Syntheses of 7H-pyrido- and 7H-pyrano[2,3,4-kl]acridin-2(3H)-ones from 9-chloroacridines

Article abstract of DOI:10.1007/s11172-006-0471-0

A method for peri-annulation of the pyridine or pyran ring to acridine was developed and used to obtain 7H-pyrido-and 7H-pyrano[2,3,4-kl]acridin-2(3H)- ones. The peri-groups were formed by a reaction of 9-chloro-1-nitroacridine with a CH-acid (malononitri

Full text of DOI:10.1007/s11172-006-0471-0

Russian Chemical Bulletin, International Edition, Vol. 55, No. 9, pp. 1664—1669, September, 2006
1664
Syntheses of 7Hꢀpyridoꢀ and 7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H )ꢀones
from 9ꢀchloroacridines
M. V. Gorelik,ꢀ S. P. Titova, and E. V. Gordievskaya
State Research Center of the Russian Federation
"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
A method for periꢀannulation of the pyridine or pyran ring to acridine was developed and
used to obtain 7Hꢀpyridoꢀ and 7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H)ꢀones. The periꢀgroups were
formed by a reaction of 9ꢀchloroꢀ1ꢀnitroacridine with a CHꢀacid (malononitrile, ethyl
cyanoacetate, and ethyl malonate) followed by reduction of the nitro group, or by a reaction of
1ꢀaminoꢀ10ꢀmethylacridone with PCl5 and then with a CHꢀacid. Replacement of the chlorine
atom in 9ꢀchloroꢀ1ꢀmethoxyacridines by the residue of the CHꢀacid with subsequent heating
in an acidic medium afforded 7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H)ꢀones, which belong to a novel
heterocyclic system.
Key words: heterocyclization, pyridoacridines, pyranoacridines, acridines, CHꢀacids.
Acridine derivatives containing a periꢀannulated
from the resulting tetracyclic intermediate B is the major
process leading to 1ꢀcyanoꢀ2ꢀethoxypyridoacridine 2a,
while elimination of an ethanol molecule gives 1ꢀcyanoꢀ
pyridoacridinone 3a.
heterocycle are of considerable interest for biological inꢀ
vestigations. Earlier,1 we have described the synthesis
of pyrido[kl]acridines by cyclization of 1ꢀacylaminoꢀ
acridones. Here we present another route to these heteroꢀ
cycles via replacement of the halogen atom in 1ꢀsubstiꢀ
tuted 9ꢀchloroacridine by a Cꢀnucleophile followed by an
attack of its electrophilic αꢀfunctional group on the subꢀ
stituent in position 1. A literature example of [kl]annulaꢀ
tion of a heterocycle with acridine is a transformation of
9ꢀethynylꢀ1,4ꢀdimethoxyacridine into 6ꢀmethoxyꢀ3Hꢀ
pyrido[2,3,4ꢀkl]acridine in the presence of sodium diꢀ
formylamide, which is regarded as electrocyclic ring cloꢀ
sure in the enamide anion.2
9ꢀChloroacridine containing the amino group in posiꢀ
tion 1 was generated by a reaction of 1ꢀaminoꢀ10ꢀ
methylacridone (1) with PCl5 (by analogy with a known3
reaction of 1ꢀaminoanthraquinone with PCl5). Treatment
of aminoacridone 1 with PCl5 in benzene and then with a
CH acid in the presence of a base directly gave pyriꢀ
do[2,3,4ꢀkl]acridine derivatives. With ethyl cyanoacetate
as a CH acid, 1ꢀcyanoꢀ2ꢀethoxyꢀ7ꢀmethylꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridine (2a) and 1ꢀcyanoꢀ7ꢀmethylꢀ7Hꢀ
pyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (3a) were obtained in
the ratio ~3 : 1 (Scheme 1). The total yield of both prodꢀ
ucts was 78%.
In the case of ethyl malonate, the cyclization yielded a
mixture of 2ꢀethoxyꢀ1ꢀethoxycarbonylꢀ7ꢀmethylꢀ7Hꢀ
pyrido[2,3,4ꢀkl]acridine (2b) and 1ꢀethoxycarbonylꢀ7ꢀ
methylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (3b) in
approximately the same ratio as for products 2a and 3a.
