(CDCl3) d: 5.67 (2H, s), 7.22 (2H, dd, Jꢂ7.8, 1.9 Hz), 7.32—7.44 (5H, m),
7.69 (1H, ddd, Jꢂ8.9, 6.9, 1.6 Hz), 8.00 (1H, dd, Jꢂ8.9, 2.0 Hz), 8.26 (1H,
d, Jꢂ2.0 Hz), 8.53 (1H, dd, Jꢂ7.8, 1.6 Hz), 8.67 (1H, d, Jꢂ8.9 Hz). 13C-
NMR (CDCl3) d: 51.1, 111.3, 115.3, 115.6, 122.8, 122.9, 125.4, 125.6,
127.9, 128.3, 129.5, 129.8, 134.3, 135.1, 142.3, 142.9, 151.1, 177.2. Anal.
Calcd for C20H14N2O3: C, 72.72; H, 4.27; N, 8.48. Found: C, 72.47; H, 4.13;
N, 8.35.
Synthesis of 10-Benzyl-3-nitroacridone (7c) from 2,2ꢀ-Difluoro-4-ni-
trobenzophenone (5a) and Benzylamine (10c) A solution of 5a (263 mg,
1 mmol) and 10c (107 mg, 1 mmol) in DMSO (20 ml) was stirred at 150 °C
for 24 h and then cooled. Water was added to the solution. The products
were extracted with ethyl acetate. The organic layer was washed with water
and brine, dried over Na2SO4, and concentrated. The residue was purified by
silica gel column chromatography (n-hexane/ethyl acetate) to obtain
acridone 7c (241 mg, 73%).
3-(2-Fluorophenyl)-1-methyl-6-nitroindazole (12) Under an argon
atomophere, methylhydrazine (576 mg, 12.5 mmol) was added to a solution
of 5a (263 mg, 1 mmol) in 1,4-dioxane (10 ml). The mixture was refluxed for
12 h, cooled, and poured into water. The products were extracted with ethyl
acetate. The organic layer was washed with water and brine, dried over
Na2SO4, and concentrated. The residue was purified by silica gel column
chromatography (n-hexane/ethyl acetate) to yield 12 (109 mg, 40%). Recrys-
tallization of the crude product from n-hexane/dichloromethane yielded
crystals of 12 as yellow needles. mp 165—167 °C. IR (KBr) cmꢁ1: 1513,
1345 (NO2). 1H-NMR (CDCl3) d: 4.26 (3H, s), 7.23—7.39 (2H, m), 7.42—
7.50 (1H, m), 7.80 (1H, td, Jꢂ7.8, 2.0 Hz), 7.95 (1H, dd, Jꢂ9.8, 2.9 Hz),
8.05 (1H, dd, Jꢂ8.8, 2.0 Hz), 8.41 (1H, d, Jꢂ2.0 Hz). 13C-NMR (CDCl3) d:
36.2, 96.1, 105.8, 115.4, 116.3 (d, JFCꢂ21.8 Hz), 119.9 (d, JFCꢂ14.5 Hz),
123.0 (d, JFCꢂ8.3 Hz), 124.6 (d, JFCꢂ3.1 Hz), 125.5, 130.5 (d, JFCꢂ8.3 Hz),
2ꢀ-Chloro-2-hydroxy-4-nitrobenzophenone (9): Yellow needles (recrystal-
lized from n-hexane/dichloromethane). mp 88—89 °C. IR (KBr) cmꢁ1: 3434
1
(OH), 1640 (CO). H-NMR (CDCl3) d: 7.36—7.55 (5H, m), 7.66 (1H, dd,
Jꢂ8.8, 2.5 Hz), 7.90 (1H, d, Jꢂ2.5 Hz), 11.99 (1H, s). GC-MS (EI) m/z: 277
(Mꢃ). Anal. Calcd for C13H8ClNO4: C, 56.23; H, 2.90; N, 5.04. Found: C,
56.11; H, 3.02; N, 4.89.
