Synthesis and optical characterization of novel azacrown ethers containing an acridinone or an N-methylacridinone unit as potential fluorescent chemosensors

Article abstract of DOI:10.1016/j.tet.2009.10.076

Four new achiral and four new chiral monoazacrown ethers containing an acridinone or an N-methylacridinone fluorescent signalling unit were prepared by reacting chloromethyl-substituted acridinone derivatives with achiral monoazacrown ethers with differen

Full text of DOI:10.1016/j.tet.2009.10.076

Tetrahedron 66 (2010) 350–358
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and optical characterization of novel azacrown ethers containing an
acridinone or an N-methylacridinone unit as potential fluorescent chemosensors
a
a,
b
,
c
d,
e
b
c,d
*
´
´
´
´
´
´
´ ´
´
´
´
Ildiko Moczar , Peter Huszthy
, Andras Mezei , Mihaly Kadar , Jozsef Nyitrai , Klara Toth
a Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, PO Box 91, H-1521 Budapest, Hungary
b Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
c Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
d Research Group of Technical Analytical Chemistry of the Hungarian Academy of Sciences, PO Box 91, H-1521 Budapest, Hungary
e Chinoin Pharmaceutical and Chemical Works Ltd., PO Box 110, H-1325 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Four new achiral and four new chiral monoazacrown ethers containing an acridinone or an N-methyl-
acridinone fluorescent signalling unit were prepared by reacting chloromethyl-substituted acridinone
derivatives with achiral monoazacrown ethers with different cavity sizes and enantiopure monoaza-18-
crown-6 ethers having two methyl and two isobutyl groups on their chiral centres, respectively. The
operation of these chemosensors is based on the photoinduced electron transfer (PET) process, thus they
show fluorescence enhancement in the presence of cationic guests. Their fluorescent behaviour as well
Received 17 August 2009
Received in revised form
29 September 2009
Accepted 22 October 2009
Available online 25 October 2009
Dedicated to Professor Ka´roly Lempert on
the occasion of his 85th birthday
as their complexation properties towards selected metal ions and the enantiomers of
ethylammonium perchlorate and potassium mandelate were examined.
a-(1-naphthyl)-
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Azacrown ethers
Acridinones
Chiral crown ethers
Fluorescent chemosensors
Cation recognition
Enantiomeric recognition
1. Introduction
primary aralkyl ammonium ions by optical spectroscopic methods
and liquid membrane transport experiments,13,17 or using them as
precursors for preparing photoswitchable macrocycles19 and
rotaxanes.20 Furthermore, the proton-ionizable properties (acidity)
of those containing electron withdrawing substituents introduced
into the acridinone core have also been examined,16,18 because these
type of crown ethers mayattain cation transport without the need of
a counter anion across a liquid membrane or in solvent extraction.
The operation of many fluorescent chemosensors is based on
either the photoinduced electron transfer (PET) or internal charge
transfer (ICT) processes.21–25 In the former case, the sensor mole-
cules have a modular structure consisting of a fluorophore unit and
a receptor unit separated by a short alkylene spacer, while in the
Fluorescent chemosensors capable of selectively recognizing
metal ions and organic cations as well as various anions and neutral
molecules have received a great interest due to their potential ap-
plication in many fields such as environmental chemistry, food
industry, medical diagnosis and life sciences.1 Fluorescence spec-
troscopy is an attractive tool owing to its sensitivity, selectivity,
versatility and relatively simple handling.2,3
Using acridinone as a fluorescent signalling unit of a sensor
molecule is very advantageous because of its strong fluorescence4–6
and great photostability.7 Acridinone8 and its certain amide, urea or
thiourea functionalized derivatives9–11 have been proved to be
efficient receptor and sensor molecules for different anions. Several
crown ethers,12–20 among them chiral ones,17 containing an acridi-
none unit incorporated into their macrorings have been synthesized
with the aim of studying their complexing ability towards metal and
latter case, the receptor is part of the
p-electron system of the
fluorophore. PET type sensor molecules exhibit a large fluorescence
enhancement upon complexation with different cations compared
to the free ionophores, providing by this a very sensitive response to
such analytes, because in the absence of them, the sensor molecules
have poor fluorescence due to an efficient quenching process (PET)
in the excited state.21–25 A number of monoazacrown ether based
PET type sensor molecules,26–46 possessing the modular structure
* Corresponding author. Tel.: þ36 1 463 1071; fax: þ36 1 463 3297.
E-mail address: huszthy@mail.bme.hu (P. Huszthy).
URL: http://www.och.bme.hu/org
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.076

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351
Scheme 1. Preparation of achiral fluorescent chemosensors 1–4.
mentioned above, have been prepared and their selectivities for
different metal ions or organic cationic guests have been studied. In
the past two decades many efforts have been devoted to the de-
velopment of fluorescent chiral chemosensors,47 among them
crown ether based ones containing various fluorescent units.48–53
One of them containing an optically active binaphthyl unit
incorporated intothe crown ether framework, and having a PET type
modular structure, showed a moderate selectivity for the enantio-
mers of 2-phenylglycinol.53 Chiral ligands are usually designed and
tested for enantiomeric recognition of chiral analytes such as amino
acid derivatives, amino alcohols and primary amines. However, it
should be noted here that the chirality of some receptor molecules
may also have appreciable effect on the selectivity towards various
biologically important metal ions.54–58 This effect can be well-
demonstrated as the stereostructure of chiral natural ionophores
such as valinomycin, monensin, lasalocid, monactin, dinactin, sali-
nomycin, narasin and nigericin plays an important role in the
selective transport of metal cations through biomembranes.57,58
Herein we report the synthesis of four new achiral and four new
chiral monoazacrown ethers in which an acridinone or an N-
methylacridinone fluorescent signalling unit was attached through
a methylene bridge to the nitrogen of the macrocycles. Their fluo-
rescent behaviour as well as their PET type complexation properties
fluorescent signalling unit were synthesized by alkylation of achiral
and chiral monoazacrown ethers 9–(S,S)-13 with the appropriate
chloromethyl-substituted acridinone derivative 14 or 15 in dry DMF
in the presence of triethylamine as a base. Achiral monoazacrown
ethers 9–11 are commercially available. Chiral monoazacrown ethers
(S,S)-12 and (S,S)-13 were prepared according to our previously
reported method.59
The synthesis of acridinone derivative 14 was performed with
a modification of the reported procedure60 and outlined as follows
(Scheme 3). Hydroxymethyl derivative 1660 was treated with
thionyl chloride in dry chloroform in the presence of a catalytic
amount of DMF. The crude 9-chloro-4-chloromethylacridine was
hydrolysed in a mixture of dioxane/water (19:1) to give chloro-
methyl-substituted acridinone 14. To obtain benzyloxy derivative
17, the aforementioned crude dichloro derivative was reacted with
benzyl alcohol followed by a treatment with methanol containing
a small amount of water. Benzyloxymethylacridinone 17 was
deprotonated with sodium hydride in dry DMF and then was
alkylated with methyl iodide to furnish N-methyl modified benzy-
loxymethylacridinone 18. Benzyl protecting group was removed by
boiling 18 in a mixture of dioxane/10% aqueous hydrochloric acid
(1:1) to obtain N-methylated hydroxymethyl derivative 19. In the
last step, 19 was treated with thionyl chloride in dry dichloro-
methane in the presence of a catalytic amount of DMF to give
N-methylated chloromethyl-substituted acridinone 15.
