Synthesis of novel fluorescent acridono- and thioacridono-18-crown-6 ligands

Article abstract of DOI:10.1016/S0040-4020(01)00408-2

Novel fluorescent 18-crown-6 type ligands containing acridono and thioacridono units were synthesised. The acridono ligand was prepared by the oxidation of its acridino analogue, and also by the cyclisation of 4,5-dihydroxyacridine-9(10H)-one and tetraeth

Full text of DOI:10.1016/S0040-4020(01)00408-2

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 4967±4975
Synthesis of novel ¯uorescent acridono-
and thioacridono-18-crown-6 ligands
a,p
Peter Huszthy, Zoltan Kontos, Borbala Vermes and Aron Pinter
b
a
b
Â
Â
Â
Â
Â
È È
aResearch Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
bInstitute for Organic Chemistry, Technical University Budapest, H-1521 Budapest, Hungary
Received 23 February 2001; revised 19 March 2001; accepted 5 April 2001
AbstractÐNovel ¯uorescent 18-crown-6 type ligands containing acridono and thioacridono units were synthesised. The acridono ligand
was prepared by the oxidation of its acridino analogue, and also by the cyclisation of 4,5-dihydroxyacridine-9510H)-one and tetraethylene
glycol di-p-tosylate in the presence of K2CO3. The acridono macrocycle was converted to the thioacridono ligand using Lawessons's
Reagent. The synthesis of several precursors leading to the preparation of an acridono-18-crown-6 ¯uorophore was also performed.
These precursors can also be very useful building blocks for acridine, acridone and thioacridone derivatives of chemotherapeutical impor-
tance. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
number of crown ether type ¯uorophores have been synthe-
sised and studied,1±6 from the point of view of our research
it is noteworthy to mention the work on the synthesis and
cation-binding properties of a 4,5-dioxyxanthone unit
containing 18-crown-6 type ligand reported by Watt and
coworkers.7 In this case the ethereal oxygens of the highly
¯uorescent 4,5-dioxyxanthone chromophore are part of the
coordination sphere which surrounds the complexed ion,
so complexation can give rise to desirable photophysical
behaviour.7
Incorporation of ¯uorogenic subunits into the 18-crown-6
type macrocyclic framework can lead to host molecules
which are very interesting from a theoretical viewpoint as
well as for practical purposes.1,2 Cationic recognition
studies using crown ether type ¯uorophore macrocycles
have increased recently, because these sensors exhibit
large changes in their ¯orescence behaviour during inter-
action with analytes and also, because spectro¯uorometry is
a very sensitive, selective and fast technique with relatively
simple handling and calculation procedures to analyse
mixtures of biologically important ions.1±6 Among a large
Recently, we described the synthesis8 of acridino-18-crown-
6 ¯uorophore 1 5see Fig. 1) and studied its complexation
Figure 1. Acridino-, acridono-, thioacridono-, pyridono-, and thiopyridono-18-crown-6 type ligands.
Keywords: acridines; crown ethers; ¯uorescence; ionophores.
Corresponding author. Tel.: 136-1-463-2111; fax: 136-1-463-3297; e-mail: huszthy.szk@chem.bme.hu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00408-2

4968
P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
Scheme 1. Formation of new acridono ligand 2 by oxidation of acridino host 1 and improved method for preparation of 1.
with organic primary ammonium salts by photoluminescence
spectroscopy.9
a 28% yield of acridine-9510H)-one by fusing acridine and
potassium hydroxide.10 Unfortunately, even prolonged
re¯uxing of ligand 1 with an excess of potassium tert-butox-
ide in THFunder an oxygen atmosphere did not give more
than 5% yield of ligand 2, while many other side products
formed as well. We substituted potassium tert-butoxide by
the stronger base NaH getting 11% yield, and when we also
replaced the solvent THFby DMSO a yield of 52% was
achieved. In this paper we also describe another, more
straightforward synthesis of acridono ligand 2 using rela-
tively simple starting materials, and its transformation to
thioacridono analogue 3 5see Fig. 1).
In the course of the synthesis of acridino ligand 1 when
monitoring the progress of the reaction by thin layer
chromatography8 5TLC) we noticed a very intense blue
¯uorescent spot on the silica gel TLC plate above the spot
of ligand 1. As the reaction progressed, the size of the blue
¯uorescent spot compared to the spot of ligand 1 grew
slowly, and this tendency continued even when the starting
material was consumed. After isolation of the highly
1
¯uorescent compound by preparative TLC H NMR, 13C
NMR, MS and IR spectra were taken, which proved its
structure to be the new acridono-18-crown-6 ether 2 5see
Fig. 1). Although its yield was only 3% we thought that it
had been formed from acridino ligand 1 under strong basic
conditions 5we used potassium tert-butoxide in THF)8 in the
presence of traces of oxygen and that we could transform
acridino ligand 1 to acridono ligand 2 in reasonable yield by
re¯uxing the reaction mixture under oxygen for a longer
period of time. We note here that Russian scientists obtained
In connection with the present research the pyridono- and
thiopyridono-18-crown-6 type ligands 4±9 5see Fig. 1)
should also be mentioned. The latter macrocycles were
prepared and studied by Bradshaw and coworkers.11±16
Acridono- and thioacridono-18-crown-6 ligands 2 and 3
seem to have several advantageous features compared to
their pyridono and thiopyridono analogues 4±9. The acri-
done and thioacridone tricyclic units make the 18-crown-6
framework more rigid conferring higher selectivity in the
molecular recognition process.17,18 Acridone and thioacri-
done derivatives have attractive coloration, crystallinity
and strong ¯uorescence.19±26 The aromatic rings of the acri-
done unit readily undergo electrophillic substitution19,20 and
by introducing appropriate substituents into them, the tauto-
merism,27 the acidity of the NH proton,19,20 the complexa-
tion properties, the chemistry19,20 and the photophysical
behaviour of ligand 2 can favourably be altered. Acridone
derivatives can also be converted simply to chloroacri-
dines19,20,28±31 which readily undergo nucleophilic substitu-
tion and other reactions19,20,28±31 creating scope for the
preparation of interesting and useful host molecules. Exploi-
tation of the above-mentioned advantages and also the
complexation studies of ligands 2 and 3 with selected
cations are in hand, and the results will be reported in future
publications.