2ꢀ-Fluoro-2-methylamino-4-nitrobenzophenone (11a) Benzophenone
5a (1.315 g, 5 mmol) was dissolved in 1,4-dioxane (10 ml) and 40% aqueous
solution of methylamine (10a) (2 ml) was added to the solution. The mixture
was refluxed for 6 h and poured into ice-water. The products were extracted
with ethyl acetate. The organic layer was washed with water and brine, dried
over Na2SO4, and concentrated. The residue was purified by silica gel col-
umn chromatography (n-hexane/ethyl acetate) to obtain 11a (1.295 g, 95%)
and acridone 7a (29 mg, 2%). Recrystallization of the crude product from n-
hexane/acetone yielded crystals of 11a as orange plates. mp 117—117.5 °C.
IR (KBr) cmꢁ1: 3326 (NH), 1629 (CO), 1535, 1345 (NO2). 1H-NMR
(CDCl3) d: 3.08 (3H, d, Jꢂ5.4 Hz), 7.17 (1H, t, Jꢂ8.9 Hz), 7.25—7.30 (2H,
m), 7.42 (1H, td, Jꢂ7.3, 2.0 Hz), 7.48—7.58 (3H, m), 8.92 (1H, bs). 13C-
NMR (CDCl3) d: 29.7, 96.1, 106.2, 107.9, 116.2 (d, JFCꢂ21.8 Hz), 120.7,
124.5 (d, JFCꢂ4.2 Hz), 127.9 (d, JFCꢂ16.6 Hz), 129.7 (d, JFCꢂ3.1 Hz), 132.5
(d, JFCꢂ8.3 Hz), 136.5 (d, JFCꢂ2.1 Hz), 152.3 (d, JFCꢂ39.4 Hz), 158.9 (d,
J
FCꢂ252.2 Hz), 195.0. GC-MS (EI) m/z: 274 (Mꢃ). Anal. Calcd for
C14H11FN2O3: C, 61.31; H, 4.04; N, 10.21. Found: C, 61.07; H, 3.82; N,
9.99.
2ꢀ-Fluoro-2-isopropylamino-4-nitrobenzophenone (11b) Isopropyl-
amine (10b) (1.48 g, 25 mmol) was added to a solution of 5a (1.315 g,
5 mmol) in 1,4-dioxane (10 ml). The mixture was refluxed for 3 h and poured
into ice-water. The products were extracted with ethyl acetate. The organic
layer was washed with water and brine, dried over Na2SO4, and concen-
trated. The residue was purified by silica gel column chromatography (n-
hexane/ethyl acetate) to obtain 11b (1.372 g, 91%). Recrystallization of the
crude product from n-hexane/dichloromethane yielded crystals of 11b as or-
ange plates. mp 83—84 °C. IR (KBr) cmꢁ1: 3314 (NH), 1632 (CO), 1528,
130.9 (d,
J
JFCꢂ4.2 Hz), 140.0 (d, JFCꢂ22.9 Hz), 146.5, 159.9 (d,
FCꢂ249.1 Hz). GC-MS (EI) m/z: 271 (Mꢃ). Anal. Calcd for C14H10FN3O2:
C, 61.99; H, 3.72; N, 15.49. Found: C, 61.95; H, 3.54; N, 15.21.
1
3-Chloro-2-(2-Fluorobenzoyl)quinoxaline (14) Under an argon atmo-
sphere, 60% sodium hydride in oil (520 mg, 13 mmol) was added to a
mixture of 2,3-dichloroquinoxaline (13) (1.99 g, 10 mmol), and 2-fluoro-
benzaldehyde (4a) (1.49 g, 12 mmol), 1,3-dimethylimidazolium iodide (1)
(672 mg, 3 mmol) in THF (50 ml). The mixture was refluxed for 5 h and
poured into ice-water. After neutralizing the water layer with acetic acid, the
products were extracted with ethyl acetate. The organic layer was washed
with water and brine, dried over Na2SO4, and concentrated. The residue was
purified by silica gel column chromatography (n-hexane/ethyl acetate) to ob-
tain recovered 13 (862 mg, 43%) and benzoylquinoxaline 14 (1.08 g, 38%).
