PREPARATION OF 1-HYDROXYXANTHEN-9(9H)-ONES AND 1-HYDROXYACRIDIN-9(10H)-ONES VIA CORRESPONDING 3,4-DIHYDRO-1,9(2H)-DIONES

Article abstract of DOI:10.1135/cccc19952127

Target 10-cyclopropyl-7-fluoro-6-(4-methyl-1-piperazinyl)acridin-9(10H)-one (IVc) and 7-fluoro-1-hydroxy-6-(4-methyl-1-piperazinyl)-9H-xanthen-9-one (IVd) were obtained from corresponding difluoro derivatives IVa and IVb, respectively.These intermediates were synthesized via respective 3,4-dihydro-1,9(2H)-diones Va and Vb.Acridine derivative (10-cyclopropyl-6,7-difluoro-3,4-dihydro-1H-acridine-1,9(2H,10H)-dione, Va) was synthesized from 1-cyclopropyl-6,7-difluoroisatoic anhydride (XI) and xanthene derivative (6,7-difluoro-3,4-dihydro-1H-xanthen-1,9(2H)-dione, Vb) from cyclohexenone derivative VIb.Several unsuccessful attempts to prepare hydroxyacridone IVc and/or some useful intermediates of its synthesis are also described.

Full text of DOI:10.1135/cccc19952127

Preparation of Hydroxyxanthenes and Hydroxyacridones
2127
PREPARATION OF 1-HYDROXYXANTHEN-9(9H)-ONES AND
1-HYDROXYACRIDIN-9(10H)-ONES VIA CORRESPONDING
3,4-DIHYDRO-1,9(2H)-DIONES
Stanislav RADL
Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3, Czech Republic
Received August 28, 1995
Accepted October 27, 1995
Target 10-cyclopropyl-7-fluoro-1-hydroxy-6-(4-methyl-1-piperazinyl)acridin-9(10H)-one (IVc) and 7-
fluoro-1-hydroxy-6-(4-methyl-1-piperazinyl)-9H-xanthen-9-one (IVd) were obtained from correspond-
ing difluoro derivatives IVa and IVb, respectively. These intermediates were synthesized via
respective 3,4-dihydro-1,9(2H)-diones Va and Vb. Acridine derivative (10-cyclopropyl-6,7-difluoro-
3,4-dihydro-1H-acridine-1,9(2H,10H)-dione, Va) was synthesized from 1-cyclopropyl-6,7-difluoroisatoic
anhydride (XI) and xanthene derivative (6,7-difluoro-3,4-dihydro-1H-xanthen-1,9(2H)-dione, Vb)
from cyclohexenone derivative VIb. Several unsuccessful attempts to prepare hydroxyacridone IVc
and/or some useful intermediates of its synthesis are also described.
Antibacterial quinolones, which exert their activity by inhibiting bacterial DNA gyrase,
have attracted increasing attention as a source of clinically useful drugs1,2. During our
research into antibacterial quinolones we were also interested in compounds having at
the position 3 various groups that could mimic the carboxylic group present in these
drugs of a general formula I. All compounds derived by a simple replacement of the
carboxy group with carboxymethyl, phosphonic, sulfonic1, hydroxy3, nitro4, amino or
acylamino5 groups have been found to be virtually inactive. On the other hand, com-
pounds of general formula II, having an isothiazolone ring annelated to the 2,3-position
of the quinolone moiety, have been found to be extremely active DNA gyrase inhibi-
tors6. Since only compounds having an unsubstituted isothiazolone nitrogen were found
to be active, we envisaged that involvement of the tautomers III may be important to
their biological action. Therefore we decided to prepare similar 1-hydroxyacridin-
9(10H)-one (IVc) and investigate the biological activity of this compound. 1-Hydroxy-
xanthen-9(9H)-one derivative IVd was also included because some flavone DNA
gyrase inhibitors have recently been reported7. For our initial study we chose a cyclo-
propyl group as the N-1 substituent and a 4-methyl-1-piperazinyl group as the cyclic
amine residue as a typical substitution pattern present in many potent quinolones. Syn-
thetic work connected with the preparation of these structures is reported herein.
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Radl:
We needed a suitable procedure for the preparation of intermediate difluoro deriva-
tives IVa and IVb. A straightforward strategy based on dehydrogenation of the respec-
tive compounds Va and Vb was chosen. We hoped that these intermediates would be
accessible by a nucleophilic cyclization of compounds VIIIb and VIIb, respectively, and
that VIIIb could be easily prepared from VIIb.