With malononitrile as a CH acid, the cyclization
through the cyano group gave 1ꢀcyanoꢀ2ꢀiminoꢀ7ꢀmeꢀ
thylꢀ2,3ꢀdihydroꢀ7Hꢀpyrido[2,3,4ꢀkl]acridine (4) as the
sole product. Pyridoacridines 3a,b were identical with
compounds obtained by acylation of 1ꢀaminoꢀ10ꢀmethylꢀ
acridone with ethyl cyanoacetate and ethyl malonate, reꢀ
spectively, followed by baseꢀcatalyzed cyclization.1
A reaction of 9ꢀchloroꢀ1ꢀnitroacridine (5) with
malononitrile in the presence of KOH in DMSO afforded
9ꢀdicyanomethylideneꢀ1ꢀnitroꢀ9,10ꢀdihydroacridine (6)
in high yield (Scheme 2). The existence of compound 6 in
the dicyanomethylidene form rather than in the tautoꢀ
meric 9ꢀdicyanomethylꢀ1ꢀnitroacridine form was evident
from the presence of the band of the N—H stretching
vibrations in its IR spectrum.
Methylation of compound 6 followed by reduction of
Nꢀmethyl derivative 7 gave the same iminopyridoacridine
4 as in the reaction of 1ꢀaminoꢀ10ꢀmethylacridone (1)
with PCl5 and malononitrile.
The reduction of the nitro group to an amino group in
both acidic and alkaline media was accompanied by inꢀ
tramolecular cyclization. For instance, treatment of comꢀ
Apparently, in an intermediate with plausible3 strucꢀ
ture A, which is initially formed by the action of PCl5, the
Cl atom is replaced by the Cꢀnucleophile, whereupon the
N atom in position 1 is attacked by the ethoxycarbonyl
rather than cyano group. Elimination of a water molecule
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1605—1610, September, 2006.
1066ꢀ5285/06/5509ꢀ1664 © 2006 Springer Science+Business Media, Inc.

Annulated acridines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
1665
Scheme 1
X = CN (a), COOEt (b)
pound 6 with SnCl2 in HCl, or with an iron powder
in aqueous ethanol containing acetic acid, or with soꢀ
dium dithionite in the presence of NaOH gave the same
product, viz., 1ꢀcyanoꢀ2ꢀiminoꢀ2,3ꢀdihydroꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridine (8) in good yields (see Scheme 2).
Starting from 9ꢀchloroacridines, one can obtain
pyridoacridines with substituents in the acridine moiety.
The literature routes to such compounds are very compliꢀ
cated. For instance, a nineꢀstep synthesis of 4ꢀmethoxyꢀ
7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone includes intramoꢀ
lecular insertion of a nitrene as a key step in the thermal
decomposition of 5ꢀazidoꢀ8ꢀmethoxyꢀ4ꢀphenylquinolinꢀ
2(1H )ꢀone.4
rivatives of mꢀnitroaniline and oꢀchlorobenzoic acid. For
illustration, we synthesized 4ꢀ and 6ꢀmethoxypyridoꢀ
acridines. Replacement of the Cl atom in 9ꢀchloroꢀ2ꢀ
methoxyꢀ (9)6 and 9ꢀchloroꢀ4ꢀmethoxyꢀ1ꢀnitroacridines
(10)7 by malononitrile in DMSO in the presence of KOH
yielded 9ꢀdicyanomethylideneꢀ2ꢀmethoxyꢀ (11) and 9ꢀdiꢀ
cyanomethylideneꢀ4ꢀmethoxyꢀ1ꢀnitroꢀ9,10ꢀdihydroacriꢀ
dines (12), respectively. Subsequent reduction of the niꢀ
tro group was accompanied by cyclization into 1ꢀcyanoꢀ
2ꢀiminoꢀ4ꢀmethoxyꢀ (13) and 1ꢀcyanoꢀ2ꢀiminoꢀ6ꢀmethꢀ
oxyꢀ2,3ꢀdihydroꢀ7Hꢀpyrido[2,3,4ꢀkl]acridines (14), reꢀ
spectively, in good yields (see Scheme 2).
Imines 4, 8, 13, and 14 can potentially exist as tautoꢀ
meric aminopyridines and ketones 3a,b, as hydroxyꢀ
pyridines. The structures of these compounds were conꢀ
firmed by a comparison of their IR spectra with the specꢀ
9ꢀChloroꢀ1ꢀnitroacridines containing desired substituꢀ
ents are prepared according to a standard procedure5 while
constructing the acridine fragment from appropriate deꢀ
Scheme 2
R1 = R2 = H (5, 6, 8); R1 = OMe, R2 = H (9, 11, 13); R1 = H, R2 = OMe (10, 12, 14)

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Gorelik et al.
tra of Oꢀalkyl derivatives 2a,b and Nꢀalkyl derivatives1
with the fixed pyridine and pyridone forms. Like the
IR spectra of Nꢀalkyl derivatives, the spectra of the comꢀ
pounds obtained show a band due to the stretching vibraꢀ
tions of the exocyclic C=N or C=O double bond at
1641—1651 cm–1, which is absent in the spectra of Oꢀalkyl
derivatives 2a,b.