Recrystallization of the crude product from n-hexane/acetone yielded crys-
1343 (NO2). H-NMR (CDCl3) d: 1.38 (6H, d, Jꢂ6.5 Hz), 3.88 (1H, octet,
Jꢂ6.5 Hz), 7.14—7.31 (3H, m), 7.42 (1H, td, Jꢂ7.3, 1.7 Hz), 7.48—7.56
(2H, m), 7.60 (1H, d, Jꢂ2.3 Hz), 8.92 (1H, bs). GC-MS (EI) m/z: 302 (Mꢃ).
Anal. Calcd for C16H15FN2O3: C, 63.57; H, 5.00; N, 9.27. Found: C, 63.41;
H, 4.64; N, 9.17.
2-Benzylamino-2ꢀ-fluoro-4-nitrobenzophenone
(11c) Benzylamine
(10c) (107 mg, 1 mmol) was added to a solution of 5a (263 mg, 1 mmol) in
anisole (10 ml). The mixture was refluxed for 6 h and poured into ice-water.
The products were extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over Na2SO4, and concentrated. The
residue was purified by silica gel column chromatography (n-hexane/ethyl

1658
Vol. 54, No. 12
tals of 14 as colorless prisms. mp 100 °C. IR (KBr) cmꢁ1: 1669 (CO). H-
NMR (CDCl3) d: 7.11 (1H, ddd, Jꢂ11.7, 8.3, 1.0 Hz), 7.38 (1H, td, Jꢂ7.8,
1.0 Hz), 7.62—7.71 (1H, m), 7.80—7.92 (2H, m), 8.07—8.13 (3H, m).
Anal. Calcd for C15H8ClFN2O: C, 62.84; H, 2.81; N, 9.77. Found: C, 62.68;
H, 2.76; N, 9.59.
1
(1944).
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Heterocycles, 43, 509—512 (1996).
2-(2-Fluorobenzoyl)-3-methylaminoquinoxaline (15) Quinoxaline 14
(573 mg, 2 mmol) was dissolved in 1,4-dioxane (10 ml) and 40% aqueous
solution of methylamine (10a) (0.8 ml) was added to the solution. After the
mixture was refluxed for 1 h, the methylamine solution (0.4 ml) was added
again. The mixture was refluxed for 30 min and concentrated. The residue
was purified by silica gel column chromatography (n-hexane/ethyl acetate)
to obtain quinoxaline 15 quantitively. Recrystallization of the crude product
from n-hexane/acetone yielded crystals of 15 as orange neeedles. mp 189—
12) Stetter H., Angew. Chem., 88, 695—704 (1976).
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1939 (2006).
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4227—4231 (2006).
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1
190 °C. IR (KBr) cmꢁ1: 3368 (NH), 1644 (CO). H-NMR (CDCl3) d: 3.21
(3H, d, Jꢂ4.9 Hz), 7.16 (1H, ddd, Jꢂ9.3, 8.3, 1.0 Hz), 7.25—7.36 (2H, m),
7.51—7.77 (5H, m), 8.19 (1H, bs). Anal. Calcd for C16H12FN3O: C, 68.32;
H, 4.30; N, 14.94. Found: C, 68.36; H, 4.25; N, 14.81.
Quinolino[2,3-b]quinoxaline 16 A mixture of quinoxaline 14 (281 mg,
1 mmol) and potassium carbonate (276 mg, 2 mmol) in DMF (5 ml) was
stirred at 150 °C for 1 h and then cooled. The mixture was poured into ice-
water. The resulting precipitates were filtered and washed with a small
amount of cooled ethyl acetate to obtain qunolinoquinoxaline 16 quanti-
tively. Recrystallization of the crude product from n-hexane/acetone yielded
crystals of 16 as orange needles. mp ꢄ300 °C. IR (KBr) cmꢁ1. 1647 (CO).