towards selected metal ions (Naþ, Kþ, Agþ, Mg2þ, Ca2þ, Zn2þ, Cu2þ
,
Pb2þ, Cd2þ) and the enantiomers of
a-(1-naphthyl)ethylammonium
perchlorate (NEA) and potassium mandelate were studied.
2.2. Fluorescent behaviour
2. Results and discussion
2.1. Synthesis
Ligands 1–(S,S)-8 have a modular (fluorophore–methylene
spacer–azacrown receptor) structure, thereby PET type fluores-
cence response was expected upon complexation with various
cations. It means that the free ligand shows reduced (near-zero)
fluorescence after excitation due to a quenching process (PET) in
Achiral (Scheme 1) and chiral (Scheme 2) azacrown ether chemo-
sensors 1–(S,S)-8 containing an acridinone or an N-methylacridinone
Scheme 2. Preparation of chiral fluorescent chemosensors (S,S)-5–(S,S)-8.

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I. Mo´czar et al. / Tetrahedron 66 (2010) 350–358
Scheme 3. Preparation of acridinone derivatives 14 and 15.
Table 1
Fluorescence quantum yields and pKa values of 1–(S,S)-8 and the parent compound
acridinone
Compound
Ff (CH2Cl2)
Ff (MeOH)
pKa (MeOH)b
Acridinone
1
2
3
0.35
0.60
0.59
0.55
0.088
0.37
0.051
0.54
0.087
0.74a
0.15
14.9c
d
0.070
0.038
0.080
0.029
0.057
0.062
0.092
16.5e
15.4
4
(S,S)-5
(S,S)-6
(S,S)-7
(S,S)-8
a
Acridinone is known to have extremely weak fluorescence in non-polar solvents
(e.g., cyclohexane) and strong fluorescence in protic solvents.6
b
The pKa values were determined according to a reported method.18
c
This value was taken from literature.18
d
The pKa of 1 could not be calculated because of the insignificant spectral changes
(fluorescence intensity and absorbance) upon titration with Me4NOH. This indicates
that the deprotonation of 1 is more difficult than that of 2.
e
The pKa of 2 could not be determined accurately, since the spectral signals
changed continuously during the addition of Me4NOH and its value is commeasu-
rable with the autoprotolysis constant of MeOH (16.7).18
Figure 1. Solvent dependence of the fluorescence quantum yields of 1–(S,S)-8.
the excited state directed from the donor nitrogen atom of the
crown ether to the acceptor fluorophore unit. Conversely,
coordination of a cation decreases the electron donating ability of
the nitrogen atom, which results in a significant fluorescence
enhancement without spectral shifts.
The fluorescence quantum yields of free ligands containing the
acridinone unit [1–3, (S,S)-5 and (S,S)-7] showed a strong solvent
dependence, namely, these ligands have relatively large quantum
yield values in dichloromethane and considerably (4–14.5 times)
lower quantum yields in methanol (Figs. 1 and 2 and Table 1). This
can be explained by the presence of a strong intramolecular H-bond
formed between the acridinone NH proton and the nitrogen atom
of the crown ether in dichloromethane, which inhibits the PET
process leading to intense fluorescence of the free sensor molecule.
In methanol, however, the intramolecular H-bonds are efficiently
destroyed by the solvent molecules, thereby causing the recovery of
the PET process and in accordance with this, significant reduction
of the fluorescence.
It can also be seen that the strength of intramolecular H-bonds
increases with the decreasing cavity size of crown ethers 1–3 based
on the comparison of their quantum yield values determined in
methanol (Fig. 1 and Table 1). Other evidence for the presence of
Figure 2. Fluorescence intensity changes of 3 (20 mM) as a function of solvent com-
position: CH2Cl2, 0.2%, 0.6%, 1.2%, 2.4%, 4%, 6%, 10%, 20%, 40%, 60% (v/v) MeOH in CH2Cl2
and MeOH, lex¼370 nm. Inset: fluorescence intensity changes at 421 nm.

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353
Figure 3. Absorption spectra of 1–3 (20 mM) in the presence of Me4NOH in MeOH. (A) 3, Me4NOH: 0, 1000, 2000, 3000, 6000, 18,000 equiv (B) 2, Me4NOH: 0, 18,000 equiv (C) 1,
Me4NOH: 0, 18,000 equiv.
intramolecular H-bonds and the dependence of their strength on
the cavity size of the crown ethers is the decrease of acidity of
acridinone NH proton in ligands 1–3 compared to unsubstituted
acridinone (Fig. 3 and Table 1).
