Cyclization of 1-acylaminoacridones into 7H-pyrido[2,3,4-kl]acridin-2(3H)- ones

Article abstract of DOI:10.1007/s11172-006-0444-3

1-Acylamino-10-methylacridones in a polar aprotic solvent underwent base-catalyzed cyclization into the corresponding 7-methyl-7H-pyrido[2,3,4-kl] acridin-2(3H)-ones. Heating of 1-butylaminoacridone in acetic anhydride in the presence of p-toluenesulfonic

Full text of DOI:10.1007/s11172-006-0444-3

Russian Chemical Bulletin, International Edition, Vol. 55, No. 8, pp. 1487—1491, August, 2006
1487
Cyclization of 1ꢀacylaminoacridones
into 7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀones
M. V. Gorelik,ꢀ S. P. Titova, and E. V. Gordievskaya
Research Institute of Organic Intermediates and Dyes,
1 ul. Bol´shaya Sadovaya, 103999 Moscow, Russian Federation.
Fax: +7 (495) 254 1200. Eꢀmail: gorelik@co.ru
1ꢀAcylaminoꢀ10ꢀmethylacridones in a polar aprotic solvent underwent baseꢀcatalyzed cyꢀ
clization into the corresponding 7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀones. Heating
of 1ꢀbutylaminoacridone in acetic anhydride in the presence of pꢀtoluenesulfonic acid and
potassium acetate afforded 3ꢀbutylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone, while heating of
1ꢀaminoacridone under the same conditions gave 9ꢀacetoxyꢀ1ꢀacetyliminoꢀ1,10ꢀdihydroxyꢀ
acridine.
Key words: heterocyclization, pyridoacridines, acridones.
A large group of alkaloids with high biological (cytoꢀ
toxic, anticancer, and antiviral) activity belongs to the
pyrido[2,3,4ꢀkl]acridine series.1—4 For this reason, much
attention is being given to methods for the synthesis of
this polycyclic system. Pyridoacridines are most often preꢀ
pared by construction of the acridine nucleus from quinoꢀ
line derivatives.5—7 The use of compounds with the acriꢀ
dine moiety as starting materials has been less studied.
Here we studied intramolecular cyclization of 1ꢀacetylꢀ
aminoacridones into 7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀ
ones. The possibility of the cyclization of 1ꢀacylaminoꢀ
acridones with participation of the periꢀCOꢀgroup has
not been investigated hitherto, although similar periꢀcyꢀ
clization of 1ꢀacylaminoanthraquinones is widely used in
the synthesis of pyridoanthrones.8 Since this reaction inꢀ
volves a nucleophilic attack on the C(9) atom, replaceꢀ
ment of the electronꢀwithdrawing carbonyl group in poꢀ
sition 10 by a nitrogen atom (when moving from
anthraquinones to acridones) will inevitably have a deacꢀ
tivating effect. The problem is how strong this effect is
and whether it hinders the cyclization. The failure in the
synthesis of pyridoacridine by the Friedlaender reaction
of 1ꢀaminoꢀ4ꢀmethylacridone with acetylacetone have
been attributed9 to the conjugation of the imino group
with the carbonyl one.
matic nucleophilic displacement of the nitro group. Their
reactions at elevated pressure and temperature gave new
NHR2ꢀcontaining acridones 5—8 (Scheme 1).