The presence of a nucleophilic heteroatom in posiꢀ
tion 1 of acridine allows the design of other tetracyclic
compounds, which has been illustrated with the synthesis
of first representatives of the pyrano[kl]acridine system
from periꢀmethoxy derivatives.
We found that the nitro group in 9ꢀdicyanomethylꢀ
ideneꢀ10ꢀmethylꢀ1ꢀnitroꢀ9,10ꢀdihydroacridine (7) can be
easily replaced by a methoxy group in a methanolic soluꢀ
tion of KOH, giving 9ꢀdicyanomethylideneꢀ1ꢀmethoxyꢀ
10ꢀmethylꢀ9,10ꢀdihydroacridine (15) (Scheme 3). Startꢀ
ing from 9ꢀchloroꢀ1,4ꢀdimethoxyacridine (16) and apꢀ
propriate CH acids, we obtained 9ꢀdicyanomethylideneꢀ
1,4ꢀdimethoxyꢀ9,10ꢀdihydroacridine (17a) and 9ꢀcyaꢀ
no(ethoxycarbonyl)methylideneꢀ1,4ꢀdimethoxyꢀ9,10ꢀ
dihydroacridine (17b). Methylation of compound 17a gave
Nꢀmethyl derivative 18 (see Scheme 3).
The methoxy group that is peri to the methylidene
substituent is involved in acidꢀcatalyzed intramolecular
cyclization leading to pyranoacridinones. Being structurꢀ
ally similar, compounds 15, 17a,b, and 18 behaved differꢀ
ently in aqueous HCl. When heated, 1ꢀmethoxy derivaꢀ
tive 15 promptly yielded 1ꢀcyanoꢀ2ꢀiminoꢀ7ꢀmethylꢀ
2,3ꢀdihydroꢀ7Hꢀpyrano[2,3,4ꢀkl]acridine (19), 1,4ꢀdiꢀ
methoxy derivative 17a somewhat more slowly turned into
1ꢀcyanoꢀ6ꢀmethoxyꢀ7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H )ꢀ
one (20), compound 17b underwent hydrolysis to 1,4ꢀdiꢀ
methoxyacridone 21, while Nꢀmethylated 1,4ꢀdimethoxy
derivative 18 remained unchanged. Refluxing of 2ꢀiminoꢀ
pyranoacridine 19 in aqueous HCl did not give pyranoꢀ
acridinꢀ2ꢀone. An analysis of the intramolecular electroꢀ
nic and steric effects that are responsible for the aforemenꢀ
tioned differences in reactivity between these structurally
similar compounds are beyond the scope of this study.
These differences were eliminated in H2SO4. Comꢀ
pounds 17a,b and 1ꢀcyanopyranoacridine 20 in
Scheme 3
X = CN (a), COOEt (b)

Annulated acridines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
1667
65% H2SO4 at 140 °C yielded 6ꢀmethoxyꢀ7Hꢀpyraꢀ
no[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (22). Under these condiꢀ
tions, Nꢀmethylated 1,4ꢀdimethoxy derivative 18 underꢀ
went cyclization into a 7ꢀmethylated analog of pyranoꢀ
acridine 22. The cyano group in position 1 of pyranoꢀ
acridines was eliminated through hydrolysis followed by
decarboxylation.
The methoxy group in position 6 of pyranoacridinone
22 was retained under the cyclization conditions in HCl
or H2SO4. It can be transformed into a hydroxy group
(Scheme 4, compound 23) by heating methoxy derivative
22 with pyridine hydrochloride or hydrobromic acid. Proꢀ
longed refluxing in HBr afforded 6ꢀhydroxyꢀ7Hꢀpyraꢀ
no[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (23) directly from 9ꢀ
dicyanomethylideneꢀ1,4ꢀdimethoxyacridine 17a, comꢀ
bining cyclization, elimination of the cyano group, and
demethylation in one step.
tion reactions. For instance, its reaction with benzeneꢀ
sulfinic acid gave 6ꢀhydroxyꢀ4ꢀphenylsulfonylꢀ7Hꢀpyraꢀ
no[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone 25 (see Scheme 4).
OꢀPhenylsulfonylation, which is inherent in some quinoꢀ
nes,8 did not take place here, because the reaction prodꢀ
uct was not hydrolyzed to a hydroxy derivative and was
inaccessible via treatment of compound 24 with benzeneꢀ
sulfonyl chloride. The PhSO2 group seems to be in posiꢀ
tion 4 (conjugated in pyranoacridinedione 24 with the
carbonyl group).