In this paper the synthesis of novel acridono-, and thioacri-
dono-18-crown-6 ligands 2 and 3, and also the preparation
of their precursors which can also be very useful building
Scheme 2. Preparation of new acridono ligand 2 from 4,5-dihydroxy-
acridine-9510H)-one 512) and its transformation to novel thioacridono-18-
crown-6 ether 3.

P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
4969
Scheme 3. Preparation of acridonediol 12 from acridinediol 10 and aminoacridone 18, respectively.
blocks for acridine, acridone and thioacridone derivatives of
chemotherapeutical importance19,20,31±36are reported.
presence of K2CO3 in DMFat 50 8C and when we isolated
and puri®ed the potassium tosylate complex of ligand 1 by
crystallisation. The free ligand 1 was obtained by decom-
plexing the product by chromatography on alumina. In the
latter case the overall yield of ligand 1 calculated for
acridinediol 10 and ditosylate 11 reached 41%. We found
that ditosylate 11 also cyclises with 4,5-dihydroxyacridine-
9510H)-one 512) in similar reaction conditions to those with
acridine-4,5-diol 510) giving a reasonable yield 545%) of
acridone ligand 2 5see Scheme 2). New acridono ligand 2
was transformed to its thioacridono analogue 3 using
Lawesson's Reagent 513, see Scheme 2) in a similar manner
to that reported14 for the preparation of thiopyridono-18-
crown-6 ethers 57±9, see Fig. 1) starting from their pyridono
analogues 4±6 5see Fig. 1). Although the 1H- and 13C NMR
spectra of 4,5-dihydroxyacridine-9510H)-one 512) are
reported37 its preparation is described only in a PhD disser-
tation38 which is not readily available. As we were fully
convinced that acridonediol 12 is not only the best precursor
for acridono ligand 2, but it can also be a very useful
building block for acridine and acridone derivatives of
photophysical,21±26,39 and pharmacological19,20,32±36,40±44
importance, we devoted a lot of effort to its synthesis and
regioselective alkylation. It was shown above that acridino
ligand 1 can be oxidised using NaH in DMSO under air.
2. Results and discussion
The acridono-18-crown-6 ligand 52) was ®rst prepared from
its acridino analogue 1 by oxidation with dry air in the
presence of NaH using either THFor DMSO as a solvent
5see Scheme 1). The yield in the latter case 552%) was much
higher than that of in the former case 511%). Carrying out
the oxidation in THFthe yield did not change when we
applied a dry air or dry oxygen atmosphere. Using DMSO
as solvent, however, the yield was higher when we carried
out the reaction under dry air than we applied a dry oxygen
atmosphere, because in the latter conditions a large amount
of dimethyl sulfone also formed which made the isolation
procedure very dif®cult with loss of a considerable amount
of ligand 2. As the reported procedure to obtain acridino
ligand 1 from acridine-4,5-diol 510) and tetraethylene glycol
di-p-tosylate 511) using potassium tert-butoxide as base in
8
THFgave only 16% yield we made some changes in the
reaction conditions to improve the outcome of this direct
route to the acridono crown ether 2. The best yield for ligand
1 was obtained when we carried out the cyclisation in the

4970
P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
Scheme 4. Preparation of 4,5-dimethoxyacridine-9510H)-one 516) from 2-amino-3-methoxybenzoic acid 520).
Keeping this in mind we ®rst prepared 4,5-dimethoxyacri-
dine 514) and 4,5-dibenzyloxyacridine 515) by alkylation of
acridinediol 10 with methyl iodide and benzyl bromide,
respectively, then oxidised acridines 14 and 15 to dimeth-
oxyacridone 16 and dibenzyloxyacridone 17 5see Scheme 3)
in the same manner as mentioned above for the preparation
of acridono ligand 2 from acridino ligand 1. Dimethoxy-
acridine45 14 and dimethoxyacridone28,45 16 are known
compounds, but they were previously prepared by different
procedures. The synthesis of dibenzyloxyacridine 15 and
dibenzyloxyacridone 17, however, to our knowledge has
not been reported. Cleavage of the O-methyl group using
pyridinium chloride at elevated temperature and the
removal of O-benzyl group by hydrogenation at room
temperature, respectively afforded acridonediol 12. 4,5-
Diaminoacridone 518) and its di-N-acetyl derivative 19 are
also suitable precursors for the preparation of acridonediol
12. Diaminoacridone 18 was prepared by the reported
procedure.46,47 As the puri®cation of diamine 18 in our
hands turned out to be very dif®cult we identi®ed it through
its di-N-acetyl derivative 19. 4,5-Diacetamidoacridine-
9510H)-one 519) was prepared by heating diaminoacridone
18 with an excess of acetic anhydride in acetic acid 5see
Scheme 3). We note here that N-acetylation of the primary
amino groups took place only at positions 4 and 5 and the
NH group at position 10 remained intact. Di-N-acetyl-
diamide 19 can easily be puri®ed by crystallisation, and
was fully characterised 5see Section 3). Both diaminoacri-
done 18 and its di-N-acetyl derivative 19 were converted to
acridonediol 12 by heating them in 70% aqueous phosphoric
acid at elevated temperature for a long time. We used this
procedure successfully earlier for the transformation of
4-amino-5-methoxyacridine to acridine-4,5-diol 510) and
1,9-diaminophenazine to phenazine-1,9-diol, respectively.8
Using di-N-acetyldiamide 19 we obtained better yield 558%,
see Scheme 3) for acridonediol 12 than starting form
diamine 18 543%, see Scheme 3).