Scheme 1
R1 = H (1, 3, 5), Me (2, 4, 6—8);
R2 = Bun (5, 6), cycloꢀC6H11 (7), 3ꢀMeC6H4 (8)
We investigated 1ꢀaminoacridones containing an
unsubstituted or substituted acetyl group at the priꢀ
mary and secondary N atoms. The starting 1ꢀnitroacriꢀ
done (1)10,11 was methylated to give 10ꢀmethylꢀ1ꢀnitroꢀ
acridone (2). Reduction of nitro compounds 1 and 2
yielded 1ꢀaminoacridone (3) and 1ꢀaminoꢀ10ꢀmethylꢀ
acridone (4), respectively.12 Both nitroacridone 2, which
is nonionizable, and nitroacridone 1 can undergo aroꢀ
1ꢀAminoacridones 3—8 were Nꢀacylated with acetic
anhydride (a), chloroacetyl chloride (b), ethyl cyanoꢀ
acetate (c), and ethyl malonate (d) to give derivaꢀ
tives 3´—8´. The acetylation of secondary amines 5—8
with acetic anhydride in the absence of any catalyst ocꢀ
curred at different rates. For instance, butylaminoꢀ
acridones 5 and 6 were successfully acetylated in boiling
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1433—1437, August, 2006.
1066ꢀ5285/06/5508ꢀ1487 © 2006 Springer Science+Business Media, Inc.

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Gorelik et al.
acetic anhydride, while for cyclohexylaminoacridone 7
and toluidinoacridone 8, heating at 200 °C for 9 h was
required to complete the reaction.
anhydride followed by addition of potassium acetate gave
3ꢀbutylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (13) in
~80% yield (Scheme 3). Without MeCOOK, the starting
reagent was recovered only. Apparently, pꢀtoluenesulfonic
acid activates the substrate molecule by protonation, while
the basic acetate anion binds the proton upon a nucleoꢀ
philic attack at position 9. In the synthesis of comꢀ
pound 13, it is expedient to start directly from amine 5,
which will be acetylated in acetic anhydride at the initial
step. As expected, this method is also applicable to the
cyclization of 10ꢀmethyl derivatives 4´a and 6´a—8´a.
This method allows "oneꢀpot" synthesis of some pyridoꢀ
acridones directly from aminoacridones without isolating
their acyl derivatives. Indeed, heating of 1ꢀbutylaminoꢀ
10ꢀmethylacridone 6 in acetic anhydride with pꢀtoluꢀ
enesulfonic acid and then with potassium acetate yielded
pyridoacridinone 10a, which was identical with the prodꢀ
uct obtained by the baseꢀcatalyzed cyclization of comꢀ
pound 6´a.
We found that 1ꢀacylaminoꢀ10ꢀmethylacridones obꢀ
tained from primary acridinylamines undergo baseꢀcataꢀ
lyzed cyclization into pyrido[2,3,4ꢀkl]acridinones only
when they contain an activating substituent (X = CN,
COOEt) in the acyl group (Scheme 2). For instance,
treatment of 1ꢀcyanoacetylaminoꢀ10ꢀmethylacridone
(4´c) with NaOH in aqueous DMF or DMSO at 30—40 °C
gave 1ꢀcyanoꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ
2(3H )ꢀone (9c) in nearly quantitative yield, while
1ꢀacetylaminoꢀ10ꢀmethylacridone (4´a) containing no
activating substituent was only deacylated under these
conditions.
Scheme 2
Scheme 3
R = H (4´, 9), Bu (6´, 10), cycloꢀC6H11 (7´, 11), 3ꢀMeC6H4 (8´, 12)
X = H (a), Cl (b), CN (c), COOEt (d)
Compounds derived from secondary acridinylamines
underwent cyclization even without an activating subꢀ
stituent in the acyl group. NꢀAcetylated 1ꢀalkylaminoꢀ
acridones 6´a and 7´a and 1ꢀarylaminoacridone 8´a were
converted into 3ꢀsubstituted pyrido[2,3,4ꢀkl]acridinones
10a—12a in high yields by stirring with KOH in DMSO at
80 to 130 °C (see Scheme 2). Apparently, this cyclization
is favored by steric factors because alkyl or aryl substituent
at the N atom facilitates the approach of the carbanionic
center of the acetyl group to the CO group to be attacked.
Chloroacetyl derivatives 6´b—8´b of the same amines unꢀ
derwent cyclization into the corresponding 1ꢀchloroꢀ
pyridoacridinones 10b—12b even at 30 °C. In reactions of
compounds 10b and 12b with potassium butoxide or butylꢀ
amine, the attempted replacement of the Cl atom in posiꢀ
tion 1 by the alkoxy or alkylamino group failed: under
mild conditions, these compounds remained unchanged,
while at elevated temperature, the Cl atom was replaced
by hydrogen.