A literature procedure8 describes a simple method for the preparation of 2-benzoyl-
cyclohexane-1,3-dione based on the O-acylation of cyclohexane-1,3-dione with ben-
zoyl chloride, followed by rearrangement of the resulting O-acyl derivative VIa to
afford the corresponding C-acyl derivative VIIa. When this method was applied to the
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Preparation of Hydroxyxanthenes and Hydroxyacridones
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rearrangement of trifluoro derivative VIb, spontaneous cyclization of intermediate VIIb
occurred providing directly Vb. As we expected, compound Vb was easily dehydroge-
nated to 1-hydroxyxanthone derivative IVb by refluxing with palladium on carbon in
ethanol. Compound IVb was then converted to the target structure IVd by treatment
with N-methylpiperazine.
Encouraged by the easy preparation of IVd, we explored various ways for the prepa-
ration of analogous acridone derivatives. Since all attempts to isolate VIIb failed, the
reactive 2-fluoro substituent was replaced by a 2-chloro atom. Application of the same
reaction sequence provided VIIc. Compounds VIIIa and VIIIc were prepared by a treat-
ment of VIIa and VIIc, respectively, with cyclopropylamine. Alternatively VIIIa was
also prepared via the corresponding morpholino derivative IXa. Attempts to cyclize
VIIIc to the corresponding acridinedione derivative Va both under nucleophilic condi-
tions (DBU, NaH, BuLi) and with copper catalysts (Cu, CuO, Cu2O, Cu(OAc)2) failed.
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Radl:
We also envisaged to utilize a strategy involving the acylation of 3-(4-morpholinyl)-
2-cyclohexen-1-one (IXb) with 2,4,5-trifluorobenzoyl chloride. 3-(4-Morpholinyl)-2-
cyclohexen-1-one (IXb), as a representative cyclic enamino ketone, could behave either
as a carbanion or as an enolate. Unfortunately, model acylation of this compound with
benzoyl chloride provided, after work-up, exclusively the O-acyl derivative VIa. The
reaction was monitored by TLC and none of the desired derivative IXa could be de-
tected.
Having compound VIIIc we tried another approach based on a report, that treatment
of 2-methoxy-2′-aminobenzophenones with sodium hydride in DMSO affords acridone
derivatives9,10. In our case, dimethoxybenzophenone Xd should lead to 1-methoxyacri-
done IVe. Since a 1-methoxy group in acridones can be easily demethylated either with
hydrochloric acid or by treatment with a Lewis acid as boron tribromide11, this ap-
proach could lead to the target 1-hydroxyacridone IVa. Our reaction pathway starts
from compound VIIIc. The first step was a potential source of trouble because similar
2-acylcyclohexane-1,3-diones had been found surprisingly resistant to dehydrogena-
tion12. Indeed, catalytic dehydrogenation of VIIIc to the corresponding resorcine deriva-
tive Xa with palladium on carbon was unsuccessful, as well as oxidation with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The only literature method for the
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Preparation of Hydroxyxanthenes and Hydroxyacridones
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oxidation of 2-acylcyclohexane-1,3-diones to 2-acylresorcine derivatives used mercuric
acetate and sodium acetate in acetic acid. Compound Xa was successfully prepared by
this method and its methylation with iodomethane provided a mixture of the dimethoxy
derivative Xb and 1-methoxyxanthen-9(9H)-one IVf. Compound Xb, when treated with
N-methylpiperazine provided derivative Xc. Some copper catalysts are useful in dis-
placement of 2-chloro atom of 2-chloroacetophenones13 and 2-chlorobenzoic14 acids
with various amines. Unfortunately attempts to convert compound Xc to Xd by treat-
ment with cyclopropyl amine under pressure failed with all copper catalysts tested (Cu,
CuO, Cu2O, Cu(OAc)2).
Compound Xa can be also used as an intermediate for the synthesis of 10-hydroxy-
xanthones. Hydroxyxanthone IVb was prepared from Xa by a nucleophilic cyclization
with sodium hydride. More surprisingly, treatment of Xa with N-methylpiperazine pro-
vided directly IVd.