New Zealand scientists reported a procedure28 for the
preparation of dimethoxyacridone 16 and we applied that
method also with some modi®cations and extensions to
obtain acridonediol 12 5see Scheme 4). 2-Amino-3-meth-
oxybenzoic acid 520) was converted by diazotisation and
Sandmeyer reaction to 2-bromo-3-methoxybenzoic acid
521). The bromo acid 21 and o-anisidine 523) were heated
in 2-ethoxyethanol in the presence of K2CO3, copper
powder and copper5I) oxide to obtain N-52-methoxy-
phenyl)-3-methoxyanthranilic acid 524). Following
exactly the reported procedure28 we obtained a low yield.
Changing the reported reaction conditions systematically,
we obtained the best yield when we used twice as much
solvent 2-ethoxyethanol as reported, and when we carried
out the reaction in the presence of copper powder and
copper5I) oxide instead of copper5II) oxide.28 Acid 24 was
also prepared in a good yield when 2-amino-3-methoxy-
benzoic acid 520) and o-bromoanisole 522) were heated in
Scheme 5. Regioselective alkylation of 4,5-dihydroxyacridine-9510H)-one 512).

P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
4971
2-ethoxyethanol in the presence of K2CO3, copper powder
and copper5I) oxide 5see Scheme 4). This new procedure has
two advantageous features compared to the reported one:28
the yield is higher by 23% and both starting materials 520
and 22) are commercially available. The latter acid 524) was
then converted to dimethoxyacridone 16 using poly-
phosphoric acid 5PPA) at a higher temperature and for a
longer time as reported.28
EtOAc to give yellow crystals 51.3 g, 56%). Rfˆ0.32
5alumina TLC, 18% EtOH in toluene); mp: 196±1988C;
IR 5KBr) nmax 3080, 3056, 3000, 2920, 2896, 2872, 1628,
1568, 1460, 1408, 1364, 1320, 1272, 1256, 1232, 1216,
1192, 1120, 1048, 1040, 1024, 1016, 944, 904, 816, 744,
720, 680, 560 cm21; 1H NMR d 2.19 5s, 3H), 3.73±3.74 5m,
4H), 3.87±3.88 5m, 4H), 4.15±4.16 5m, 4H), 4.34±4.35 5m,
4H), 6.87 5d, Jˆ7 Hz, 2H), 7.00 5d, Jˆ7 Hz, 2H), 7.41 5t,
Jˆ8 Hz, 2H), 7.57 5d, Jˆ8 Hz, 2H), 7.69 5d, Jˆ7 Hz, 2H),
8.71 5s, 1H); 13C NMR d 21.34, 68.01, 68.22, 69.83, 70.80,
108.18, 121.04, 126.08, 126.17, 128.09, 128.32, 136.85,
138.74, 140.59, 144.11, 154.08. Anal. calcd for
C28H30NO8SK: C, 57.99; H, 5.22; N, 2.42. Found: C,
58.00; H, 5.25; N, 2.40. The complex was subjected to
chromatography on alumina using 12% EtOH in toluene
as an eluent. The free ligand 1 was recrystallised from
ether±CH2Cl2 mixture to give 1 5610 mg, 73%) as pale
yellow crystals. Rfˆ0.32 5alumina TLC, 18% EtOH in
toluene); mp: 104±1068C 5ether-CH2Cl2), 5lit.8 104±1068C
5ether±CH2Cl2)). Other physical properties and spectral
data were also identical to those reported8 for ligand 1.
We were interested to ®nd out whether the regioselective
alkylation observed in the case of formation of acridono
crown ether 2 from ditosylate 11 and acridonediol 12 in
weak basic conditions is a general phenomenon. To this
end acridonediol 12 was treated with methyl iodide and
benzyl bromide, respectively in similar reaction conditions
5see Scheme 5) to those applied for the preparation of acri-
dono crown ether 2 5see Scheme 2). We should note here
1
that according to the IR, H- and 13C NMR spectra of
products 16 and 17 only O-alkylation at positions 4 and 5
took place and all their physical and spectroscopic data were
identical to those of acridones 16 and 17 prepared by the
other methods described above.
3.1.2. 2,5,8,11,14-Pentaoxa-26-azatetracyclo[13.9.3.0.19,27
21,25]heptacosa-1024),15,17,19027),21025),22-heptaene-
.