The presumption that the undesirable effect of the intra-
molecular H-bond can be eliminated by N-methylation of the
acridinone unit seemed to be correct as the free ligands 4, (S,S)-6
and (S,S)-8 showed poor fluorescence both in dichloromethane and
Figure 4. Fluorescence enhancement of 3 (A) and (S,S)-7 (C) at 421 nm, 4 (B) and (S,S)-8 (D) at 450 nm in the presence of various metal ions in MeOH (concentrations of the free
ligands were 20 M).
m

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354
observations,59 the isobutyl groups in the crown ether ring
appreciably decrease the complexing ability of ligands (S,S)-7 and
(S,S)-8 towards Kþ with respect to their achiral analogues 3 and 4.
This can be attributed to the conformational changes of the crown
ether ring owing to the bulky isobutyl groups as we discussed
earlier.59 It should be noted that in the case of N-methyl modified
ligands 4 and (S,S)-8, Kþ, Mg2þ, Ca2þ, Zn2þ and Cd2þ ions caused
1.5–3-fold fluorescence intensity enhancement only in a large ex-
cess (400-fold) of cations, which means that they formed signifi-
cantly weaker complexes than Cu2þ and Pb2þ (not shown).
Table 2
Stability constants for metal ion complexes of 3, 4, (S,S)-7 and (S,S)-8 in MeOH
log Ks
3
4
(S,S)-7
(S,S)-8
Cu2þ
Pb2þ
Agþ
Kþ
3.47
2.68
3.17
2.28
4.87
3.59
2.80
4.88
4.44
4.37
2.66
4.98
a
3.32
a
4.09
a
The log Ks values could not be calculated because of the insignificant increase of
the fluorescent signal (ca. 15–20%) upon addition of metal ions.
It is known that Cu2þ can quench fluorescence upon interaction
with a fluorophore due to its paramagnetic nature.21–25 The
quenching mechanism is usually attributed to the PET (photoinduced
electron transfer)/EET (electronic energy transfer) processes caused
by the open shell ion.21–25 Several chemosensors for Cu2þ based on
selective quenching of the fluorescence have been reported,21–25,62,63
but also much research has been focused on the development of
sensor molecules exploiting other effects resulting in fluorescence
methanol, and also their fluorescence quantum yields are hardly
influenced by solvent polarity (Fig. 1 and Table 1).
2.3. Complexation studies
We investigated the complexation properties of ligands 3, 4,
(S,S)-7 and (S,S)-8 towards various metal ions (Naþ, Kþ, Agþ, Mg2þ
,
Figure 5. (A) Fluorescence emission series of spectra of (S,S)-7 (20
m
M) on increasing addition of Cu2þ (0–200 equiv) in MeOH, lex¼370 nm. Inset: titration curve (0–300 equiv) at
421 nm. (B) Benesi–Hildebrand plot of (S,S)-7 (20
m
M) in the presence of Cu2þ (14–150 equiv) at 421 nm, log Ks¼3.59 (correlation coefficient: R¼0.996).
Ca2þ, Zn2þ, Cu2þ, Pb2þ, Cd2þ) using methanol as a solvent. These
ligands can really be considered as PET type sensor molecules,
because they showed significant fluorescence enhancement by
factors of 2–15 upon complexation with metal ions with quite small
[3–6 nm in the case of 3 and (S,S)-7, and even smaller in the case of
4 and (S,S)-8] blue-shift of their emission spectra. Comparison of
the fluorescence intensity changes of ligands 3, 4, (S,S)-7 and (S,S)-8
in the presence of various metal ions is represented in Figure 4,
while the stability constants of the metal ion–ligand complexes are
summarized in Table 2. The absorbances of ligands at the excitation
wavelength used (370 nm) were essentially unchanged upon
complexation with the exception of those of 3 and (S,S)-7, which are
slightly influenced by the effect of Cu2þ and Pb2þ. The log Ks values
were determined from the Benesi–Hildebrand plots52,61 valid for
1:1 stoichiometry (Fig. 5B).
enhancement upon complexation with Cu2þ ion.22–25,62–67 In
our case, coordination of the Cu2þ ion to the nitrogen atom of the
crown ether reduces the efficiency of the PET process, thereby causes
The largest fluorescence enhancements for ligands 3, 4, (S,S)-7
and (S,S)-8 were induced by Cu2þ and Pb2þ ions, while Agþ
produced minor effects. In general, ligands containing the acridi-
none NH proton [3 and (S,S)-7] exhibited larger fluorescence en-
hancement upon complexation, but formed less stable complexes
than their N-methyl analogues [4 and (S,S)-8]. Furthermore, it can
also be seen that the presence of isobutyl groups in ligands (S,S)-7
and (S,S)-8 improves the selectivity towards Cu2þ compared to their
achiral counterparts 3 and 4. The latter effect is much more pro-
nounced in the case of (S,S)-7. In accordance with our previous
Figure 6. Fluorescence emission series of spectra of (S,S)-8 (20 mM) on increasing
addition of (R)-NEA (0–12 equiv) in CH2Cl2/MeOH (97:3), lex¼370 nm. Inset: titration
curve (0–30 equiv) at 450 nm.

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355
Table 3
potassium mandelate), both (S,S)-7 and (S,S)-8 also formed com-
plexes, but no enantiomeric recognition could be observed proba-
bly due to the too flexible conformation of these ligands. A more
rigid macrocyclic framework containing an acridinone or an N-
methylacridinone fluorescent signalling moiety is expected to
show a higher degree of enantiomeric recognition. Work on this has
already been started and we will report the results in due course.
Stability constants for complexes of (S,S)-7 and (S,S)-8 with the enantiomers of NEA
and potassium mandelate in CH2Cl2/MeOH (97:3) and MeCN/H2O (97.5:2.5),
respectively
log Ks
(S,S)-7
(S,S)-8
(R)-NEA
(S)-NEA
K (R)-mandelate
K (S)-mandelate
3.73ꢁ0.04
5.07ꢁ0.10
5.06ꢁ0.08
3.17ꢁ0.08
3.15ꢁ0.03
3.78ꢁ0.03
a
4. Experimental
4.1. General
a
a
No fluorescence enhancement upon addition of salts could be observed.