Since we failed to construct the acridone skeleton from any intermediates we had
used for the synthesis of corresponding xanthone analogs, we decided to adopt a differ-
ent approach. N-Unsubstituted isatoic anhydrides are known to react with sodium salt
of cyclohexane-1,3-dione at 50–100 °C to provide their corresponding dioxoacridine
derivatives15. The same treatment of 1-cyclopropyl-6,7-difluoroisatoic anhydride (XI),
which was prepared from 2-chloro-4,5-difluorobenzoic acid according to the literature
procedure14, provided a complex mixture. However, when the reaction was performed
at room temperature, the desired compound Va was obtained in good yield. 1-Hydroxy-
acridone derivative IVa was prepared from Va by catalytic dehydrogenation similarly
as described for analogous 1-hydroxyxanthone derivative IVb. Nucleophilic displace-
ment of fluorine at position 6 in IVa by N-methylpiperazine provided the target struc-
ture IVc.
EXPERIMENTAL
Melting points were measured on Thomas Hoover capillary apparatus and are uncorrected. IR spectra
were taken on a Digilab FTS 15E spectrophotometer (wavenumbers in cm–1) and UV spectra on a
1
Cary 17D spectrometer. H NMR spectra were recorded on a Varian XL-200 instrument (200 MHz).
Chemical shifts are given in ppm (δ-scale), coupling constants (J) in Hz. Mass spectra were obtained
on a VG 7070 E-HF spectrometer. Flash and vacuum chromatography were done on silica gel 60
(230–400 mesh) from EM Science. A model 7924T Chromatotron from Marrilon Research was
used for radial chromatography.
3-(2,4,5-Trifluorobenzoyloxy)-2-cyclohexen-1-one (VIb)
A mixture of 2,4,5-trifluorobenzoic acid (4.40 g, 25 mmol), thionyl chloride (15 ml, 0.2 mol) and a
drop of DMF was refluxed for 2 h, and then thionyl chloride was evaporated in vacuo, the residue
was dissolved in dichloromethane (20 ml) and the solution was added dropwise to a stirred solution
of cyclohexane-1,3-dione (2.8 g, 25 mmol) and pyridine (2 ml, 25 mmol) in dichloromethane (100 ml)
and the reaction mixture was stirred at room temperature overnight. Then the reaction mixture
was washed with 5 M hydrochloric acid (40 ml), saturated solution of sodium hydrogen carbonate
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Radl:
(2 × 20 ml), and water (2 × 20 ml) and dried with magnesium sulfate. The residue was dissolved in
dichloromethane and purified by vacuum chromatography yielding 4.65 g of oily product (68%, dried
1
under high vacuum). The compound was used for the next step without further purification. H NMR
spectrum (CDCl3): 2.08–2.19 m, 2 H (CH2); 2.45–2.65 m, 4 H (CH2–C=O, CH2–C=); 6.03 s, 1 H
(CH); 7.00–7.15 m, 1 H (H-3); 7.76–7.90 m, 1 H (H-6).
3-(2-Chloro-4,5-difluorobenzoyloxy)-2-cyclohexen-1-one (VIc)
A mixture of 2-chloro-4,5-difluorobenzoic acid (9.63 g, 50 mmol), thionyl chloride (30 ml, 0.4 mol)
and a drop of DMF was refluxed for 2 h, then thionyl chloride was evaporated in vacuo, the residue
was dissolved in dichloromethane (40 ml) and the solution was added dropwise to a stirred solution
of cyclohexane-1,3-dione (5.6 g, 50 mmol) and pyridine (4 ml, 50 mmol) in dichloromethane (200 ml)
and the reaction mixture was stirred at room temperature overnight. Then the mixture was washed
with 5 M hydrochloric acid (100 ml), saturated solution of sodium hydrogen carbonate (2 × 50 ml), and
water (2 × 50 ml) and dried with magnesium sulfate. The residue was dissolved in dichloromethane
and purified by vacuum chromatography to give 8.4 g of oily product (58.6%, dried under high vacuum)
which was used for the next step without identification.