0
20-one 2. 5see Fig. 1). Starting from crown ether 1 and
using THF as a solvent 5see Scheme 1). To a well stirred
suspension of NaH 5240 mg, 6 mmol, 60% dispersion in
mineral oil) in dry THF515 mL), was added at room
temperature 5rt) and under dry air acridino crown ether 1
5739 mg, 2 mmol). The reaction mixture was stirred at rt for
15 min then warmed up to 508C and it was stirred at this
temperature for 5 days. Acetic acid 5600 mg, 10 mmol) was
slowly added to the ice-cold reaction mixture and it was
stirred at 08C for 15 min then at rt for 30 min. The solvent
was removed at rt and the residue was taken up in a mixture
of water 530 mL) and CH2Cl2 560 mL). The aqueous phase
was extracted with CH2Cl2 53£30 mL). The combined
organic phase was dried over MgSO4, ®ltered, and the
solvent was removed. The crude product was puri®ed by
chromatography on alumina using 12% EtOH in toluene
as an eluent. The pale yellow solid was recrystallised
from ethanol to give pure crystals of 2 585 mg, 11%). Rfˆ
0.35 5silica gel TLC, 5% MeOH in CH2Cl2); mp: 184±
1858C 5EtOH); IR 5KBr) nmax 3424, 3008, 2920, 1628,
1616, 1592, 1536, 1488, 1448, 1268, 1244, 1224, 1080,
3. Experimental
3.1. General
Infrared spectra were obtained on a Zeiss Specord IR 75
spectrometer. 1H 5500 MHz) and 13C 5125 MHz) NMR
spectra were taken on a Bruker DRX-500 Avance spectro-
meter in CDCl3 unless otherwise indicated. Molecular
weights were determined by a VG-ZAB-2 SEQ reverse
geometry mass spectrometer. Elemental analyses were
performed in the Microanalytical Laboratory of the Depart-
È
È
ment of Organic Chemistry, L. Eotvos University, Buda-
pest, Hungary. Melting points were taken on a Boetius
micro melting point apparatus and were uncorrected.
Starting materials were purchased from Aldrich Chemical
Company unless otherwise noted. Silica gel 60 F254 5Merck)
and aluminium oxide 60 F254 neutral type E 5Merck) plates
were used for TLC. Aluminium oxide 5neutral, activated,
Brockman I) and silica gel 60 570±230 mesh, Merck) were
used for column chromatography. Solvents were dried and
puri®ed according to well established48 methods. Evapo-
rations were carried out under reduced pressure unless
otherwise stated.
1
804, 748, 600 cm21; H NMR d 2.94 5s, broad, shifted
up®eld by 0.19 ppm when warming, 0.5 mol H2O, 1H),
3.71±3.72 5m, 4H), 3.78±3.79 5m, 4H), 3.99±4.00 5m,
4H), 4.32±4.34 5m, 4H), 7.06 5d, Jˆ8 Hz, 2H), 7.14 5t,
Jˆ8 Hz, 2H), 8.06 5d, Jˆ8 Hz, 2H), 9.68 5s, broad, shifted
up®eld by 0.11 ppm when warming, NH, 1H); 13C NMR d
68.83, 69.49, 70.64, 71.54, 112.39, 118.74, 120.84, 122.25,
131.72, 147.01, 178.03; HRMS calcd for C21H23NO6:
385.1525. Found: 385.1531; Anal. calcd for:
C21H23NO6´0.5H2O: C, 63.95; H, 6.13; N, 3.55. Found: C,
63.86; H, 6.15; N, 3.41.
3.1.1. 2,5,8,11,14-Pentaoxa-26-azatetracyclo[13.9.3.0.19,27
21,25]heptacosa-1025),15,17,19,21,23,26-heptaene 1. 5see
.
0
Fig. 1 and Scheme 1). To a well stirred mixture of ®nely
powdered anhydrous K2CO3 52.20 g, 16 mmol) and acri-
dine-4,5-diol8 510) 5844 mg, 4 mmol) in dry DMF545 mL)
was added at 08C and under argon a solution of ditosylate8
11 52.10 g, 4 mmol) dissolved in DMF515 mL). The reac-
tion mixture was stirred at 08C for 15 min then warmed up to
508C and it was stirred at this temperature for 5 days. The
solvent was removed at 458C and the residue was taken up
in a mixture of ice±water 550 mL) and CH2Cl2 5100 mL).
The aqueous phase was extracted with CH2Cl2 53£50 mL).
The combined organic phase was dried over MgSO4,
®ltered, and the solvent was removed. The crude KOTs
complex of 1 was puri®ed by recrystallisation from
Starting from crown ether 1 and using DMSO as a solvent
5see Scheme 1). To a well stirred suspension of NaH
5240 mg, 6 mmol, 60% dispersion in mineral oil, previously
washed with dry pentane under Ar) in dry DMSO 515 mL)
was added at rt and under dry air, acridino crown ether 1
5369 mg, 1 mmol). The reaction mixture was stirred at rt for

4972
P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
15 min then warmed up to 608C and it was stirred at this
temperature for one day. Acetic acid 5600 mg, 10 mmol)
was slowly added to the reaction mixture at rt and it was
stirred at this temperature for 20 min. The solvent was
removed at 508C and the residue was taken up in a
mixture of water 520 mL) and CH2Cl2 540 mL). The
aqueous phase was extracted with CH2Cl2 53£20 mL).
The combined organic phase was dried over MgSO4,
®ltered, and the solvent was removed. The crude product
was puri®ed as above to give 2 5200 mg, 52%) which was
identical in every respect to that prepared by the previous
procedure.
mp: .3608C; IR 5KBr) nmax 3392, 1636, 1620, 1568, 1544,
1536, 1432, 1400, 1336, 1280, 1208, 1068, 1008, 732,
1
540 cm21; H NMR 5DMSO-d6) d 3.41 5s, broad, H2O,
2H), 7.09 5t, Jˆ8 Hz, 2H), 7.18 5d, Jˆ8 Hz, 2H), 7.70 5d,
Jˆ8 Hz, 2H), 9.07 5s, broad, NH, 1H), 10.87 5s, broad, OH,
2H); 13C NMR 5DMSO-d6) d 115.56, 115.94, 121.04,
121.33, 130.43, 145.45, 176.77; MS5EI) 227 5M1);
HRMS. calcd for C13H9NO3: 227.0582. Found: 227.0585;
Anal. calcd for: C13H9NO3´H2O: C, 63.67; H, 4.52; N, 5.71.
Found: C, 63.55; H, 4.58; N, 5.87.