Under analogous conditions, aminoacridone 3 conꢀ
taining a primary amino group formed a mixture of
monoacetyl derivative 3´a and diacetylated product 14;
the latter can be deacetylated to give compound 3´a
(Scheme 4). Similar diacetyl derivative 15 was obtained
from 10ꢀmethyl analog 4´a, for which acetylation at the
ring N atom is excluded. The choice between the strucꢀ
tures of N,Nꢀ and N,Oꢀdiacetyl derivatives in favor of the
latter was made from mass and IR spectroscopic data.
The mass spectrum of N,Oꢀdiacetyl derivative 14 conꢀ
tains a very intense peak of the [M – CH3COOH]+ ion
due to the elimination of acetic acid but shows virtuꢀ
ally no molecular ion peak, which is inherent in acetic
acid esters. The peaks of the [M – CH2CO]+ and
[M – CH3COOH – CH2CO]+ ions are due to the elimiꢀ
nation of ketene characteristic of acetamides.13 The
IR spectrum of N,Oꢀdiacetyl derivative 15 shows, along
with the band due to the νCO stretching vibrations in the
amide fragment at 1700 cm–1, the longerꢀwavelength band
of the ester group at 1719 cm–1, while the spectrum of
Unlike N(10)ꢀsubstituted derivatives, 10ꢀunsubstituted
1ꢀacylaminoacridones 3´a and 5´a turned to be reluctant
to baseꢀcatalyzed cyclization. For this reason, we studied
their cyclization in the presence of an acid. Heating of
aminoacridone 5´a with pꢀtoluenesulfonic acid in acetic
monoacetyl derivative 4´a exhibits a band at 1690 cm–1
.
The formation of the N,Oꢀdiacetyl derivative sugꢀ
gests possible tautomerization of Nꢀacetylated 1ꢀaminoꢀ

Pyridoacridinones from acylaminoacridones
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1489
Scheme 4
1ꢀCyclohexylaminoꢀ10ꢀmethylacridone (7) was obtained
by heating nitroacridone 2 with cyclohexylamine (16 h,
200 °C). On cooling, DMF (15 mL) was added and the mixꢀ
ture was poured into water. The resulting precipitate was
separated, washed with water, dried, and chromatographed.
The second yellow zone was collected. The yield was
1.75 g (57%), m.p. 150—152 °C (from aqueous PriOH).
Found (%): C, 78.88; H, 7.16; N, 9.16. C20H22N2O. Calcuꢀ
lated (%): C, 78.40; H, 7.24; N, 9.14. IR, ν/cm–1: 1624 (CO);
3440 (NH).
10ꢀMethylꢀ1ꢀ(3ꢀmethylphenylamino)acridone (8) was obꢀ
tained by heating nitroacridone 2 with mꢀtoluidine (9 h, 300 °C).
After the reaction was completed, the excess of mꢀtoluidine was
steamꢀdistilled. The oily residue was dissolved in CHCl3 and
chromatographed. The yield was 1.83 g (58%), m.p. 155 °C
(from AcOH). Found (%): C, 79.96; H, 5.48; N, 8.82.
C21H18N2O. Calculated (%): C, 80.23; H, 5.77; N, 8.91. IR,
ν/cm–1: 1623 (CO); 3446 (NH).
Acetylation of aminoacridones with acetic anhydride (general
procedure). Aminoacridone (2 mmol) was treated with acetic
anhydride (10 mL), the mixture was poured into water (100 mL),
and the precipitate was separated. Reactions with primary amines
3 and 4 were carried out at ~20 °C for 1 h, reactions with amines
5 and 6 under reflux, and reactions with amines 7 and 8 at
180—200 °C for 8—10 h.