2-(2-Chloro-4,5-difluorobenzoyl)-1,3-cyclohexandione (VIIc)
A solution of VIc (2.87 g, 10 mmol) in 1,2-dichloroethane (10 ml) was added dropwise at room tem-
perature to a stirred suspension of aluminium chloride (3 g, 22.5 mmol) in 1,2-dichloroethane (50 ml)
and the mixture was stirred at room temperature overnight. Then the mixture was poured onto a mix-
ture of ice (10 g) and concentrated hydrochloric acid (10 ml). Water layer was extracted with 1,2-di-
chloroethane (10 × 20 ml), organic extracts were combined, washed with water and dried with
magnesium sulfate. Crystallization of the crude product from hexane–acetone (9 : 1) provided 2.35 g
(82%) of white crystals, m.p. 107–108 °C. For C13H9ClF2O3 (286.7) calculated: 54.47% C, 3.16% H,
12.37% Cl, 13.25% F; found: 54.26% C, 2.92% H, 12.39% Cl, 13.54% F. 1H NMR spectrum
(CDCl3): 2.03–2.10 m, 2 H (CH2); 2.45–2.49 m, 2 H (CH2); 2.78–2.81 m, 2 H (CH2); 7.04–7.08 m,
1 H (arom. H); 7.20–7.24 m, 1 H (arom. H). IR spectrum (CHCl3): 1 676 (C=O). UV spectrum, λmax
(log ε): 213 (4.04), 228 (4.05), 282 (4.03). Mass spectrum (m/z, %): 251 (M – Cl, 100).
2-Benzoyl-3-(4-morpholinyl)-2-cyclohexen-1-one (IXb)
A mixture of 2-benzoylcyclohexane-1,3-dione (VIIa) (0.4 g, 1.85 mmol), morpholine (0.26 g, 3 mmol),
benzene (20 ml) and a crystal of 4-toluenesulfonic acid monohydrate was refluxed for 4 h, evapo-
rated to dryness and the residue was crystallized from toluene; yield 0.5 g (95%) of yellow crystals,
m.p. 229–230 °C. For C17H19NO3 (285.3) calculated: 71.56% C, 6.71% H, 4.91% N; found: 71.67%
C, 6.76% H, 4.88% N. 1H NMR spectrum (CDCl3): 1.91–2.00 m, 2 H (CH2); 2.45 m, 4 H (CH2–
C=O, CH2–C=); 3.60–4.00 m, 8 H (H of morpholine); 7.30–7.50 m, 5 H (H of phenyl). IR spectrum
(CHCl3): 1 631, 1 577 (C=O). UV spectrum, λmax (log ε): 248 (4.39), 300 (3.56), 362 (3.81). Mass
spectrum (m/z, %): 285 (M+), 284 (100).
2-Benzoyl-3-(cyclopropylamino)-2-cyclohexen-1-one (VIIIa)
A) Cyclopropylamine (140 ml, 2 mmol) was added via syringe to a stirred solution of IXb (0.43 g,
1.5 mmol) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 24 h.
Then another portion of cyclopropylamine was added (20 µl, 0.3 mmol) and stirring continued for
additional 24 h. The mixture was washed with water, dried with magnesium sulfate and purified by
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Preparation of Hydroxyxanthenes and Hydroxyacridones
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radial chromatography on Chromatotron (hexane–ethyl acetate 1 : 1). Crystallization from hexane
provided 0.36 g (95%) of white crystals, m.p. 114–115 °C. For C16H15NO2 (253.3) calculated:
75.87% C, 5.97% H, 5.53% N; found: 75.74% C, 6.01% H, 5.41% N. 1H NMR spectrum (CDCl3):
0.70–0.79 m, 4 H (CH2 of cyclopropyl); 1.86–1.89 m, 2 H (CH2); 2.40–2.55 m, 5 H (CH2–C=O,
CH2–C=, CH of cyclopropyl); 7.19–7.51 m, 5 H (H of phenyl). IR spectrum (CHCl3): 1 643 (C=O).
UV spectrum, λmax (log ε): 252 (4.17), 317 (4.17). Mass spectrum (m/z, %): 255 (M+, 77), 199 (100).
B) A mixture of 2-benzoylcyclohexane-1,3-dione (VIIa; 0.22 g, 1 mmol), cyclopropylamine
(0.1 ml, 1.4 mmol) and dichloromethane (5 ml) was stirred at room temperature for 24 h, then evap-
orated and crystallized from hexane yielding 0.21 g (83%) of the product, m.p. 114–115 °C.