Starting from 4,5-dibenzyloxyacridine-9,10H)-one 517, see
Scheme 3). To a stirred mixture of ®nely powdered diben-
zyloxyacridone 17 51.3 g 3.19 mmol) and 10% palladium on
charcoal catalyst 50.26 g) MeOH 5390 mL) was added under
Ar. Ar was replaced by hydrogen and hydrogenation was
carried out in the usual way at rt and atmospheric pressure to
give acridonediol 12 50.77 g, 98%) which was puri®ed as
above. Pure 12 50.57 g, 73%) was identical in every aspect
to that prepared by the previous procedure.
Starting from acridonediol 12 5see Scheme 2). A mixture of
acridonediol 12 5454 mg, 2 mmol), ditosylate8 11 51.11 g,
2.2 mmol), ®nely powdered anhydrous K2CO3 52.76 g,
20 mmol) and dry DMF535 mL) was stirred under Ar at
rt for 10 min then at 508C for one day. The solvent was
removed at 458C and the residue was taken up in a mixture
of water 560 mL) and CH2Cl2 5120 mL). The aqueous phase
was extracted with CH2Cl2 53£60 mL). The combined
organic phase was dried over MgSO4, ®ltered, and the
solvent was removed. The crude product was puri®ed as
above to give 2 5355 mg, 45%) which was identical in
every respect to that prepared by the previous procedure.
Starting from 4,5-diaminoacridine-9,10H)-one 518, see
Scheme 3). A mixture of ®nely powdered diamine 1846,47
51.8 g, 8.0 mmol) and 70% 5w/w) aqueous H3PO4 540 mL)
was stirred in an oil bath at 1808C under Ar for 20 days
using a very-long-neck ¯ask equipped with a re¯ux con-
denser. The reaction mixture was cooled to rt, poured into
ice-cold water 5500 mL) and its pH was adjusted to 5.0 with
solid NaOAc. The precipitate was ®ltered, washed with
water 53£30 mL) and dried. It was ®nely powdered and
stirred with boiling MeOH 53£150 mL) for 30 min. The
hot solutions were ®ltered and combined. The combined
solution was stirred and boiled with charcoal 50.2 g) for
10 min, ®ltered and the solvent was removed. The crude
product was recrystallised from DMFto give acridonediol
12 50.84 g, 43%) which was identical in every aspect to that
prepared by the previous procedure.
3.1.3. 2,5,8,11,14-Pentaoxa-26-azatetracyclo[13.9.3.0.19,27
21,25]heptacosa-1024),15,17,19027),21025),22-heptaene-
.
0
20-thione 3. 5see Scheme 2). A mixture of acridono crown
ether 2 5174 mg, 0.44 mmol), Lawesson's Reagent 513,
200 mg, 0.49 mmol) and dry benzene 56 mL) was stirred
under Ar at rt for 10 min then at re¯ux temperature for
8 h. Dry CH2Cl2 510 mL) was added to the cold reaction
mixture and the clear solution so formed was used for
preparative thin layer chromatography 5silica gel, eluent
for chromatography 5% MeOH in CH2Cl2). The product
was eluted from the adsorbent using 16% MeOH in
CH2Cl2, the solvent was removed and the red crystals
were recrystallised from dry 1,2-dichloroethane to give
118 mg 564%) of pure 3. Rfˆ0.55 5silica gel TLC, 5%
MeOH in CH2Cl2); mp: 205±2078C 51,2-dichloroethane);
IR 5KBr) nmax 3400, 3040, 2928, 2896, 2864, 1616, 1577,
1520, 1488, 1452, 1420, 1288, 1280, 1272, 1264, 1228,
Starting from 4,5-diacetamidoacridine-9,10H)-one 519, see
Scheme 3). Acridonediol 12 was also prepared from
diacetamide 19 52.47 g, 8.0 mmol) as described above start-
ing from diamine 18. Compound 12 51.14 g, 58%) obtained
this way was identical in every aspect to that prepared by the
previous procedure.
1
1136, 1048, 944, 808, 744, 632, 560, 512 cm21; H NMR
5DMSO-d6, 708C) d 3.27 5s, broad, H2O, 2H), 3.67 5s, broad,
4H), 3.70 5s, broad, 4H), 3.95 5s, broad, 4H), 4.42 5s, broad,
4H), 7.33 5t, Jˆ8 Hz, 2H), 7.43 5d, Jˆ8 Hz, 2H), 8.41 5d,
Jˆ8 Hz, 2H), 9.84 5s, broad, NH, 1H); 13C NMR 5DMSO-
d6, 708C) d 68.35, 69.11, 69.47, 70.16, 112.57, 120.81,
122.77, 125.75, 129.66, 146.82, 197.72; HRMS. calcd for
C21H23NO5S: 401.1297. Found: 401.1297; Anal. calcd for:
C21H23NO5S´H2O: C, 60.13; H, 6.01; N, 3.34; S, 7.64.
Found: C, 59.97; H, 6.07; N, 3.25; S, 7.82.