R = H (3, 3´a, 14), Me (4, 4´а, 15)
acridones into 9ꢀhydroxyacridinꢀ1ꢀimines
Scheme 4).
A (see
1ꢀAcetylaminoacridone (3´a) was obtained from aminoꢀ
acridone 3. The yield was 0.34 g (67%), m.p. 330 °C (decomp.)
(from BunOH). Found (%): C, 71.34; H, 4.84; N, 10.79.
C15H12N2O2. Calculated (%): C, 71.42; H, 4.79; N, 11.10. IR,
ν/cm–1: 1640, 1663 (CO); 3277, 3442 (NH).
1ꢀAcetylaminoꢀ10ꢀmethylacridone (4´a) was obtained from
aminoacridone 4. The yield was 0.40 g (75%), m.p. 192 °C (from
aqueous EtOH). Found (%): C, 71.96; H, 5.22; N, 10.23.
C16H14N2O2. Calculated (%): C, 72.17; H, 5.30; N, 10.52. IR,
ν/cm–1: 1619, 1689 (CO); 3448 (NH).
1ꢀ(NꢀAcetylꢀNꢀbutylamino)acridone (5´a) was obtained from
amine 5. The yield was 0.60 g (97%), m.p. 248 °C (from BunOH).
Found (%): C, 73.71; H, 6.62; N, 8.87. C19H20N2O2. Calcuꢀ
lated (%): C, 74.00; H, 6.54; N, 9.08. IR, ν/cm–1: 1605, 1639
(CO); 3186 (NH).
1ꢀ(NꢀAcetylꢀNꢀbutylamino)ꢀ10ꢀmethylacridone (6´a) was obꢀ
tained from acridone 6. The yield was 0.52 g (81%), m.p. 160 °C
(from aqueous PriOH). Found (%): C, 74.27; H, 6.85; N, 8.65.
C20H22N2O2. Calculated (%): C, 74.51; H, 6.88; N, 8.69. IR,
ν/cm–1: 1629, 1656 (CO).
1ꢀ(NꢀAcetylꢀNꢀcyclohexylamino)ꢀ10ꢀmethylacridone (7´a)
was obtained by heating acridone 7 with acetic anhydride
(200 °C, 8 h). The yield was 0.47 g (67%), m.p. 240 °C (from
PriOH). Found (%): C, 74.55; H, 6.73; N, 8.09. C22H24N2O2.
Calculated (%): C, 75.83; H, 6.94; N, 8.04. IR, ν/cm–1: 1631,
1647 (CO).
1ꢀ[NꢀAcetylꢀNꢀ(3ꢀmethylphenyl)amino]ꢀ10ꢀmethylacridone
(8´a) was obtained by heating acridone 8 with acetic anhydride
(180 °C, 10 h). The yield was 0.570 g (80%), m.p. 178 °C (from
aqueous PriOH). Found (%): C, 77.67; H, 5.65; N, 7.71.
C23H20N2O2. Calculated (%): C, 77.51; H, 5.66; N, 7.86. IR,
ν/cm–1: 1631, 1666 (CO).
Thus, the presented periꢀcyclization of 1ꢀacetylaminoꢀ
acridones affords promising 1ꢀ and 3ꢀsubstituted and
ꢀunsubstituted 7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀones.
Experimental
Mass spectra were recorded on a Kratos MS 30 instrument
(EI, 70 eV, ionization chamber temperature 250 °C, direct inlet
probe). IR spectra were recorded on an FSM 1201 FTIR specꢀ
trometer (KBr pellets). The course of the reactions was moniꢀ
tored and the purity of the products obtained was checked by
TLC on Silufol UV 254 plates. Preparative separation was carꢀ
ried out by column chromatography on silica gel (60/100 µm)
with CHCl3 as an eluent. Samples for elemental analysis were
dried in vacuo over P2O5 at 70—80 °C. 1ꢀNitroacridone (1),
1ꢀaminoacridone (3),10,11 10ꢀmethylꢀ1ꢀnitroacridone (2),12 and
1ꢀaminoꢀ10ꢀmethylacridone (4)12 were prepared as described
earlier.