2-(2-Chloro-4,5-difluorobenzoyl)-3-(cyclopropylamino)-2-cyclohexen-1-one (VIIIc)
Cyclopropylamine (1.5 ml, 21.6 mmol) was added to a solution of VIIc (2.87 g, 10 mmol) in
dichloromethane (60 ml) and the mixture was stirred at room temperature overnight, evaporated and
the residue was purified by radial chromatography on Chromatotron (hexane–acetone 9 : 1) giving
after crystallization from hexane 2.2 g (67%) of white crystals, m.p. 111–113 °C. For
C16H14ClF2NO2 (325.7) calculated: 59.00% C, 4.33% H, 10.88% Cl, 11.66% F, 4.30% N; found:
1
58.50% C, 4.21% H, 11.18% Cl, 11.44% F, 4.44% N. H NMR spectrum (CDCl3): 0.66–0.90 m, 4 H
(CH2 of cyclopropyl); 1.86–1.99 m, 2 H (CH2); 2.42–2.54 m, 5 H (CH2–C=O, CH2–C=, CH of cyclo-
propyl); 6.96 dd, 1 H, J = 8 and 10 (arom. H); 7.32 dd, 1 H, J = 8 and 10 (arom. H); 13.26 bs, 1 H
(NH). IR spectrum (CHCl3): 1 644 (C=O). UV spectrum, λmax (log ε): 252 (4.13), 318 (4.23). Mass
spectrum (m/z, %): 326 (M + H, 1), 290 (M – Cl, 100).
6,7-Difluoro-3,4-dihydro-1H-xanthen-1,9(2H)-dione (Vb)
Solution of VIb (2.3 g, 8.5 mmol) in 1,2-dichloroethane (10 ml) was added dropwise to a stirred
mixture of aluminium chloride (2.5 g, 18.7 mmol) in 1,2-dichloromethane (60 ml) at 0 °C. Then the
mixture was stirred at room temperature for 24 h and poured into a mixture of ice (15 g) and con-
centrated hydrochloric acid (15 ml). Aqueous layer was extracted with 1,2-dichloroethane (5 × 25 ml),
organic solutions were combined, washed with 5 M hydrochloric acid (2 × 25 ml) and water (2 × 50 ml)
and dried with magnesium sulfate. The residue after evaporation of 1,2-dichloroethane was dissolved
in ethanol (25 ml) and refluxed for 1 h, evaporated and crystallized from ethanol; yield 1.35 g (54%),
m.p. 203–205 °C. For C13H8F2O3 (250.2) calculated: 62.41% C, 3.22% H, 15.19% F; found: 62.20%
C, 3.18% H, 14.93% F. 1H NMR spectrum (CDCl3): 2.10–2.26 m, 2 H (CH2); 2.58–2.65 m, 2 H
(CH2); 2.98–3.04 m, 2 H (CH2); 7.28 dd, 1 H, J = 8 and 10 (H-5); 7.94–8.07 dd, 1 H, J = 8 and 10
(H-8). IR spectrum (CHCl3): 1 706 (C=O). UV spectrum, λmax (log ε): 205 (4.27), 225 (4.24), 237
(4.27), 247 (4.24), 289 (3.74), 300 (3.74). Mass spectrum (m/z, %): 250 (M+, 68), 222 (100).
6,7-Difluoro-1-hydroxy-9H-xanthen-9-one (IVb)
A) A mixture of Vb (0.25 g, 1 mmol), ethanol (20 ml), and 10% Pd on carbon (0.1 g) was refluxed
with a stream of nitrogen bubbled through the mixture for 2 h, then the catalyst was filtered off
through a cellite pad and washed with hot ethanol. The filtrate was cooled and the formed crystals
were filtered off. The filtrate was concentrated to one third of its volume and another crop was ob-
tained; yield 0.23 g (93%), m.p. 200–201 °C. For C13H6F2O3 (248.2) calculated: 62.91% C, 2.44% H,
15.31% F; found: 62.83% C, 2.39% H, 15.16% F. 1H NMR spectrum (CDCl3): 6.82 d, 1 H, J = 8
(H-2 or H-4); 6.97 d, 1 H, J = 8 (H-2 or H-4); 7.36 dd, 1 H, J = 7 and 9 (H-5); 7.64 t, 1 H, J = 8
(H-3); 8.06 dd, 1 H, J = 7 and 9 (H-8). IR spectrum (CHCl3): 1 649 (C=O). UV spectrum, λmax (log ε):
226 (4.37), 244 (4.41), 285 (3.88), 361 (3.72). Mass spectrum (m/z, %): 248 (M+, 100).
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Radl:
B) A solution of DDQ (0.25 g, 1.1 mmol) in dioxane (5 ml) was added to a solution of Vb (0.25 g,
1 mmol) in dioxane (150 ml) and the mixture was stirred at room temperature for 24 h. Insoluble
portion was filtered off, washed with dichloromethane and the combined organic solutions were
evaporated and purified by radial chromatography on Chromatotron (dichloromethane) yielding 0.06 g
(24%) of the product, m.p. 198–200 °C.