Infrared spectra were recorded on a Zeiss Specord IR 75 spec-
trometer. Optical rotations were taken on a Perkin–Elmer 241 po-
larimeter that was calibrated by measuring the optical rotations of
both enantiomers of menthol. NMR spectra were recorded either
on a Bruker DRX-500 Avance spectrometer (at 500 MHz for 1H and
125.8 MHz for 13C spectra) or on a Bruker 300 Avance spectrometer
(at 300 MHz for 1H and 75.5 MHz for 13C spectra) and it is indicated
in each individual case. Mass spectra were recorded on a ZQ2000
MS instrument (Waters Corp.) using ESI method. Elemental anal-
yses were performed in the Microanalytical Laboratory of the De-
partment of Organic Chemistry, Institute of Chemistry, L. Eo¨tvo¨s
University, Budapest, 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 (Merck) and aluminium
oxide 60 F254 neutral type E (Merck) plates were used for TLC. Silica
gel 60 (70–230 mesh, Merck) and aluminium oxide (neutral, acti-
vated, Brockman I) were used for column chromatography. Romil
Ltd (Cambridge, UK) SuperPurity Solvent grade THF stored under
argon was used as purchased. All other solvents were dried and
purified according to well-established methods.71 Evaporations
were carried out under reduced pressure.
UV–vis spectra were taken on a UNICAM UV4-100 spectropho-
tometer controlled by VISION 3.4 software (ATI UNICAM, Cam-
bridge, UK). Fluorescence spectra were recorded on a Perkin–Elmer
LS 50B luminescent spectrometer supplied with an FL WinLab 3.0Ô
software (Perkin–Elmer Corp., USA). Both the emission and exci-
tation spectra were corrected by the spectrometer software. Quartz
cuvettes with path length of 1 cm were used. Fluorescence quan-
tum yields were determined relative to quinine sulfate (Ff¼0.546 in
0.5 M H2SO4).2 Spectrophotometric titrations were carried out
according to the literature.18,59 Determination of the pKa values
were performed by titration with 1.0 M solution of Me4NOH in
a relatively large emission increase similarly to the reported
examples.64,66,67
Among the four ligands studied, (S,S)-7 showed the best selec-
tivity towards Cu2þ and almost 10-fold fluorescence enhancement
could be measured upon titration with Cu2þ (Fig. 5). It is also
notable that the complex 3–Cu2þ fluoresced 15 times more in-
tensely than the free ionophore 3. Ligand (S,S)-8 also exhibited
good selectivity towards Cu2þ and Pb2þ and formed relatively
stable complexes with these ions causing about 5-fold fluorescence
enhancement upon complexation. Both (S,S)-7 and (S,S)-8 contain
isobutyl groups in the crown ether ring, which increase their
lipophilicity, thus it is advantageous for incorporating them into
optode membranes.68
The complex formation of chiral ligands (S,S)-7 and (S,S)-8 with
the enantiomers of
a-(1-naphthyl)ethylammonium perchlorate
(NEA) and potassium mandelate was also studied similarly to the
reported examples69,70 using dichloromethane/methanol (97:3)
and acetonitrile/water (97.5:2.5), respectively. Complexation with
these salts did take place causing fluorescent enhancement (1.5–
3.5-fold) with a slight blue-shift (3–4 nm) in their emission spectra
(Fig. 6). The Benesi–Hildebrand evaluation52,61 was also applied for
the calculation of log Ks values assuming 1:1 stoichiometry. Un-
fortunately, no enantiomeric recognition could be observed as the
data in Table 3 show.
3. Conclusion
The synthesis and characterization of four new achiral and four
new chiral monoazacrown ethers containing an acridinone and an
N-methylacridinone fluorescent signalling units [1–(S,S)-8] and
their unreported precursors have been performed. These ligands
have a modular (fluorophore–methylene spacer–azacrown re-
ceptor) structure, so they exhibited PET type fluorescence response
in the presence of various cations as expected. The fluorescence
quantum yields of the free ligands containing the acridinone unit
[1–3, (S,S)-5 and (S,S)-7] showed significant solvent dependence
due to intramolecular H-bonds, while those of the N-methyl ana-
logues [4, (S,S)-6 and (S,S)-8] were hardly influenced by solvent
polarity. The strength of intramolecular H-bonds increased with
the decreasing cavity size of crown ethers 1–3. Among the four li-
gands [3, 4, (S,S)-7 and (S,S)-8] of which complexation properties
MeOH. Absorption spectra of ligands 1–3 (20 mM) in the presence of
large excess (6000 and 18,000 equiv) of Me4NOH were corrected
with the spectrum of the latter compound, because its absorbance
is not entirely negligible in those concentrations. Perchlorate salts
of the metal cations were used in general with the exception of
AgNO3 and KSCN. All of metal ion salts were of analytical grade.
Enantiomers of NEA72 and potassium mandelate73 were prepared
in our laboratory. Ratios of solvents are given in volumes (v/v) in all
cases.
were studied towards selected metal ions (Naþ, Kþ, Agþ, Mg2þ
,
4.2. General procedure for the synthesis of crown ethers
Ca2þ, Zn2þ, Cu2þ, Pb2þ, Cd2þ), ligand (S,S)-7 had the best selectivity
towards Cu2þ with almost 10-fold fluorescence enhancement upon
complexation. The 15 times larger fluorescence quantum yield of
complex 3-Cu2þ with respect to the free ionophore is also notable.
Ligand (S,S)-8 also showed good selectivity towards Cu2þ and Pb2þ
and formed relatively stable complexes with these ions causing
about 5-fold fluorescence enhancement upon complexation. Mac-
rocycles (S,S)-7 and (S,S)-8 contain lipophilic isobutyl groups at
their chiral centres, so these ligands can be good candidates for the
sensing unit of an optode membrane. With chiral guests (NEA or
1–(S,S)-8
A solution of the appropriate monoazacrown ether 9–(S,S)-13
(0.41 mmol), acridinone derivative 14 (100 mg, 0.41 mmol) or 15
(106 mg, 0.41 mmol) and triethylamine (114 mL, 0.82 mmol) in dry
DMF (1.5 mL) was stirred under Ar at rt for a day. The volatile
compounds were evaporated at 40 ꢀC and the residue was
dissolved in a mixture of CH2Cl2 (4 mL) and water (4 mL). The pH of
the aqueous phase was adjusted to 9 by addition of 5% aqueous
Me4NOH solution and the phases were mixed well and separated.