The possibilities of the synthesis of tetracyclic systems
from periꢀsubstituted 9ꢀchloroacridines can be enhanced
by variation of the CH acid, introduction of substituents
into the acridine moiety, and replacement of the heteroꢀ
atom in position 1.
Experimental
Mass spectra were recorded on a Kratos MS 30 instrument
(EI, 70 eV, ion source temperature 250 °C, direct inlet probe).
IR spectra were recorded on a FSM 1201 FTIRꢀspectrometer
(in KBr pellets). Electronic absorption spectra were recorded on
a Specord M40 spectrophotometer. The course of the reactions
was monitored and the purity of the products was checked by
TLC on Silufol UVꢀ254 plates. Preparative chromatography was
carried out on silica gel (60/100 µm) with chloroform as an
eluent. The products were identified by TLC (from Rf values)
and IR spectroscopy. 1ꢀAminoꢀ10ꢀmethylacridone (1),9
9ꢀchloroꢀ1ꢀnitroacridine (5),10 9ꢀchloroꢀ2ꢀmethoxyꢀ1ꢀnitroꢀ
acridine (9),6 9ꢀchloroꢀ4ꢀmethoxyꢀ1ꢀnitroacridine (10),7 and
9ꢀchloroꢀ1,4ꢀdimethoxyacridine (16)11,12 were prepared accordꢀ
ing to known procedures.
Scheme 4
1ꢀCyanoꢀ2ꢀethoxyꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridine
(2a) and 1ꢀcyanoꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]acridinꢀ2(3H )ꢀ
one (3a). Phosphorus pentachloride (0.46 g, 2.2 mmol) was added
at 40 °C to a solution of aminoacridone 1 (0.45 g, 2 mmol) in
benzene (60 mL). The reaction mixture was stirred for 45 min
and the resulting red suspension was added at 5 °C to a solution
of ethyl cyanoacetate (1.13 g, 10 mmol) and triethylamine
(1.52 g, 15 mmol) in benzene (30 mL). After 30 min, the mixꢀ
ture was filtered and concentrated in vacuo. The residue was
chromatographed in CHCl3 to give ethoxypyridoacridine 2a
(0.36 g, 60%) and then in ethyl acetate to give pyridoacridinone
3a (0.10 g, 18%) (cf. Ref. 1). Compound 2a, m.p. 172—174 °C
(from methanol). Found (%): C, 76.06; H, 4.97; N, 14.19.
C
19H15N3O. Calculated (%): C, 75.73; H, 5.02; N, 13.94. IR,
ν/cm–1: 2205 (CN).
2ꢀEthoxyꢀ1ꢀethoxycarbonylꢀ7ꢀmethylꢀ7Hꢀpyrido[2,3,4ꢀkl]ꢀ
acridine (2b) and 1ꢀethoxycarbonylꢀ7ꢀmethylꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (3b) were obtained analogously
from a potassium salt of diethyl malonate (10 mmol) and triꢀ
ethylamine (15 mmol). Column chromatography gave ethoxyꢀ
pyridoacridine 2b (0.36 g, 52%) and pyridoacridinone 3b (0.09 g,
14%) (cf. Ref. 1). Compound 2b, m.p. 157 °C (from methanol).
Found (%): C, 72.17; H, 5.83; N, 7.97. C21H20N2O3. Calcuꢀ
lated (%): C, 72.40; H, 5.79; N, 8.04. IR, ν/cm–1: 1717
(COOEt). MS, m/z: 348 [M]+.
Pyrano[2,3,4ꢀkl]acridineꢀ2,6ꢀdione (24) with a quinoꢀ
noid structure was obtained by oxidation of 6ꢀhydroxy
derivative 23 with lead tetraacetate. This unstable comꢀ
pound was characterized by IR and electronic absorption
spectra (λmax = 510 and 550 nm). Like quinones, pyranoꢀ
acridinedione 24 can be involved in nucleophilic addiꢀ
9ꢀDicyanomethylideneꢀ1ꢀnitroꢀ9,10ꢀdihydroacridine (6).
A solution of nitroacridine 5 (0.52 g, 2 mmol) in DMSO (20 mL)

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Gorelik et al.
was added to a solution of malononitrile (0.33 g, 5 mmol) and
KOH (0.28 g, 5 mmol) in DMSO (15 mL). The reaction mixture
was stirred for 1 h, diluted with water (100 mL), and acidified
N, 17.60. IR, ν/cm–1: 1320, 1580 (NO2); 1616 (C=C); 2210
(CN); 3305 (NH).