Reactions of 1ꢀnitroacridone (1) and 10ꢀmethylꢀ1ꢀnitroꢀ
acridone (2) with amines (general procedure). A mixture of
nitroacridone (10 mmol) and an amine (20 g) was heated withꢀ
out stirring in a 100ꢀmL steel autoclave on a Wood´s alloy bath.
1ꢀButylaminoacridone (5) was obtained by heating nitroꢀ
acridone 1 and nꢀbutylamine (4 h, 180 °C). On cooling, the
reaction mixture was poured into water (200 mL) and the resultꢀ
ing precipitate was separated, washed with water, and dried. The
yield was 2.10 g (78%), m.p. 196 °C (from aqueous PriOH).
Found (%): C, 76.09; H, 6.80; N, 10.24. C18H20N2O. Calcuꢀ
lated (%): C, 76.66; H, 6.81; N, 10.52. IR, ν/cm–1: 1624 (CO);
3186, 3275 (NH).
1ꢀButylaminoꢀ10ꢀmethylacridone (6) was obtained analoꢀ
gously from nitroacridone 2. The yield was 2.40 g (85%), m.p.
82 °C (from aqueous PriOH). Found (%): C, 77.35; H, 6.91;
N, 9.88. C18H20N2O. Calculated (%): C, 77.11; H, 7.19; N, 9.99.
IR, ν/cm–1: 1624 (CO); 3444 (NH).
Acylation of aminoacridones with chloroacetyl chloride (genꢀ
eral procedure). A mixture of aminoacridone (2 mmol) and
chloroacetyl chloride (0.76 mL, 10 mmol) in benzene (10 mL)
was refluxed for 30 min. Hexane (8 mL) was added and the

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Gorelik et al.
resulting precipitate was separated and washed with benzene
and hexane.
Found (%): C, 70.95; H, 5.55; Cl, 10.20; N, 8.29. C20H19ClN2O.
Calculated (%): C, 70.90; H, 5.65; Cl, 10.46; N, 8.27. IR,
ν/cm–1: 1629 (CO).
1ꢀ(NꢀButylꢀNꢀchloroacetylamino)ꢀ10ꢀmethylacridone (6´b)
was obtained from amine 6. The yield was 0.52 g (72%), m.p.
195 °C (from aqueous PriOH). Found (%): C, 67.01; H, 5.95;
Cl, 10.09; N, 7.76. C20H21ClN2O2. Calculated (%): C, 67.32;
H, 5.93; Cl, 9.93; N, 7.85. IR, ν/cm–1: 1627, 1665 (CO).
1ꢀ(NꢀChloroacetylꢀNꢀcyclohexylamino)ꢀ10ꢀmethylacridone
(7´b) was obtained from amine 7. The yield was 0.56 g (73%),
m.p. 268 °C (from EtOH). Found (%): C, 69.57; H, 6.03;
Cl, 9.15; N, 7.29. C22H23ClN2O2. Calculated (%): C, 69.01;
H, 6.05; Cl, 9.26; N, 7.32. IR, ν/cm–1: 1627, 1660 (CO).
1ꢀ[NꢀChloroacetylꢀNꢀ(3ꢀmethylphenyl)amino]ꢀ10ꢀmethylꢀ
acridone (8´b) was obtained from amine 8. The yield was 0.39 g
(50%), m.p. 98 °C (from PriOH). Found (%): C, 70.65; H, 4.57;
Cl, 9.03; N, 7.02. C23H19ClN2O2. Calculated (%): C, 70.68;
H, 4.90; Cl, 9.07; N, 7.17. IR, ν/cm–1: 1627, 1694 (CO).
1ꢀCyanoacetylaminoꢀ10ꢀmethylacridone (4´c). A mixture of
aminoacridone 4 (0.56 g, 2.5 mmol) and ethyl cyanoacetate
(10 mL) was heated at 180 °C for 1 h. On cooling, EtOH (50 mL)
was added and the resulting precipitate was filtered off and
washed with EtOH. The yield was 0.43 g (74%), m.p. 220 °C
(from BunOH). Found (%): C, 69.90; H, 4.37; N, 14.57.