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356
The aqueous phase was extracted with CH2Cl2 (3ꢂ2 mL). The
combined organic phase was dried over MgSO4, filtered and the
solvent was removed. The crude products were purified as
described below for each compound.
Anal. Calcd for C27H36N2O6$0.5H2O: C, 65.70; H, 7.56; N, 5.68.
Found: C, 65.61; H, 7.28; N, 5.67.
4.2.5. 4-[(2S,12S)-2,12-Dimethyl-1,4,7,10,13-pentaoxa-16-azacy-
clooctadecan-16-ylmethyl]acridin-9(10H)-one [(S,S)-5]. The crude
product was purified by column chromatography on alumina using
4.2.1. 4-(1,4,7-Trioxa-10-azacyclododecan-10-ylmethyl)acridin-
9(10H)-one (1). The crude product was purified by recrystallization
from MeOH to give 1 (89 mg, 57%) as yellow crystals. Mp: 170–
172 ꢀC; Rf¼0.37 (silica gel TLC, 1:2 acetone/hexane); IR (KBr) nmax
3432, 3256, 2936, 2880, 2840, 1620, 1608, 1596, 1528, 1484, 1440,
1344,1288, 1254, 1152, 1100, 1052, 992, 920, 840, 760, 692, 616, 564,
1:140 EtOH/toluene as an eluent to give (S,S)-5 (78 mg, 38%) as
25
a yellow oil. Rf¼0.32 (silica gel TLC, 1:2 acetone/hexane); [
a]
ꢃ6.7
D
(c 0.93, acetone); IR (neat) nmax 3080, 2952, 2888, 2872, 1616, 1608,
1600, 1528, 1448, 1344, 1260, 1112, 1000, 952, 824, 760, 692 cmꢃ1
1H NMR (500 MHz, CDCl3)
;
d
1.02 (d, J¼6 Hz, 6H), 2.38 (br s, 0.5 mol
544 cmꢃ1
;
1H NMR (500 MHz, CDCl3)
d
1.85 (br s, 0.5 mol of com-
of complexed H2O, 1H), 2.73–3.04 (m, 4H), 3.42–3.52 (m, 4H), 3.60–
3.85 (m, 14H), the benzylic –CH2– gives an AB quartet, dA 3.93, dB
4.28 (JAB¼14 Hz, 2H), 7.15 (t, J¼8 Hz, 1H), 7.22–7.27 (m, 1H), 7.44 (d,
J¼8 Hz, 1H), 7.61–7.68 (m, 2H), 8.43 (d, J¼8 Hz, 1H), 8.48 (d, J¼8 Hz,
plexed H2O, 1H), 2.86 (br s, 4H), 3.58–3.77 (m, 12H), 4.00 (s, 2H),
7.15 (t, J¼8 Hz, 1H), 7.25 (t, J¼8 Hz, 1H), 7.43 (d, J¼8 Hz, 1H), 7.65 (t,
J¼8 Hz, 1H), 7.87 (d, J¼8 Hz, 1H), 8.45 (d, J¼8 Hz, 1H), 8.46 (d,
J¼8 Hz, 1H), 12.03 (s, 1H); 13C NMR (125.8 MHz, CDCl3)
d
55.34,
1H),12.23 (s,1H); 13C NMR (125.8 MHz, CDCl3)
d 16.90, 53.98, 58.93,
60.49, 70.13, 70.71, 70.90, 119.42, 120.62, 121.66, 121.86, 122.25,
124.45, 126.85, 127.02, 133.26, 133.36, 141.22, 141.58, 178.93; MS:
383 (Mþ1)þ. Anal. Calcd for C22H26N2O4$0.5H2O: C, 67.50; H, 6.95;
N, 7.16. Found: C, 67.34; H, 6.96; N, 7.03.
67.83, 70.87, 70.93, 74.98, 75.87, 118.30, 120.16, 121.00, 121.30,
121.58,124.25,126.22,126.66,132.86,132.96,140.60,141.06,178.53;
MS: 499 (Mþ1)þ. Anal. Calcd for C28H38N2O6$0.5H2O: C, 66.25; H,
7.74; N, 5.52. Found: C, 66.45; H, 7.76; N, 5.32.
4.2.2. 4-(1,4,7,10-Tetraoxa-13-azacyclopentadecan-13-ylmethyl)acri-
din-9(10H)-one (2). The crude product was purified by re-
crystallization from EtOH/hexane to give 2 (93 mg, 53%) as yellow
crystals. Mp: 95–97 ꢀC; Rf¼0.28 (silica gel TLC,1:2 acetone/hexane);
IR (KBr) nmax 3288, 2932, 2885, 2856, 2810, 1616, 1608, 1596, 1540,
4.2.6. 10-Methyl-4-[(2S,12S)-2,12-dimethyl-1,4,7,10,13-pentaoxa-16-
azacyclooctadecan-16-ylmethyl]acridin-9(10H)-one
[(S,S)-6]. The
crude product was purified by column chromatography on alumina
using first 1:140 EtOH/toluene then CH2Cl2 as eluents to give (S,S)-6
(78 mg, 37%) as a yellow oil. Rf¼0.30 (silica gel TLC, 1:2:0.03 ace-
1526, 1440, 1344, 1120, 1108, 1096, 1048, 936, 760, 696, 616 cmꢃ1
;
tone/hexane/triethylamine); [
a
]
D
þ7.3 (c 1.26, acetone); IR (neat)
25
1H NMR (500 MHz, CDCl3)
d
1.87 (br s, 0.5 mol of complexed H2O,
nmax 2962, 2908, 2864, 1636, 1608, 1600, 1592, 1496, 1460, 1440,
1416, 1356, 1276, 1192, 1124, 996, 892, 760, 696 cmꢃ1 1H NMR
(500 MHz, CDCl3)
1H), 2.87 (t, J¼6 Hz, 4H), 3.61–3.74 (m, 16H), 4.05 (s, 2H), 7.15 (t,
J¼8 Hz, 1H), 7.25 (t, J¼8 Hz, 1H), 7.43 (d, J¼8 Hz, 1H), 7.64 (t, J¼8 Hz,
1H), 7.71 (d, J¼8 Hz, 1H), 8.44 (d, J¼8 Hz, 1H), 8.47 (d, J¼8 Hz, 1H),
;
d
0.95 (d, J¼6 Hz, 6H), 2.62–2.75 (m, 4H), 2.69 (br
s, 0.5 mol of complexed H2O, 1H), 3.31–3.40 (m, 4H), 3.44–3.63 (m,
14H), the benzylic –CH2– gives an AB quartet, dA 3.95, dB 4.07
(JAB¼14 Hz, 2H), 3.96 (s, 3H), 7.15–7.21 (m, 2H), 7.42 (d, J¼8 Hz, 1H),
7.63 (t, J¼8 Hz,1H), 7.83 (d, J¼8 Hz,1H), 8.33–8.37 (m, 2H); 13C NMR
12.18 (s, 1H); 13C NMR (125.8 MHz, CDCl3)