9ꢀDicyanomethylideneꢀ4ꢀmethoxyꢀ1ꢀnitroꢀ9,10ꢀdihydroꢀ
acridine (12) was obtained from acridine 10 as described for
compound 6. The yield was 0.40 g (63%), m.p. >350 °C (from
aqueous acetone). Found (%): C, 64.10; H, 3.18; N, 17.27.
with acetic acid.
The precipitate was filtered off, washed with
water, and dried. The yield was 0.49 g (85%), m.p. >350 °C
(from butanol). Found (%): C, 66.48; H, 2.76; N, 19.18.
C
16H8N4O2. Calculated (%): C, 66.67; H, 2.80; N, 19.44. IR,
C17H10N4O3. Calculated (%): C, 64.15; H, 3.17; N, 17.60. IR,
ν/cm–1: 1377, 1531 (NO2); 2212 (CN); 3281 (NH).
ν/cm–1: 1320, 1580 (NO2); 1612 (C=C); 2210 (CN); 3274 (NH).
1ꢀCyanoꢀ2ꢀiminoꢀ4ꢀmethoxyꢀ2,3ꢀdihydroꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridine (13) was obtained by reduction of dicyanoꢀ
methylideneacridine 11 with iron as described for imine 8 (proꢀ
cedure A). The yield was 49%, m.p. >350 °C (from aqueous
DMF). Found (%): C, 70.64; H, 4.05; N, 19.06. C17H12N4O.
Calculated (%): C, 70.82; H, 4.20; N, 19.43. IR, ν/cm–1: 1635
(C=N), 2190 (C≡N), 3293 (NH). MS, m/z: 288 [M]+.
9ꢀDicyanomethylideneꢀ10ꢀmethylꢀ1ꢀnitroꢀ9,10ꢀdihydroꢀ
acridine (7). Finely powdered KOH (1.20 g) was added to a
solution of compound 6 (0.46 g, 1.6 mmol) in DMF (30 mL). To
the resulting blueꢀviolet solution MeI (1.2 mL, 20 mmol) was
added and the reaction mixture was stirred at 30—35 °C for 1 h
and then poured into water (100 mL). The precipitate was filꢀ
tered off, washed with water, and dried. The yield was 0.37 g
(75%), m.p. 308 °C. Found (%): C, 67.48; H, 3.30; N, 18.62.
C17H10N4O2. Calculated (%): C, 67.55; H, 3.33; N, 18.53. IR,
ν/cm–1: 1368, 1524 (NO2); 2212 (CN).
1ꢀCyanoꢀ2ꢀiminoꢀ7ꢀmethylꢀ2,3ꢀdihydroꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridine (4). A. A mixture of 9ꢀdicyanomethylideneꢀ
10ꢀmethylꢀ1ꢀnitroacridine (7) (0.45 g, 1.5 mmol), conc. HCl
(10 mL), and SnCl2•2H2O (2.5 g) was refluxed for 1 h, cooled,
and diluted with water (50 mL). The precipitate of iminoꢀ
pyridoacridine 4 was filtered off, washed with water, and dried.
The yield was 0.31 g (75%), m.p. 288—290 °C (from aqueous
PriOH). Found (%): C, 74.90; H, 4.27; N, 20.60. C17H12N4.
Calculated (%): C, 74.98; H, 4.44; N, 20.57. IR, ν/cm–1: 1644
(C=N); 2187 (C≡N); 3406, 3472 (NH).
1ꢀCyanoꢀ2ꢀiminoꢀ6ꢀmethoxyꢀ2,3ꢀdihydroꢀ7Hꢀpyriꢀ
do[2,3,4ꢀkl]acridine (14) was obtained by reduction of diꢀ
cyanomethylideneacridine 12 with SnCl2•2H2O as described
for imine 8 (procedure B). The yield was 54%, m.p. >350 °C
(from aqueous DMF). Found (%): C, 70.62; H, 4.05; N, 19.14.
C17H12N4O. Calculated (%): C, 70.82; H, 4.20; N, 19.43.
IR, ν/cm–1: 1639 (C=N), 2206 (C≡N), 3318 (NH). MS,
m/z: 288 [M]+.
9ꢀDicyanomethylideneꢀ1ꢀmethoxyꢀ10ꢀmethylꢀ9,10ꢀdihydroꢀ
acridine (15). Potassium hydroxide (0.70 g, 12 mmol) was added
to a boiling solution of 1ꢀnitroacridone 7 (0.36 g, 1.2 mmol) in
MeOH (100 mL). The reaction mixture was stirred for 30 min
and concentrated by partially removing the solvent (60 mL).
The residue was cooled and the precipitate was filtered off and
washed with water. The yield of compound 15 was 0.28 g (81%),
m.p. 235 °C (from MeOH). Found (%): C, 74.96; H, 4.54;
N, 14.82. C18H13N3O. Calculated (%): C, 75.25; H, 4.56;
N, 14.62. IR, ν/cm–1: 2204 (CN). MS, m/z: 287 [M]+.