3.1.5. 4,5-Dimethoxyacridine 14. 5see Scheme 3). A
mixture of acridine-4,5-diol8 510) 5910 mg, 4.31 mmol),
methyl iodide 52.45 g, 1.07 mL, 17.26 mmol), ®nely
powdered anhydrous K2CO3 55.94 g, 43 mmol) and pure
and dry DMF538 mL) was stirred under Ar at rt for one
day. The solvent was removed at 408C and the residue was
taken up in a mixture of water 580 mL) and CH2Cl2
5100 mL). The aqueous phase was extracted with CH2Cl2
53£40 mL). The combined organic phase was dried over
MgSO4, ®ltered, and the solvent was removed. The crude
product was recrystallised from MeOH to give 14 53.68 g,
89%) as pale yellow crystals. Rfˆ0.68 5silica gel TLC, 5%
MeOH in CH2Cl2); mp: 197±1988C; 5lit.45 mp: 195±1968C
5aqueous EtOH)); IR 5KBr) nmax 3180, 3130, 3070, 3050,
2960, 2950, 2930, 2880, 2850, 2840, 1715, 1620, 1560,
1460, 1435, 1400, 1360, 1320, 1270, 1125, 1080, 970,
3.1.4. 4,5-Dihydroxyacridine-9010H)-one 012). Starting
from 4,5-dimethoxyacridine-9,10H)-one 516, see Scheme
3). Dimethoxyacridone 16 54.0 g, 15.67 mmol) and pyridi-
nium chloride 556 g) were stirred at 2208C for 2 h. The
reaction mixture was mixed with water 5900 mL) and stirred
at 08C for 1 h. The precipitate was ®ltered, washed with
water 53£50 mL) and dried. The crude product was recrys-
tallised from DMFto give pure 12 52.97 g, 77%) as yellow
crystals. Rfˆ0.51 5silica gel TLC, 9% MeOH in CH2Cl2);
1
910, 860, 740, 710 cm21; H NMR d 4.12 5s, 6H), 7.02
5d, Jˆ7 Hz, 2H), 7.47 5t, Jˆ8 Hz, 2H), 7.57 5d, Jˆ8 Hz,

P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
4973
2H), 8.75 5s, 1H); 13C NMR d 56.11, 106.58, 119.67,
126.50, 127.98, 136.21, 140.63, 155.35.
3.1.8. 4,5-Dibenzyloxyacridine-9010H)-one 017). Starting
from 4,5-dibenzyloxyacridine 515, see Scheme 3). Dibenzyl-
oxyacridone 17 was prepared from dibenzyloxyacridine 15
51.57 g, 4 mmol), NaH 5960 mg, 24 mmol, 60% dispersion
in mineral oil) and dry DMSO 530 mL) as described above
for obtaining acridono crown ether 2 starting from acridino
ligand 1. The crude product was puri®ed by column
chromatography on silica gel using 1% MeOH in CH2Cl2
as an eluent to give 17 5962 mg, 59%) as pale yellow solid.
Rfˆ0.6 5silica gel TLC, 3% MeOH in CH2Cl2); mp: 176±
1788C; IR 5KBr) nmax 3424, 1624, 1616, 1596, 1532, 1488,
1456, 1420, 1384, 1268, 1216, 1072, 1064, 1048, 976, 744,
696, 592 cm21; 1H NMR d 5.22 5s, 4H), 7.13±7.17 5m, 4H),
7.30±7.36 5m, 6H), 7.40 5d, Jˆ7 Hz, 4H), 8.05±8.07 5m,
2H), 9.15 5s, broad, shifted by warming, exchangeable with
D2O, NH, 1H); 13C NMR d 71.22, 113.19, 118.95, 120.94,
122.27, 127.48, 128.46, 128.99, 131.53, 136.19, 146.76,
178.10; Anal. calcd for: C27H21NO3: C, 79.59; H, 5.19; N,
3.44. Found: C, 79.30; H, 5.24; N, 3.70.
3.1.6. 4,5-Dibenzyloxyacridine 15. 5see Scheme 3). A
mixture of acridine-4,5-diol8 510) 51.32 g, 6.25 mmol),
benzyl bromide 52.67 g, 1.86 mL, 15.63 mmol), ®nely
powdered anhydrous K2CO3 58.64 g, 62.5 mmol) and dry
DMF555 mL) was stirred under Ar at rt for 10 min then
at 508C for 2 days. The solvent was removed at 458C and the
residue was taken up in a mixture of ice±water 5100 mL)
and CH2Cl2 5120 mL). The aqueous phase was extracted
with CH2Cl2 53£50 mL). The combined organic phase was
dried over MgSO4, ®ltered, and the solvent was removed.
The crude product was recrystallised from toluene to give
15 51.59 g, 65%) as pale yellow crystals. Rfˆ0.64 5silica gel
TLC, 5% MeOH in CH2Cl2); mp: 152±1538C 5toluene); IR
5KBr) nmax 3070, 3030, 3010, 2950, 2920, 2880, 1620, 1595,
1580, 1550, 1470, 1460, 1440, 1400, 1380, 1310, 1270,
1180, 1120, 1080, 1060, 900, 830, 720, 690 cm21 1H
;
NMR d 5.45 5s, 4H), 7.13 5d, Jˆ8 Hz, 2H), 7.36±7.39 5m,
6H), 7.44 5t, Jˆ8 Hz, 2H), 7.59 5d, Jˆ8 Hz, 2H), 7.66±7.67
5m, 4H), 8.70 5s, 1H); 13C NMR d 71.10, 109.16, 120.32,
126.25, 127.51, 127.75, 128.09, 128.67, 135.46, 137.33,
141.64, 155.10. Anal. calcd for: C27H21NO2: C, 82.84; H,
5.41; N, 3.58. Found: C, 82.68; H, 5.52; N, 3.56.
Starting from acridonediol 512, see Scheme 5). Dibenzyl-
oxyacridone 17 was also prepared from acridonediol 12
51.53 g, 6.25 mmol) as described above for obtaining 4,5-
dibenzyloxyacridine 515) starting from acridine-4,5-diol
510). The reaction was completed at 508C in 40 h. The
crude product was puri®ed as above to give 17 51.73 g,
68%) which was identical in every respect to that prepared
by the previous procedure.
3.1.7. 4,5-Dimethoxyacridine-9010H)-one 016). Starting
from 4,5-dimethoxyacridine 514, see Scheme 3). Dimethoxy-
acridone 16 was prepared from dimethoxyacridine 14
5957 mg, 4 mmol), NaH 5960 mg, 24 mmol, 60% dispersion
in mineral oil) and dry DMSO 525 mL) as described above
for obtaining acridono crown ether 2 starting from acridino
ligand 1. The crude product was recrystallised from glacial
acetic acid to give 16 5613 mg, 60%) as pale yellow crystals.