d 54.80, 60.26, 69.14,
70.37, 70.65, 71.04, 118.71, 120.28, 121.18, 121.46, 121.78, 123.92,
126.55, 126.68, 132.86, 132.96, 140.77, 141.21, 178.51; MS: 427
(Mþ1)þ. Anal. Calcd for C24H30N2O5$0.5H2O: C, 66.19; H, 7.17; N,
6.43. Found: C, 66.02; H, 7.09; N, 6.28.
(75.5 MHz, CDCl3)
d 17.25, 42.61, 54.13, 60.42, 67.96, 71.09 (very
high, probably two carbon 13 signals together), 74.95, 76.06, 116.84,
121.54, 121.87, 123.06, 125.28, 126.58, 127.20, 128.39, 133.76, 137.87,
145.69, 146.27, 179.06; MS: 513 (Mþ1)þ. Anal. Calcd for
C29H40N2O6$0.5H2O: C, 66.77; H, 7.92; N, 5.37. Found: C, 66.74; H,
7.87; N, 5.30.
4.2.3. 4-(1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-ylmethyl)-
acridin-9(10H)-one (3). The crude product was purified by re-
crystallization from MeOH to give 3 (87 mg, 45%) as yellow crystals.
Mp: 72–74 ꢀC; Rf¼0.15 (silica gel TLC, 1:2 acetone/hexane); IR (KBr)
nmax 3534, 3512, 2952, 2888, 2872, 1620, 1608, 1596, 1528, 1440,
4.2.7. 4-[(2S,12S)-2,12-Diisobutyl-1,4,7,10,13-pentaoxa-16-azacy-
clooctadecan-16-ylmethyl]acridin-9(10H)-one [(S,S)-7]. The crude
product was purified by column chromatography on alumina using
1344, 1112, 760 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d 2.43 (br s, 1 mol
of complexed H2O, 2H), 2.87 (br s, 4H), 3.55–3.77 (m, 20H), 4.06 (s,
2H), 7.10–7.18 (m, 1H), 7.20–7.28 (m, 1H), 7.41–7.46 (m, 1H), 7.63–
7.74 (m, 2H), 8.44 (d, J¼8 Hz, 1H), 8.47 (d, J¼8 Hz, 1H), 12.25 (s, 1H);
1:200 EtOH/toluene as an eluent to give (S,S)-7 (79 mg, 33%) as
25
a yellow oil. Rf¼0.50 (silica gel TLC, 1:2 acetone/hexane); [
a]
D
13C NMR (125.8 MHz, CDCl3)
d
54.07, 59.08, 69.29, 70.85, 71.27,
ꢃ25.6 (c 2.04, acetone); IR (neat) nmax 3080, 2952, 2888, 2872, 1620,
71.29, 71.42, 119.05, 120.60, 121.48, 121.76, 122.09, 124.44, 126.81,
127.00, 133.34, 133.67, 141.20, 141.46, 178.89; MS: 471 (Mþ1)þ. Anal.
Calcd for C26H34N2O6$H2O: C, 63.92; H, 7.43; N, 5.73. Found: C,
63.72; H, 7.32; N, 5.59.
1608, 1600, 1528, 1448, 1352, 1264, 1112, 1000, 948, 824, 760,
692 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
0.66 (d, J¼7 Hz, 6H), 0.69 (d,
J¼7 Hz, 6H), 0.91–0.99 (m, 2H), 1.16–1.24 (m, 2H), 1.41–1.53 (m, 2H),
1.95 (br s, 0.5 mol of complexed H2O, 1H), 2.68–2.88 (m, 4H), 3.32–
3.46 (m, 6H), 3.52–3.70 (m, 10H), 3.88–3.95 (m, 2H), the benzylic
–CH2– gives an AB quartet, dA 3.95, dB 4.16 (JAB¼14 Hz, 2H), 7.06 (t,
J¼8 Hz, 1H), 7.15 (t, J¼8 Hz, 1H), 7.35 (d, J¼8 Hz, 1H), 7.52 (d, J¼8 Hz,
1H), 7.55 (t, J¼8 Hz, 1H), 8.34 (d, J¼8 Hz, 1H), 8.39 (d, J¼8 Hz, 1H),
4.2.4. 10-Methyl-4-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-
ylmethyl)acridin-9(10H)-one (4). The crude product was purified by
column chromatography first on alumina using 1:110 EtOH/toluene
as an eluent then on silica gel using 1:10 MeOH/acetone as an el-
uent to give 4 (107 mg, 54%) as a yellow oil. Rf¼0.18 (silica gel TLC,
1:2:0.03 acetone/hexane/triethylamine); IR (neat) nmax 2952, 2888,
2872, 1636, 1608, 1600, 1592, 1496, 1460, 1440, 1416, 1356, 1280,
12.18 (s, 1H); 13C NMR (125.8 MHz, CDCl3)
d 22.35, 23.30, 24.70,
41.03, 54.28, 59.71, 68.90, 71.16, 71.28, 75.53, 77.89, 118.63, 120.38,
121.22, 121.58, 121.81, 124.49, 126.47, 126.95, 133.03, 133.14, 140.87,
141.41, 178.80;
C34H50N2O6$0.5H2O: C, 69.01; H, 8.69; N, 4.73. Found: C, 68.78; H,
MS:
583
(Mþ1)þ.