9ꢀDicyanomethylideneꢀ1,4ꢀdimethoxyꢀ9,10ꢀdihydroacridine
(17a). A mixture of malononitrile (0.66 g, 10 mmol) and powꢀ
dered KOH (1.40 g, 25 mmol) in DMSO (30 mL) was stirred
for 1 h. A suspension of acridine 16 (2.74 g, 10 mmol) in DMSO
(30 mL) was added. The reaction mixture was heated at 50 °C
for 1 h, poured into water with ice (250 mL), and acidified with
acetic acid. The orange precipitate was filtered off, washed with
water, and dried. The yield of compound 17a was 2.52 g (83%),
m.p. 218—220 °C (from butanol—hexane). Found (%): C, 71.29;
H, 4.19; N, 13.72. C18H13N3O2. Calculated (%): C, 71.28;
H, 4.32; N, 13.85. IR, ν/cm–1: 2202 (CN), 3289 (NH).
9ꢀCyano(ethoxycarbonyl)methylideneꢀ1,4ꢀdimethoxyꢀ9,10ꢀ
dihydroacridine (17b) was obtained analogously from acridine 16
and ethyl cyanoacetate. The yield was 0.22 g (62%), m.p.
290—292 °C (from benzene—hexane). Found (%): C, 68.24;
H, 4.88; N, 8.03. C20H18N2O4. Calculated (%): C, 68.56;
H, 5.18; N, 8.00. IR, ν/cm–1: 1701 (C=O); 2192 (CN); 3310,
3327 (NH).
B. Compound 4 was obtained from aminoacridone 1, PCl5,
and malononitrile (10 mmol) as described for compounds 2a
and 3a. The yield of product 4 purified by column chromatograꢀ
phy was 0.34 g (62%).
1ꢀCyanoꢀ2ꢀiminoꢀ2,3ꢀdihydroꢀ7Hꢀpyrido[2,3,4ꢀkl]acridine
(8). A. Nitro compound 6 (0.29 g, 1 mmol) was added for 10 min
to a mixture of an iron powder (0.5 g), water (20 mL), conc. HCl
(0.5 mL), and propanꢀ2ꢀol (20 mL). The reaction mixture was
refluxed with stirring for 1 h and diluted with water (40 mL).
Sodium carbonate was added to pH 8.5 and the precipitate was
filtered off and triturated with DMF (50 mL). The mixture was
filtered and imine 8 was precipitated from the filtrate with water
(150 mL). The yield was 0.18 g (70%), m.p. 350—353 °C (from
aqueous PriOH). Found (%): C, 74.42; H, 4.25; N, 21.43.
C16H10N4. Calculated (%): C, 74.41; H, 3.90; N, 21.69.
IR, ν/cm–1: 1639 (C=N), 2200 (C≡N), 3348 (NH). MS,
m/z: 258 [M]+.
B. A mixture of nitro compound 6 (0.44 g, 1.5 mmol),
conc. HCl (10 mL), and SnCl2•2H2O (2.5 g) was refluxed for 1 h,
cooled, and diluted with water (50 mL). The precipitate was
filtered off and washed with water and propanꢀ2ꢀol. The yield of
imine 8 was 0.30 g (77%).
C. Sodium dithionite (1 g) was added to a suspension of
nitro compound 6 (0.29 g, 1 mmol) in aqueous 1.5% NaOH
(20 mL). The reaction mixture was stirred at 50 °C for 30 min
and diluted with water (30 mL). The precipitate was filtered off,
washed with water, and dried. The yield of imine 8 was
0.16 g (62%).
9ꢀDicyanomethylideneꢀ1,4ꢀdimethoxyꢀ10ꢀmethylꢀ9,10ꢀdiꢀ
hydroacridine (18). Powdered KOH (1.87 g) and MeI (4 mL,
6.4 mmol) were added to a solution of compound 17a (1.52 g,
5 mmol) in DMSO (50 mL). The reaction mixture was stirred at
30—35 °C for 1 h and poured into water (200 mL). The precipiꢀ
tate was filtered off, washed with water, and dried. The yield
of compound 18 was 1.27 g (80%), m.p. 233—235 °C (from
PriOH). Found (%): C, 71.97; H, 4.75; N, 13.30. C19H15N3O2.