Rfˆ0.75 5silica gel TLC, 5% MeOH in CH2Cl2); mp: 277±
2788C 5AcOH); 5lit. mp: 268±2698C 5DMF±H2O)28, 274±
2758C 5EtOH)45); IR 5KBr) nmax 3440, 3064, 2984, 2944,
2872, 2840, 1628, 1616, 1596, 1536, 1488, 1472, 1448,
1408, 1376, 1272, 1224, 1076, 968, 824, 744, 576, 536,
3.1.9. 4,5-Diacetamidoacridine-9010H)-one 19. 5see
Scheme 3). To a vigorously stirred mixture of 4,5-di-
aminoacridine-9510H)-one46,47 518) 56.76 g, 30 mmol) in
acetic acid 5120 mL) was added acetic anhydride 59.19 g,
8.76 mL, 90 mmol) at 908C. After addition, the reaction
mixture was stirred for 30 min, the yellow slurry formed
was cooled down to rt and the crystals were ®ltered. The
dry crude product was recrystallised from DMFto give 19
57.89 g, 85%) as yellow crystals. Rfˆ0.7 5silica gel TLC,
1:1:9:2 HCOOH/AcOH/EtOAc/H2O); mp: .3608C; IR
5KBr) nmax 3419, 3328, 3274, 3127, 3008, 2949, 1711,
1668, 1624, 1565, 1525, 1519, 1461, 1426, 1357, 1328,
1
528 cm21; H NMR d 4.05 5s, 6H), 7.08 5d, Jˆ8 Hz, 2H),
7.17 5t, Jˆ8 Hz, 2H), 8.06 5d, Jˆ8 Hz, 2H), 9.11 5s, broad,
shifts to a great extent by warming, NH, 1H); 13C NMR d
56.21, 111.48, 118.48, 120.93, 122.02, 131.29, 147.61,
178.04.
1
1264, 1202, 1027, 811, 712, 537 cm21; H NMR 5DMSO-
d6) d 2.22 5s, 6H), 7.27 5t, Jˆ8 Hz, 2H), 7.66 5d, Jˆ7 Hz,
2H), 8.15 5d, Jˆ8 Hz, 2H), 9.88 5s, 3H, broad, exchangeable
with D2O, NH protons, 3H); 13C NMR d 22.73, 120.49,
121.32, 123.28, 126.25, 129.57, 135.08, 169.34, 176.51;
MS5EI) 309 5M1), 267, 249, 225 5base peak), 169, 43;
Anal. calcd for: C17H15N3O3: C, 66.01; H, 4.89; N, 13.58.
Found: C, 65.94; H, 4.97; N, 13.39.
Starting from N-,2-methoxyphenyl)-3-methoxyanthranilic
acid 524, see Scheme 4). Acid 24 54.87 g, 17.82 mmol)
was stirred in PPA 567 g) under Ar at 1258C for 2 h. Then
the warm reaction mixture was slowly poured into vigor-
ously stirred warm water 5670 mL) and the resulting slurry
was stirred for 30 min. The mixture was kept in an ice-water
bath for 2 h, and then ®ltered. The crude product was
washed with water 53£40 mL), dried, and it was puri®ed
as above to give 16 53.68 g, 91%) which was identical in
every respect to that prepared by the previous procedure.
3.1.10. 2-Bromo-3-methoxybenzoic acid 21. 5see Scheme
4). To a well stirred mixture of 2-amino-3-methoxybenzoic
acid 520) and 10% 5w/w) aqueous HBr 5165 g, 204 mmol)
was added at 258C a solution of NaNO2 55.0 g,
72.45 mmol) in water 550 mL) dropwise. After addition,
the reaction mixture was stirred at 258C for 10 min, and
at this temperature a solution of copper5I) bromide 511.35 g,
79.12 mmol) in 48% 5w/w) aqueous HBr 597.0 g, 0.575
mol) was added to it. Stirring was continued at rt for 1 h
then in a hot water bath for 3 h. The mixture was cooled to
08C, kept at this temperature for 2 h and the bromo acid 21
was ®ltered off. It was washed with ice-cold water
53£40 mL) and recrystallised from water to give pure 21
Starting from acridonediol 12 5see Scheme 5). Dimethoxy-
acridone 16 was also prepared from acridonediol 12 51.06 g,
4.31 mmol) as described above for obtaining 4,5-dimethoxy-
acridine 514) starting from acridinediol 10. The reaction was
completed at rt in 16 h. The crude product was puri®ed as
above to give 16 5825 mg, 75%) which was identical in
every respect to that prepared by the previous procedure.

4974
P. Huszthy et al. / Tetrahedron 57 ,2001) 4967±4975
4. Balzani, V.; Scandola, F. Supramolecular Photochemistry,
Horwood: Chichester, U.K., 1991.
514.05 g, 85%) as white crystals. Rfˆ0.32 5silica gel TLC,
25% EtOH in toluene); mp: 155±1568C 5H2O); 5lit.28 mp:
154±1558C 5H2O)).
5. Czarnik, A. W. Fluorescent Chemosensors for Ion and
Molecule Recognition, ACS Symposium Series 538, ACS
Books: Washington, DC, 1993.