Anal.
Calcd
for
1192,1120, 948, 760, 696 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
2.71 (br
s, 4H), 2.71 (br s, 0.5 mol of complexed H2O, 1H), 3.42–3.62 (m,
20H), 3.95 (s, 3H), 3.98 (s, 2H), 7.14–7.23 (m, 2H), 7.43 (d, J¼8 Hz,
1H), 7.63 (t, J¼8 Hz, 1H), 7.83 (br s, 1H), 8.34 (d, J¼8 Hz, 2H); 13C
8.76; N, 4.57.
4.2.8. 10-Methyl-4-[(2S,12S)-2,12-diisobutyl-1,4,7,10,13-pentaoxa-
16-azacyclooctadecan-16-ylmethyl]acridin-9(10H)-one [(S,S)-8]. The
crude product was purified by column chromatography on alumina
using first 1:200 EtOH/toluene then 2:1 CH2Cl2/hexane as eluents
NMR (125.8 MHz, CDCl3)
d 42.51, 53.72, 59.89, 69.66, 70.14, 70.59,
70.64, 70.76, 116.68, 121.36, 121.70, 122.81, 125.03, 126.40, 126.92,
127.89, 133.58, 137.60, 145.47, 146.03, 178.77; MS: 485 (Mþ1)þ.

´
I. Mo´czar et al. / Tetrahedron 66 (2010) 350–358
357
to give (S,S)-8 (78 mg, 32%) as a yellow oil. Rf¼0.49 (silica gel TLC,
(approximately 6 h). The volatile compounds were evaporated at
40 ꢀC and the residue was stirred in benzyl alcohol (40 mL) at 90 ꢀC
for 3 h. The reaction mixture was cooled down to rt and stirred with
a mixture of MeOH/H2O (400:1, 401 mL) for 30 min. The precipitate
was filtered off and dried. The crude product was recrystallized
from DMF to give 17 (3.47 g, 50%) as pale orange crystals. Mp: 228–
230 ꢀC; Rf¼0.46 (silica gel TLC,1:1:20 EtOH/AcOH/toluene); IR (KBr)
nmax 3280, 3208, 2896, 2856, 1624, 1612, 1600, 1592, 1576, 1528,
1496, 1448, 1352, 1264, 1088, 1064, 1000, 912, 824, 752, 728, 688,
25
2:1:0.03 EtOAc/hexane/triethylamine); [
tone); IR (neat) nmax 2952, 2888, 2872, 1636, 1608, 1600, 1592, 1496,
1416, 1356, 1256, 1192, 1112, 948, 824, 760, 696 cmꢃ1 1H NMR
(300 MHz, CDCl3)
0.83 (d, J¼7 Hz, 6H), 0.85 (d, J¼7 Hz, 6H), 1.01–
a
]
ꢃ10.2 (c 2.24, ace-
D
;
d
1.09 (m, 2H), 1.23–1.31 (m, 2H), 1.56–1.70 (m, 2H), 2.66–2.82 (m,
4H), 2.75 (br s, 0.5 mol of complexed H2O, 1H), 3.34–3.85 (m, 18H),
the benzylic –CH2– gives an AB quartet, dA 4.02, dB 4.16 (JAB¼14 Hz,
2H), 4.04 (s, 3H), 7.24 (t, J¼8 Hz, 1H), 7.28 (d, J¼8 Hz, 1H), 7.50 (d,
J¼8 Hz,1H), 7.71 (t, J¼8 Hz,1H), 7.89 (d, J¼8 Hz,1H), 8.42 (d, J¼8 Hz,
616, 552, 464 cmꢃ1 1H NMR (500 MHz, DMSO-d6)
; d 4.64 (s, 2H),
1H), 8.44 (d, J¼8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3)
d
22.48, 23.47,
5.00 (s, 2H), 7.24–7.41 (m, 7H), 7.74 (t, J¼8 Hz, 1H), 7.77 (d, J¼8 Hz,
24.76, 41.25, 42.55, 54.40, 60.84, 68.92, 71.16, 71.22, 75.65, 77.53,
116.83, 121.55, 121.87, 123.11, 125.33, 126.65, 127.26, 128.38, 133.77,
137.90, 145.71, 146.29, 179.11; MS: 597 (Mþ1)þ. Anal. Calcd for
C35H52N2O6$0.5H2O: C, 69.39; H, 8.82; N, 4.62. Found: C, 69.27; H,
8.78; N, 4.57.
1H), 7.86 (d, J¼8 Hz, 1H), 8.23 (d, J¼8 Hz, 1H), 8.25 (d, J¼8 Hz, 1H),
10.59 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6)
d 68.21, 71.33, 118.04,
120.38, 120.50, 120.96, 121.38, 125.24, 125.72, 125.97, 127.49, 127.60,
128.24, 133.33, 133.37, 138.16, 138.84, 140.79, 176.81. Anal. Calcd for
C21H17NO2: C, 79.98; H, 5.43; N, 4.44. Found: C, 79.81; H, 5.64; N,
4.28.
4.3. 4-Chloromethylacridin-9(10H)-one (14)
4.6. 4-Benzyloxymethyl-10-methylacridin-9(10H)-one (18)
A mixture of 1660 (1.44 g, 6.4 mmol), thionyl chloride (14 mL,
0.19 mol), dry DMF (0.2 mL) and dry CHCl3 (70 mL) was stirred at
reflux temperature until the TLC analysis showed that the reaction
was completed (approximately 6 h). The volatile compounds were
evaporated at 40 ꢀC and the residue was stirred in a mixture of
dioxane/water (19:1, 140 mL) at rt for a day. The reaction mixture
was condensed to third of its original volume by evaporation of the
volatile components and the deposited crystals were filtered off.