C17H13N3O2. Calculated (%): C, 70.09; H, 4.50; N, 14.42. IR,
ν/cm–1: 1618, 1695 (CO); 2260 (CN); 3424 (NH).
1ꢀ(Ethoxycarbonylacetylamino)ꢀ10ꢀmethylacridone (4´d) was
obtained by heating aminoacridone 4 (0.67 g, 3 mmol) in ethyl
malonate (10 mL) (155 °C, 5 h). The yield was 0.270 g (40%),
m.p. 145 °C (from EtOH). Found (%): C, 67.75; H, 5.16;
N, 8.62. C19H18N2O4. Calculated (%): C, 67.45; H, 5.36;
N, 8.28. IR, ν/cm–1: 1619, 1684, 1737 (CO); 3449 (NH).
Baseꢀcatalyzed cyclization of Nꢀacetyl derivatives of 1ꢀaminoꢀ
10ꢀmethylacridones 4´ and 6´—8´ (general procedure). A mixꢀ
ture of an acetyl derivative (2 mmol) and powdered KOH (1 g,
18 mmol) in DMSO (20 mL) was heated at 80 °C for 2 h and
poured into water (100 mL). The resulting precipitate was sepaꢀ
rated and washed with water.
1ꢀCyanoꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone
(9c) was obtained from compound 4´c. The yield was 0.51 g
(93%). Stirring of compound 4´c (2 mmol) in a mixture of DMF
(50 mL) and aqueous 30% NaOH (17 mL) at 40 °C for 3 h gave
pyridoacridine 9c in approximately the same yield. The product
did not melt below 340 °C (from EtOH). Found (%): C, 74.72;
H, 4.05; N, 15.75. C17H11N3O. Calculated (%): C, 74.71;
H, 4.06; N, 15.38. IR, ν/cm–1: 1651 (CO); 2200 (CN);
3449 (NH). MS, m/z (Irel (%)): 273 [M]+ (100); 258 [M – Me]+
(45), 230 [M – Me – CO]+ (21).
1ꢀEthoxycarbonylꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ
2(3H )ꢀone (9d) was obtained from compound 4´d. The yield
was 0.486 g (76%), m.p. 304 °C (from EtOH). Found (%):
C, 71.10; H, 5.33; N, 8.98. C19H16N2O3. Calculated (%):
C, 71.24; H, 5.03; N, 8.74. IR, ν/cm–1: 1622, 1637 (CO).
3ꢀButylꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone
(10a) was obtained from compound 6´a. The yield was 0.475 g
(78%), m.p. 158—160 °C (from aqueous PriOH). Found (%):
C, 78.68; H, 6.57; N, 9.13. C20H20N2O. Calculated (%):
C, 78.92; H, 6.62; N, 9.20. IR, ν/cm–1: 1629 (CO). MS,
m/z (Irel (%)): 304 [M]+ (61); 248 [M – C4H8]+ (100).
3ꢀButylꢀ1ꢀchloroꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ
2(3H )ꢀone (10b) was obtained from compound 6´b. The yield
was 0.570 g (83%), m.p. 127 °C (from benzene—hexane).
Heating of 1ꢀchloropyridoacridine 10b (1 mmol) at 80 °C
for 10 h in BuOH (15 mL) containing BuOK (3 mmol) followed
by steam distillation of BuOH and chromatography of the
residue with CHCl3 as an eluent gave pyridoacridine 10a
(0.120 g, 38%). The same compound was obtained by heating of
1ꢀchloropyridoacridine 10b (1 mmol) at 180 °C for 10 h in
butylamine (10 mL) in the presence of Cu(OAc)2.
3ꢀCyclohexylꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀ
one (11a) was obtained from compound 7´a. The yield was
0.463 g (70%), m.p. 308 °C (from EtOH). Found (%): C, 80.00;
H, 6.93; N, 8.51. C22H22N2O. Calculated (%): C, 79.97; H, 6.71;
N, 8.48. IR, ν/cm–1: 1629 (CO). MS, m/z (Irel (%)): 330 [M]+
(19); 248 [M – C6H10]+ (100); 233 [M – C6H10 – Me]+ (15);
205 [M – C6H10 – Me – CO]+ (25).
1ꢀChloroꢀ3ꢀcyclohexylꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acriꢀ
dinꢀ2(3H )ꢀone (11b) was obtained from compound 7´b. The
yield was 0.672 g (92%), m.p. 237 °C (from aqueous PriOH).
Found (%): C, 72.53; H, 5.83; Cl, 9.50; N, 7.78. C22H21ClN2O.
Calculated (%): C, 72.42; H, 5.80; Cl, 9.72; N, 7.68. IR, ν/cm–1
:
1633 (CO).
7ꢀMethylꢀ3ꢀ(3ꢀmethylphenyl)ꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ
2(3H )ꢀone (12a) was obtained from compound 8´a. The
yield was 0.589 g (87%), m.p. 260 °C (from aqueous
PriOH). Found (%): C, 82.07; H, 5.81; N, 7.91. C23H18N2O.
Calculated (%): C, 81.63; H, 5.36; N, 8.28. IR, ν/cm–1
:
1644 (CO).
1ꢀChloroꢀ7ꢀmethylꢀ3ꢀ(3ꢀmethylphenyl)ꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (12b) was obtained from comꢀ
pound 8´b. The yield was 0.537 g (72%), m.p. 240 °C (from
aqueous PriOH). Found (%): C, 73.86; H, 4.52; Cl, 9.42; N, 7.43.
C23H17ClN2O3. Calculated (%): C, 74.09; H, 4.60; Cl, 9.51;
N, 7.51. IR, ν/cm–1: 1633 (CO).
As in the case of compound 10b, heating of compound 12b
with BuOK in butanol did not result in alkoxylation; instead,
dechlorination occurred to give pyridoacridine 12a.
Acidꢀcatalyzed cyclization of Nꢀacetyl derivatives of 1ꢀaminoꢀ
acridones. 3ꢀButylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (13).
pꢀToluenesulfonic acid hydrate (0.95 g, 5 mmol) and anhydrous
AcOK (4 g, 40 mmol) were added to a solution of 1ꢀbutylꢀ
aminoacridone 5 or its Nꢀacetyl derivative 5´a (1 mmol) in
acetic anhydride (10 mL). The reaction mixture was refluxed for
10 min, cooled, and mixed with water (100 mL). The resulting
precipitate was filtered off, washed with water, and dried to give
pyridoacridine 13 (0.205 g, 70%) as greenish yellow needles,
m.p. 268 °C (from aqueous PriOH). Found (%): C, 78.37;
H, 6.16; N, 9.59. C19H18N2O. Calculated (%): C, 78.59; H, 6.25;
N, 9.62. IR, ν/cm–1: 1626 (CO); 3269 (NH).
Organic material was extracted from the filtrate with CH2Cl2
(3×25 mL). The organic layer was separated, dried over Na2SO4,
and concentrated to recover acetyl derivative 5´a (0.06 g). The
yield of pyridoacridine 13 with respect to the consumed starting
compound 5´a was 87%.
Under analogous conditions, the cyclization of 1ꢀbutylꢀ
aminoꢀ10ꢀmethylacridone 6 gave 3ꢀbutylꢀ7ꢀmethylpyridoꢀ
acridine 10a, which was isolated by extraction followed by chroꢀ
matography. This product was identical with pyridoacridine 10a
obtained by the cyclization of acetyl derivative 6´a in the presꢀ
ence of KOH.