1H-NMR (CDCl3) d: 4.23 (3H, s), 7.38 (1H, td, Jꢂ8.3, 1.0 Hz), 7.65 (1H, d,
Jꢂ8.8 Hz), 7.73 (1H, ddd, Jꢂ8.3, 6.8, 1.5 Hz), 7.83—7.92 (2H, m), 8.06
(1H, dd, Jꢂ8.8, 1.5 Hz), 8.43 (1H, dd, Jꢂ8.3, 1.0 Hz), 8.66 (1H, dd, Jꢂ8.3,
1.5 Hz). Anal. Calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C,
73.55; H, 4.24; N, 15.98.
Thianaphtho[2,3-b]quinoxaline 17 A mixture of benzoylquinoxaline
14 (500 mg, 1.75 mmol) was dissolved in methanol (10 ml) and thioacetic
acid (0.5 ml) was added to the solution. After the mixture was refluxed for
2 h, thioacetic acid (0.5 ml) was added again. The mixture was refluxed for
another 2 h, cooled, and poured into ice-water. The products are extracted
with dichloromethane. The organic layer was concentrated. Sodium hydrox-
ide (2 N) and ethyl acetate were added to the residue. The organic layer was
dried over Na2SO4 and concentrated to obtain thianaphthoquinoxaline 17
(212 mg, 46%). The water layer was neutralized and the product was ex-
tracted with dichloromethane. The organic layer was dried over Na2SO4 and
concentrated to obtain compound 18 (212 mg, 43%).
Thianaphtho[2,3-b]quinoxaline 17: Yellow needles (recrystallized from n-
1
hexane/acetone). mp 263 °C. IR (KBr) cmꢁ1: 1666 (CO). H-NMR (CDCl3)
d: 7.54 (1H, ddd, Jꢂ8.3, 6.8, 1.5 Hz), 7.65 (1H, dd, Jꢂ8.3, 1.5 Hz), 7.72
(1H, ddd, Jꢂ8.3, 6.8, 1.5 Hz), 7.86 (1H, ddd, Jꢂ8.3, 6.8, 1.5 Hz), 7.95 (1H,
ddd, Jꢂ8.3, 6.8, 1.5 Hz), 8.10 (1H, dd, Jꢂ8.3, 1.0 Hz), 8.44 (1H, dd, Jꢂ8.3,
1.0 Hz), 8.67 (1H, dd, Jꢂ8.3, 1.5 Hz). GC-MS (EI) m/z: 264 (Mꢃ). Anal.
Calcd for C15H8N2OS: C, 68.17; H, 3.05; N, 10.60. Found: C, 68.31; H,
3.27; N, 10.26.
33) Sandifer R. M., Bhattacharya A. K., Harris T. M., J. Org. Chem., 46,
2260—2267 (1981).
34) Goldberg A. A., Wragg A. H., J. Chem. Soc., 1958, 4227—4234
(1958).
35) Goldberg A. A., Wragg A. H., J. Chem. Soc., 1958, 4234—4241
(1958).
36) Hassall C. H., Lewis J. R., J. Chem. Soc., 1961, 2312—2315 (1958).
37) Jones G., “Comprehensive Heterocyclic Chemistry,” Vol. 2, eds. by
Katritzky A., Rees C. W., Pergamon Press, Oxford, 1984, pp. 395—
510.
2-(2-Fluorobenzoyl)-3-mercaptoquinoxaline (18): Orange plates (recrys-
tallized from n-hexane/dichloromethane). mp 211.5—212.5 °C. IR (KBr)
1
cmꢁ1: 3228 (SH), 1653 (CO). H-NMR (CDCl3) d: 7.08 (1H, dd, Jꢂ11.2,
8.7 Hz), 7.31—7.37 (2H, m), 7.46 (1H, td, Jꢂ8.3, 1.7 Hz), 7.59—7.66 (2H,
m), 7.92 (1H, dd, Jꢂ8.3, 1.7 Hz), 8.20 (1H, td, Jꢂ7.5, 1.7 Hz), 11.34 (1H,
bs). MS (FAB) m/z: 285 (M+1). Anal. Calcd for C15H9FN2OS: C, 63.37; H,
3.19; N, 9.85. Found: C, 63.23; H, 3.18; N, 9.84.
References
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