C) Sodium hydride (80% suspension in mineral oil, 0.1 g, 9.3 mmol) was added portionwise to a
stirred solution of Xa (0.285 g, 1 mmol) in THF (5 ml) and the mixture was stirred at room tempera-
ture under nitrogen for 4 h, evaporated, the residue was dissolved in water and acidified with hydro-
chloric acid. Insoluble portion was filtered off, washed with water and dried. The crude product was
dissolved in dichloromethane and purified by vacuum chromatography (dichloromethane). Crystal-
lization from ethanol provided 0.21 g (85%) of the product, m.p. 200–201 °C.
7-Fluoro-1-hydroxy-6-(4-methyl-1-piperazinyl)-9H-xanthen-9-one (IVd)
A) A mixture of IVb (0.25 g, 1 mmol), acetonitrile (20 ml), triethylamine (1 ml, 7 mmol), and
N-methylpiperazine (0.2 g, 2 mmol) was stirred at 50 °C under nitrogen for 20 h. The mixture was
evaporated, the residue was triturated with water, the insoluble portion was filtered off, washed with
water, dried and crystallized from ethanol; yield 0.27 g (82%), m.p. 166–168 °C. For C18H17FN2O3
(328.3) calculated: 65.85% C, 5.22% H, 5.79% F, 8.53% N; found: 65.66% C, 4.93% H, 6.00% F,
8.42% N. 1H NMR spectrum (CDCl3): 2.41 s, 3 H (CH3); 2.68 m, 4 H (CH2); 3.39 m, 4 H (CH2);
6.80–6.89 m, 3 H (H-2, H-4, H-8); 7.26 s, 1 H (H-5); 7.57 t, 1 H, J = 8 (H-3); 7.81 d, 1 H, J(H,F) = 13
(H-8). IR spectrum (CHCl3): 1 646 (C=O). UV spectrum, λmax (log ε): 228 (4.44), 240 (4.31), 250
(4.79), 274 (3.87), 293 (3.92), 365 (4.28), λinfl 340 (4.21). Mass spectrum (m/z, %): 328 (M+, 55), 43
(100).
A sample was converted to its hydrochloride salt m.p. 288–295 °C (decomposition). For
C18H17FN2O3 . HCl (364.8) calculated: 59.26% C, 4.97% H, 9.72% Cl, 5.21% F, 7.68% N; found:
58.97% C, 4.81% H, 9.69% Cl, 5.34% F, 7.70% N.
B) A mixture of Xa (2.0 g, 7 mmol), N-methylpiperazine (1.5 g, 15 mmol) and acetonitrile (10 ml)
was stirred under nitrogen for 5 h, the mixture was evaporated, the residue was triturated with water,
the insoluble portion was washed with water and dried. Crystallization of the crude product from
ethanol provided 1.6 g (69%) of IVd, m.p. 167–168 °C.
2-(2-Chloro-4,5-difluorobenzoyl)-1,3-dihydroxybenzene (Xa)
A mixture of VIIc (2.87 g, 10 mmol), mercuric acetate (9.6 g, 30 mmol), sodium acetate (2.5 g, 30 mmol)
and acetic acid (25 ml) was stirred at 120 °C for 5 h under nitrogen. The mixture was cooled, 1 M HCl
was added (50 ml) and the mixture was stirred at room temperature for 30 min. Then ethyl acetate
was added (50 ml) and the mixture was filtered through a cellite pad and washed with ethyl acetate.
The washings were used for extraction of the aqueous layer, organic extracts were combined, washed
with 5% sodium hydrogen sulfite (100 ml), 5% sodium hydrogen carbonate (4 × 100 ml) and water
(2 × 50 ml) and dried with magnesium sulfate. After evaporation, 2.7 g of yellow oil (95%) was
obtained which after prolonged standing yielded yellow crystals, m.p. 66–84 °C. The crude product
was used for the next step without further purification 1H NMR spectrum (CDCl3): 6.62 d, 2 H
(arom. H); 7.15–7.46 m, 3 H (arom. H).