Pyridoacridinones from acylaminoacridones
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 8, August, 2006
1491
9ꢀAcetoxyꢀ1ꢀacetyliminoꢀ1,10ꢀdihydroacridine (14). A soluꢀ
tion of 1ꢀacetylaminoacridone 3´a (0.252 g, 1 mmol) in acetic
anhydride (10 mL) was treated with pꢀtoluenesulfonic acid and
potassium acetate under the reaction conditions described for
3ꢀbutylpyridoacridine 13. The mixture was diluted with water
and the unreacted starting acridone 3´a (0.170 g, 67%) was
filtered off. The product from the filtrate was extracted with
ethyl acetate. The organic layer was separated, dried with
Na2SO4, and concentrated. The residue was chromatographed
to collect at first unreacted acridone 3´a and then fractions with
diacetyl derivative 14. Solutions of product 14 exhibited intense
bluish violet fluorescence. The yield was 0.043 g (44%) with conꢀ
sideration of the recovery of compound 3´a, m.p. 236—238 °C
(from MeOH). Found (%): C, 68.93; H, 4.75; N, 9.54.
C17H14N2O3. Calculated (%): C, 69.37; H, 4.79; N, 9.52. IR,
ν/cm–1: 1630 (C=N); 1675 w, 1691 (CO); 3297 (NH). MS,
m/z (Irel (%)): 294 [M]+ (0.5), 252 [M – CH2CO]+ (34), 234
[M – CH3COOH]+ (100); 210 [M – 2 CH2CO]+ (93), 182
[M – 2 CH2CO – CO]+ (12), 165 [M – 2 CH2CO – CO –
NH2]+ (36).
References
1. T. Ozturk, in The Alkaloids, Ed. G. A. Cordell, Academic
Press, New York, 1997, 49, p. 79.
2. T. F. Molinsky, Chem. Rev., 1993, 93, 1825.
3. P. J. Wenzel and P. Crews, J. Nat. Prod., 2003, 66, 873.
4. D. Skyler and C. H. Heathcock, J. Nat. Prod., 2002, 65, 1573.
5. T. Ozturk and A. McKillop, Can. J. Chem., 2000, 78, 1158.
6. E. Delfourne, C. Roubin, and J. Bastide, J. Org. Chem.,
2000, 65, 5476.
7. S. Nakahara, J. Matsui, and A. Kubo, Tetrahedron Lett.,
1998, 39, 5521.
8. M. V. Gorelik, Khimiya antrakhinonov i ikh proizvodnykh
[The Chemistry of Anthraquinones and Their Derivatives],
Khimiya, Moscow, 1983, 296 pp. (in Russian).
9. G. Gellerman, A. Rudi, and Y. Kashman, Tetrahedron Lett.,
1992, 33, 5577.
10. K. Lehmstedt and K. Schrader, Ber., 1937, 70, 838.
11. A. A. Goldberg and W. Kelly, J. Chem. Soc., 1946, 102.
12. D. K. C. Hodgeman and R. H. Prager, Austr. J. Chem., 1972,
25, 191.
13. N. S. Vul´fson, V. G. Zaikin, and A. I. Mikaya, Massꢀ
spektrometriya organicheskikh soedinenii [Mass Spectrometry
of Organic Compounds], Khimiya, Moscow, 1986, p. 239 (in
Russian).
In aqueous methanol in the presence of NaOH, compound
14 changed into 1ꢀacetylaminoacridone 3´a.
9ꢀAcetoxyꢀ1ꢀacetyliminoꢀ10ꢀmethylꢀ1,10ꢀdihydroacridine
(15) was obtained analogously from 1ꢀaminoꢀ10ꢀmethylacridone
(4) (0.224 g, 1 mmol) and isolated by column chromatography.
The yield of acetylimine 15 was 0.041 g (13%), m.p. 203—205 °C
(from MeOH). Found (%): C, 69.96; H, 5.47; N, 8.81.
C18H16N2O3. Calculated (%): C, 70.12; H, 5.23; N, 9.09. IR,
ν/cm–1: 1630 (C=N); 1700, 1719 (CO).
Received April 13, 2006;
in revised form June 9, 2006