3.1.11. N-02-methoxyphenyl)-3-methoxyanthranilic acid
024). Starting from bromo acid 21 and o-anisidine 523) 5see
Scheme 4). A mixture of bromo acid 21 56.16 g, 26.66
mmol), o-anisidine 53.48 g, 28.26 mmol), ®nely powdered
anhydrous K2CO3 53.68 g, 26.63 mmol), copper powder
540 mg), copper5I) oxide 540 mg) and dry 2-ethoxyethanol
516 mL) was stirred vigorously under Ar at rt for 10 min,
then the temperature was raised to 1408C and it was stirred
at this temperature for 1 h. The solvent was removed at 508C
and the residue was taken up in a mixture of ether 5200 mL)
and 0.5% 5w/w) aqueous NaOH 5250 g). The aqueous phase
was extracted with ether 52£150 mL) and the ethereal
phases were discarded. Charcoal 51.0 g) was added to the
aqueous solution, boiled for 10 min, ®ltered, then cooled to
08C in an ice-water bath. Precipitation with AcOH gave acid
24 which was washed with ice-cold water 53£50 mL) and
dried. Crystallisation of the crude product from toluene gave
pure 24 54.3 g, 59%) as yellow crystals. Rfˆ0.30 5silica gel
TLC, 2% MeOH in CH2Cl2); mp: 176±1778C 5toluene)
5lit.28 mp: 169±1708C 5aqueous EtOH)); IR 5KBr) nmax
3360, 3050, 3010, 2936, 2840, 1672, 1600, 1524, 1456,
1440, 1432, 1328, 1264, 1172, 1116, 1064, 1024, 920,
744, 536 cm21; 1H NMR d 3.74 5s, 3H), 3.97 5s, 3H), 6.41
5d, Jˆ8 Hz, 1H), 6.75±6.78 5m, 1H), 6.91±6.96 5m, 2H),
7.15 5d, Jˆ8 Hz, 1H), 7.32 5t, Jˆ8 Hz, 1H), 7.90 5d, Jˆ
8 Hz, 1H); 13C NMR d 56.06, 56.27, 110.64, 115.90,
116.42, 120.95, 122.39, 123.77, 126.62, 132.11, 134.23,
149.45, 154.72, 168.04.
6. Desvergne, J. P.; Czarnik, A. W. Chemosensors of Ion and
Molecule Recognition, NATO ASISC, Vol. 492; Kluwer:
Dordrecht, The Netherlands, 1997.
7. Cox, B. G.; Hurwood, T. V.; Prodi, L.; Montalti, M.; Bolletta,
F.; Watt, C. I. F. J. Chem. Soc., Perkin Trans. 2 1999, 289±
296.
Â
8. Huszthy, P.; Samu, E.; Vermes, B.; Mezey-Vandor, G.;
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Nogradi, M.; Bradshaw, J. S.; Izatt, R. M. Tetrahedron
1999, 55, 1491±1504.
9. Prodi, L.; Bolletta, F.; Montalti, M.; Zaccheroni, N.; Huszthy,
P.; Samu, E.; Vermes, B. New J. Chem. 2000, 24, 781±785.
10. Pozharskii, A. F.; Konstantinchenko, A. A. Khim. Geterotsckl.
Soedin. 1972, 8, 1673±1675 engl.: 1518±1520; Chem. Abstr.
1973, 78, 71876m.
11. Nakatsuji, Y.; Bradshaw, J. S.; Tse, P. K.; Arena, G.; Wilson,
B. E.; Dalley, N. K.; Izatt, R. M. J. Chem. Soc., Chem.
Commun. 1985, 749±751.
12. Izatt, R. M.; Lindh, G. C.; Clark, G. A.; Bradshaw, J. S.;
Nakatsuji, Y.; Lamb, J. D.; Christensen, J. J. J. Chem. Soc.,
Chem. Commun. 1985, 1676±1677.
13. Bradshaw, J. S.; Nakatsuji, Y.; Huszthy, P.; Wilson, B. E.;
Dalley, N. K.; Izatt, R. M. J. Heterocycl. Chem. 1986, 23,
353±360.
14. Bradshaw, J. S.; Huszthy, P.; Koyama, H.; Wood, S. G.;
Stobel, S. A.; Davidson, R. B.; Izatt, R. M.; Dalley, N. K.;
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Biernat, J. F.; Koyama, H.; McDaniel, C. W.; Wood, S. A.;
Nielsen, R. B.; LindH, G. C.; Bruening, R. L.; Lamb, J. D.;
Christensen, J. J. Stud. Org. Chem. 1986, 31, 553±560.
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Starting from methoxyanthranilic acid 20 and o-bromo-
anisole 522, see Scheme 4). A mixture of methoxyanthrani-
lic acid 20 54.60 g, 27.52 mmol), o-bromoanisole 522)
55.66 g, 30.27 mmol), ®nely powdered anhydrous K2CO3
53.68 g, 26.63 mmol), copper powder 540 mg), copper5I)
oxide, 540 mg), and pure and dry 2-ethoxyethanol 516 mL)
was stirred vigorously under Ar at rt for 10 min, then the
temperature was raised to 1408C and it was stirred at this
temperature for 2 days. The reaction mixture was worked
up, and the crude product was puri®ed as described above to
give 24 56.17 g, 82%) which was identical in every respect
to that prepared by the previous procedure.
17. 5a) Izatt, R. M.; Pawlak, K.; Bradshaw, J. S.; Bruening, R. L.
Chem. Rev. 1991, 91, 1721. 5b) Izatt, R. M.; Pawlak, K.;
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18. Lehn, J. M. Supramolecular Chemistry, VCH: Weinheim
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19. Albert, A. The Acridines, 2nd ed.; Edward Arnold: London,
1966.
Acknowledgements
20. Acheson, R. M. In The Chemistry of Heterocyclic Compounds,
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Wiley: New York, 1973; Vol. 9.
Financial support from the Hungarian Scienti®c Research
Fund 5OTKA T-25071) is gratefully acknowledged.
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