9ꢀDicyanomethylideneꢀ2ꢀmethoxyꢀ1ꢀnitroꢀ9,10ꢀdihydroꢀ
acridine (11) was obtained from chloroacridine 9 as described
for compound 6. The yield was 0.51 g (80%), red needles (from
pentanol), m.p. 283—285 °C. Found (%): C, 64.33; H, 3.31;
N, 17.38. C17H10N4O3. Calculated (%): C, 64.15; H, 3.17;
Calculated (%): C, 71.97; H, 4.76; N, 13.24. IR, ν/cm–1
:
2210 (CN).

Annulated acridines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 9, September, 2006
1669
1ꢀCyanoꢀ2ꢀiminoꢀ7ꢀmethylꢀ2,3ꢀdihydroꢀ7Hꢀpyraꢀ
no[2,3,4ꢀkl]acridine (19). 1ꢀMethoxyacridine 15 (0.29 g,
1 mmol) was refluxed in conc. HCl (10 mL) for 30 min. The
precipitate was filtered off and washed with water. The yield of
compound 19 was 0.25 g (91%), m.p. >350 °C (from DMF).
Found (%): C, 74.67; H, 4.24; N, 15.12. C17H11N3O. Calcuꢀ
lated (%): C, 74.71; H, 4.06; N, 15.38. IR, ν/cm–1: 1641 (C=N),
2201 (C≡N), 3370 (NH). MS, m/z (Irel (%)): 273 [M]+ (100);
258 [M – Me]+ (15).
1ꢀCyanoꢀ6ꢀmethoxyꢀ7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone
(20). A mixture of compound 17a (1.21 g, 4 mmol) and conc. HCl
(70 mL) in PriOH (35 mL) was heated at 80 °C for 2 h until the
starting reagent was completely consumed. Water (100 mL) was
added and the solvent was removed as an azeotrope. The residue
was neutralized with aqueous ammonia and the precipitate was
filtered off, washed with water, and dried. The yield of comꢀ
pound 20 was 0.91 g (78%), m.p. >350 °C (from DMF).
Found (%): C, 69.92; H, 3.69; N, 9.78. C17H10N2O3. Calcuꢀ
lated (%): C, 70.34; H, 3.47; N, 9.65. IR, ν/cm–1: 1690 (C=O),
2195 (CN), 3230 (NH).
for 40 min and then cooled to 90 °C. A saturated solution of
NaHCO3 was added at this temperature. The precipitate was
filtered off and refluxed in acetone (100 mL). After filtration,
the filtrate was concentrated. The yield of hydroxy derivative 23
was 0.53 g (70%).
Pyrano[2,3,4ꢀkl]acridineꢀ2,6ꢀdione (24). Lead tetraacetate
(1.20 g, 27 mmol) in AcOH (30 mL) was added at 25 °C to a
suspension of finely ground compound 23 (0.52 g, 2 mmol) in
benzene (100 mL). The reaction mixture was stirred for 20 min.
The resulting violet solution was diluted with water (200 mL).
The benzene layer was separated and compound 24 was preꢀ
cipitated with hexane (100 mL). The yield was 0.12 g. IR,
ν/cm–1: 1721, 1682 (C=O). UVꢀVIS (dioxane in the presence of
Pb(OAc)4), λmax/nm: 510, 550. Dione 24 was reduced with an
aqueous solution of hydrazine hydrate or sodium dithionite to
the starting compound 23; product 24 is unstable in storage and
in solutions.
6ꢀHydroxyꢀ4ꢀphenylsulfonylꢀ7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ
2(3H )ꢀone (25). A solution of compound 24 in benzene, which
was prepared as described above, was mixed with a solution of
benzenesulfinic acid (0.56 g, 4 mmol) in acetonitrile (40 mL).
The resulting colorless mixture was stirred at 20 °C for 1 h and
the precipitate was filtered off. An additional crop of the solid
product was obtained by concentrating the filtrate. The total
yield of compound 25 was 0.51 g (65%), m.p. 326—328 °C (from
ethanol). Found (%): C, 64.47; H, 3.85; N, 3.54. C15H9NO3.
Calculated (%): C, 64.44; H, 3.35; N, 3.58. IR, ν/cm–1: 1680
(C=O), 3250 br (OH, NH). MS, m/z (Irel (%)): 391 [M]+ (100),
251 [M – PhSO2 — CO]+ (23).
1,4ꢀDimethoxyacridone (21). Compound 17b (0.35 g,
1 mmol) was refluxed in conc. HCl (20 mL) with PriOH (10 mL)
for 3 h until the starting reagent was completely consumed.
Water was added and aqueous propanꢀ2ꢀol was distilled off. The
residue was neutralized with aqueous ammonia. The yield of
compound 21 was 0.21 g (82%); the product was identical with
the earlier reported one.11
6ꢀMethoxyꢀ7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (22).