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2-(2-Chloro-4,5-difluorobenzoyl)-1,3-dimethoxybenzene (Xb) and 6,7-Difluoro-1-methoxy-
9H-xanthen-9-one (IVf)
A mixture of Xa (2.56 g, 9 mmol), potassium carbonate (5.6 g, 40 mmol) and iodomethane (5 ml, 80 mmol)
in acetone (50 ml) was stirred at room temperature for 10 h. Then the mixture was evaporated, the
residue was triturated with water, the insoluble portion was filtered off, washed with water and dried
(2.75 g). The crude mixture was purified by flash chromatography (dichloromethane). First fraction
was eluted with dichloromethane and provided after crystallization from hexane 2.1 g of Xb (75%),
m.p. 78–79 °C. For C15H11ClF2O3 (312.7) calculated: 57.62% C, 3.55% H, 11.34% Cl, 12.15% F;
1
found: 56.87% C, 3.55% H, 11.56% Cl, 11.42% F. H NMR spectrum (CDCl3): 3.74 s, 6 H (CH3);
6.58 d, 2 H (arom. H); 7.20–7.48 m, 3 H (arom. H). IR spectrum (CHCl3): 1 688 (C=O). UV spec-
trum, λmax (log ε): 202 (4.72), 244 (3.89), 284 (3.63). Mass spectrum (m/z, %): 312 (M+, 28), 165
(100). Another compound obtained by eluting with ethyl acetate and following crystallization from
acetic acid (0.55 g, 23%) was identified as IVf, m.p. 205–207 °C. For C14H8F2O3 (262.2) calculated:
64.13% C, 3.08% H, 14.49% F; found: 61.25% C, 3.05% H, 14.48% Cl, 13.54% F. 1H NMR spec-
trum (CDCl3): 4.03 s, 3 H (CH3); 6.82–7.07 m, 2 H (H-2, H-4); 7.20–7.24 m, 1 H (H-5); 7.63 t, 1 H,
J = 8 (H-3); 8.07 dd, 1 H, J = 8 and 10 (H-8). IR spectrum (CHCl3): 1 658 (C=O). UV spectrum,
λmax (log ε): 229 (4.37), 246 (4.38), 273 (3.84), 293 (3.69), 345 (3.84). Mass spectrum (m/z, %): 262
(M+, 100).
2-[2-Chloro-5-fluorobenzoyl-4-(4-methyl-1-piperazinyl)]-1,3-dimethoxybenzene (Xc)
A mixture of Xb (0.62 g, 2 mmol), acetonitrile (5 ml), and N-methylpiperazine (0.5 g, 5 mmol) was
stirred at room temperature for 3 days, evaporated, the residue was dissolved in dichloromethane and
purified by vacuum chromatography (chloroform–methanol 95 : 5) providing after crystallization
from hexane 0.75 g (96%) of yellow crystals, m.p. 96–97 °C. For C13H9ClF2O3 (286.7) calculated:
54.47% C, 3.16% H, 12.37% Cl, 13.25% F; found: 54.26% C, 2.92% H, 12.39% Cl, 13.54% F. 1H
NMR spectrum (CDCl3): 2.42 s, 3 H (CH3N); 2.68–2.75 m, 4 H (CH2); 3.31–3.36 m, 4 H (CH2);
3.78 s, 6 H (CH3O); 6.58 d, 2 H, J = 8 (arom. H); 6.87 d, 1 H, J = 9 (arom. H); 7.28–7.42 m, 2 H,
J = 8 (arom. H). IR spectrum (CHCl3): 1 675 (C=O). UV spectrum, λmax (log ε): 247 (3.95), 322
(4.23). Mass spectrum (m/z, %): 392 (M+, 52), 165 (34), 71 (71), 70 (48), 43 (100), 42 (25), 28 (29).
10-Cyclopropyl-6,7-difluoro-3,4-dihydro-1H-acridine-1,9(2H,10H)-dione (Va)
A solution of cyclohexane-1,3-dione (0.28 g, 2.5 mmol) in DMF (2 ml) was added dropwise during
30 min to a suspension of sodium hydride (80% suspension in mineral oil, 75 mg, 2.5 mmol) in DMF
(2 ml) stirred at 0 °C. Then the mixture was stirred at room temperature for 1 h, cooled to 0 °C and a
solution of 1-cyclopropyl-6,7-difluoroisatoic anhydride (XI; 0.56 g, 2.3 mmol) in DMF (2 ml) was
added and the mixture was stirred at room temperature overnight. The mixture was poured into ice
water (50 ml) containing 1 M HCl (4 ml), the insoluble portion was filtered off, washed with water
and dried. Crystallization from ethanol provided 0.5 g (74%) of white crystals; m.p. 270–272 °C. For
C16H13F2NO2 (289.3) calculated: 66.43% C, 4.53% H, 13.13% F, 4.84% N; found: 66.50% C, 4.43% H,
1
12.96% F, 4.62% N. H NMR spectrum (CDCl3): 1.05–1.20 m, 2 H (CH2 of cyclopropyl); 1.44–1.60 m,
2 H (CH2 of cyclopropyl); 2.10–2.22 m, 2 H (CH2); 2.56–2.64 m, 2 H (CH2); 3.22–3.34 m, 3 H
(CH2, CH–N); 7.72 dd, 1 H, J = 8 and 10 (H-5); 8.15 dd, 1 H, J = 8 and 10 (H-8). IR spectrum
(KBr): 1 677 (C=O). UV spectrum, λmax (log ε): 217 (4.45), 255 (4.12), 264 (4.21), 316 (4.01), 355
(4.33). Mass spectrum (m/z, %): 289 (M+, 100), 288 (68), 260 (28), 246 (32), 233 (32), 232 (36), 41
(28).