A
mixture of dicyanomethylideneacridine 17a (0.46 g,
0.15 mmol) and 65% H2SO4 (7 mL) was stirred at 140 °C for
30 min, cooled, and poured into water (170 mL). The precipiꢀ
tate was filtered off, washed with water, and dried. The yield of
compound 22 was 0.27 g (71%), m.p. 263—265 °C (from PriOH).
Found (%): C, 72.64; H, 4.15; N, 5.31. C16H11NO3. Calcuꢀ
lated (%): C, 72.44; H, 4.18; N, 5.28. IR, ν/cm–1: 1684, 1701
(C=O); 3234 (NH).
The identical compound was obtained under the same conꢀ
ditions from acridine 17b or pyranoacridinone 20 in 85—90%
yield.
6ꢀMethoxyꢀ7ꢀmethylꢀ7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H )ꢀ
one was obtained analogously from dicyanomethylideneacridine
18, m.p. 168—170 °C (from methanol). Found (%): C, 73.36;
H, 4.80; N, 4.82. C17H13NO3. Calculated (%): C, 73.11; H, 4.68;
N, 5.01. IR, ν/cm–1: 1684, 1701 (C=O).
References
1. M. V. Gorelik, S. P. Titova, and E. V. Gordievskaya, Izv.
Akad. Nauk, Ser. Khim., 2006, 1433 [Russ. Chem. Bull., Int.
Ed., 2006, 55, 1487].
2. M. Alvarez, L. Feliu, W. Ajana, J. A. Joule, and J. L.
FernandezꢀPuentes, Eur. J. Org. Chem., 2000, 849.
3. M. V. Gorelik, S. P. Titova, and T. Kh. Gladysheva, Izv.
Akad. Nauk, Ser. Khim., 1998, 1179 [Russ. Chem. Bull., 1998,
47, 1147 (Engl. Transl.)].
4. T. Ozturk and A. McKillop, Can. J. Chem., 2000, 78, 1158.
5. J. M. F. Gagan, in Acridines, Ed. R. M. Acheson, 2nd ed.,
Wiley, New York, 1973, 218.
6. A. T. Troshchenko, Zh. Obshch. Khim., 1958, 28, 2207
[J. Gen. Chem. USSR, 1958, 28 (Engl. Transl.)].
7. N. S. Drozdov and N. S. Lezneva, Zh. Obshch. Khim., 1935,
5, 690 [J. Gen. Chem. USSR, 1935, 5 (Engl. Transl.)].
8. M. V. Gorelik, Zh. Org. Khim., 1968, 4, 513 [J. Org. Chem.
USSR, 1968, 4, 505 (Engl. Transl.)].
6ꢀHydroxyꢀ7Hꢀpyrano[2,3,4ꢀkl]acridinꢀ2(3H )ꢀone (23).
A. Compound 22 (0.27 g, 1 mmol) was refluxed in conc. HBr
(10 mL) for 5 h until the starting reagent was completely conꢀ
sumed. The reaction mixture was poured into water (100 mL)
and neutralized with aqueous ammonia. The precipitate was
filtered off and washed with water. The yield of compound 23
was 0.23 g (92%), m.p. 336—338 °C (from aqueous ethanol).
Found (%): C, 71.58; H, 3.84; N, 5.30. C15H9NO3. Calcuꢀ
lated (%): C, 71.71; H, 3.61; N, 5.57. IR, ν/cm–1: 1662 (C=O),
3300 (OH). UVꢀVIS (dioxane), λmax/nm (ε): 435 (9700). MS,
m/z (Irel (%)): 251 [M]+ (100); 223 [M – CO]+ (25); 195
[M – 2 CO]+ (28).
9. D. K. C. Hodgeman and R. H. Prager, Aust. J. Chem., 1972,
25, 191.
10. K. Lehmstedt and K. Schrader, Ber., 1937, 70, 838.
11. S. M. Sherlin, G. I. Braz, A. Ya. Yakubovich, E. I. Vorob´eva,
and F. E. Rabinovich, Zh. Obshch. Khim., 1938, 8, 884
[J. Gen. Chem. USSR, 1938, 8 (Engl. Transl.)].
12. M. Jonescu and J. Mester, Rev. Roum. Chim., 1969, 14, 789;
Chem. Abstr., 1970, 72, 21787.
The identical compound was obtained in 90% yield by reꢀ
fluxing 9ꢀdicyanomethylideneꢀ1,4ꢀdimethoxyacridine 17a in
conc. HBr for 12 h.
B. A mixture of 6ꢀmethoxypyranoacridinone 22 (0.80 g,
3 mmol) and pyridine hydrochloride (7.5 g) was heated at 200 °C
Received April 13, 2006;
in revised form June 9, 2006