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Radl:
10-Cyclopropyl-6,7-difluoro-1-hydroxyacridin-9(10H)-one (IVa)
A solution of Va (0.1 g, 0.34 mmol) in ethanol (10 ml) was refluxed with 10% palladium on carbon
(0.05 g) under a stream of argon for 10 h. Then the catalyst was filtered off, the filtrate was eva-
porated to dryness and the residue was crystalllized from ethanol to provide 0.06 g of white crystals
(60%), m.p. 225–226 °C. For C16H11F2NO2 (287.3) calculated: 66.90% C, 3.86% H, 13.23% F,
1
4.88% N; found: 66.63% C, 3.56% H, 13.11% F, 4.52% N. H NMR spectrum (CDCl3): 0.95–1.01 m,
2 H (CH2 of cyclopropyl); 1.48–1.58 m, 2 H (CH2 of cyclopropyl); 3.20–3.30 m, 1 H (CH–N); 6.72 d,
1 H, J = 8 (H-2 or H-4); 7.28 d, 1 H, J = 7 (H-2 or H-4); 7.56–7.77 m, 2 H (arom. H); 8.14 dd, 1 H,
J = 10 (H-8). IR spectrum (KBr): 1 643 (C=O). UV spectrum, λmax (log ε): 213 (3.24), 241 (4.36),
264 (4.68), 300 (3.73), 309 (3.74), 403 (3.87). Mass spectrum (m/z, %): 287 (M+, 100), 286 (72), 272
(34), 218 (24), 28 (36).
10-Cyclopropyl-7-fluoro-1-hydroxy-6-(4-methyl-1-piperazinyl)acridin-9(10H)-one (IVc)
A solution of IVa (0.1 g, 0.35 mmol) and N-methylpiperazine (50 µl, 0.45 mmol) in acetonitrile (10 ml)
was stirred at 50 °C for 50 h under argon. The reaction mixture was evaporated, the residue was
triturated with water and the insoluble portion was filtered off, dried and crystallized from ethanol
providing 0.11 g of yellow crystals (86%), m.p. 216–218 °C. For C21H22FN3O2 (367.4) calculated:
1
68.65% C, 6.04% H, 5.17% F, 11.44% N; found: 68.38% C, 6.04% H, 5.19% F, 11.48% N. H NMR
spectrum (CDCl3): 0.92–1.00 m, 2 H (CH2 of cyclopropyl); 1.44–1.56 m, 2 H (CH2 of cyclopropyl);
2.55 s, 3 H (N–CH3); 2.78 m, 4 H (CH2 of piperazine); 3.20–3.30 m, 1 H (N–CH); 3.47 m, 4 H (CH2
of piperazine); 6.68 d, 1 H, J = 12 (arom. H); 7.22–7.30 m, 2 H (arom. H); 7.55 d, 1 H, J = 7 (H-5);
7.96 d, 1 H, J = 12 (H-8). IR spectrum (KBr): 1 626 (C=O). UV spectrum, λmax (log ε): 251 (4.49),
264 (4.38), 293 (4.49), 341 (4.16), 398 (4.03). Mass spectrum (m/z, %): 367 (M+, 94), 297 (20), 71
(50), 70 (68), 43 (100).
A sample was converted to its soluble monohydrochloride which decomposes without melting at
about 310–320 °C. For C21H22FN3O2 . HCl (403.9) calculated: 62.45% C, 5.74% H, 8.78% Cl, 4.70% F,
10.40% N; found: 62.05% C, 5.69% H, 8.67% Cl, 4.53% F, 9.91% N.
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