The mother liquor was stirred at rt for a day and a second crop was
collected by filtration. The two crops were combined to give 14
(1.17 g, 75%) as pale orange crystals. Mp: >360 ꢀC [lit.60 mp:
>360 ꢀC (EtOH)]; Rf¼0.39 (silica gel TLC, 1:1:20 EtOH/AcOH/tolu-
ene); IR (KBr) nmax 3280, 3208, 3144, 1624, 1608, 1592, 1576, 1528,
1496, 1484, 1464, 1448, 1344, 1256, 1192, 1152, 1000, 920, 824, 752,
In a three neck flask equipped with a reflux condenser, Ar inlet
and a dropping funnel was stirred a suspension of 17 (1.39 g,
4.4 mmol) and NaH (2.64 g, 66 mmol, 60% dispersion in mineral oil)
in dry DMF (28 mL) under Ar at 60 ꢀC for 2 h. Methyl iodide (5.5 mL,
88 mmol) was added dropwise to the reaction mixture at 60 ꢀC and
stirring was continued at this temperature for a day. The volatile
compounds were evaporated and the residue was taken up in
a mixture of CH2Cl2 (50 mL) and ice-cold water (50 mL). The phases
were mixed well and separated. The aqueous phase was extracted
with CH2Cl2 (3ꢂ25 mL). The combined organic phase was dried
over MgSO4, filtered and the solvent was removed. The residue was
purified by column chromatography on silica gel using 1:6 dioxane/
hexane (dioxane was freshly distilled prior to use) as an eluent to
give 18 (0.58 g, 40%) as yellow crystals. Mp: 90–91 ꢀC; Rf¼0.33
(silica gel TLC, 1:4 dioxane/hexane); IR (KBr) nmax 3104, 2848, 1636,
1616, 1608, 1600, 1592, 1500, 1464, 1448, 1424, 1352, 1284, 1264,
696, 654, 632, 586, 572, 536 cmꢃ1 1H NMR (500 MHz, DMSO-d6)
;
d
5.28 (s, 2H), 7.26 (t, J¼8 Hz,1H), 7.30 (t, J¼8 Hz,1H), 7.77 (t, J¼8 Hz,
1H), 7.87 (d, J¼8 Hz, 1H), 7.89 (d, J¼8 Hz, 1H), 8.23 (d, J¼8 Hz, 1H),
8.29 (d, J¼8 Hz, 1H), 10.88 (s, 1H); 13C NMR (125.8 MHz, DMSO-d6)
1192, 1064, 1000, 904, 864, 816, 752, 696, 672, 664, 620 cmꢃ1
;
1H
d
43.00, 117.81, 120.13, 120.56, 121.05, 121.48, 124.69, 125.55, 127.10,
NMR (500 MHz, CDCl3) 3.97 (s, 3H), 4.64 (s, 2H), 4.80 (s, 2H), 7.27–
d
133.41, 135.29, 138.39, 140.60, 176.35.
7.40 (m, 7H), 7.45 (d, J¼8 Hz, 1H), 7.72 (t, J¼8 Hz, 1H), 7.76 (d,
J¼8 Hz, 1H), 8.47 (d, J¼8 Hz, 1H), 8.52 (d, J¼8 Hz, 1H); 13C NMR
4.4. 4-Chloromethyl-10-methylacridin-9(10H)-one (15)
A mixture of 19 (1.32 g, 5.5 mmol), thionyl chloride (0.8 mL,
(75.5 MHz, CDCl3) d 42.00, 71.09, 72.95, 116.66, 121.79, 121.95,
122.93, 125.19, 126.08, 127.26, 127.88, 128.15, 128.23, 128.70, 133.97,
137.63, 138.46, 145.20, 145.81, 178.77. Anal. Calcd for C22H19NO2: C,
80.22; H, 5.81; N, 4.25. Found: C, 80.17; H, 5.92; N, 4.23.
11 mmol), dry DMF (10 mL) and dry CH2Cl2 (26 mL) was stirred at
reflux temperature for 1 h. The volatile compounds were evapo-
rated. The residue and triethylamine (0.85 mL, 6.1 mmol) were
stirred in THF (66 mL) at rt for 15 h. The precipitate was filtered off,
washed with THF (identified as triethylamine hydrochloride by
comparison of its IR spectrum to that of an authentic sample) and
the solvent was removed to give 15 (1.36 g, 96%) as pale orange
crystals. Mp: 166–168 ꢀC; Rf¼0.51 (silica gel TLC, 1:2 acetone/hex-
ane); IR (KBr) nmax 1632, 1616, 1608, 1600, 1592, 1500, 1448, 1416,
4.7. 4-Hydroxymethyl-10-methylacridin-9(10H)-one (19)
A solution of 18 (1.38 g, 4.2 mmol) in a mixture of freshly dis-
tilled dioxane/10% aqueous HCl solution (1:1, 140 mL) was stirred at
reflux temperature for 3 h. The reaction mixture was cooled down
to 0 ꢀC and kept at this temperature while its pH was adjusted to 8
by addition of 20% aqueous NaOH solution. The mixture was sat-
urated with solid NaCl and EtOAc (60 mL) was added to it. The
phases were mixed well and separated. The aqueous phase was
extracted with EtOAc (3ꢂ30 mL). The combined organic phase was
dried over MgSO4, filtered and the solvent was removed. The res-
idue was purified by column chromatography on silica gel using 1:3
EtOAc/toluene as an eluent to give 19 (0.44 g, 44%) as yellow
crystals. Mp: 170–172 ꢀC; Rf¼0.29 (silica gel TLC, 1:2 acetone/hex-
ane); IR (KBr) nmax 3384, 1608, 1600, 1588, 1504, 1488, 1480, 1440,
1416, 1360, 1280, 1264, 1192, 1160, 1136, 1008, 952, 896, 760, 704,
1364, 1280, 1260, 1080, 984, 804, 752, 652, 584 cmꢃ1
;
1H NMR
(500 MHz, CDCl3) 4.00 (s, 3H), 4.85 (s, 2H), 7.18–7.25 (m, 2H), 7.40
d
(d, J¼8 Hz, 1H), 7.66 (t, J¼8 Hz, 1H), 7.69 (d, J¼8 Hz, 1H), 8.34 (d,
J¼8 Hz, 1H), 8.41 (d, J¼8 Hz, 1H); 13C NMR (125.8 MHz, CDCl3)
d
42.83, 45.76, 116.82, 122.19, 122.40, 123.21, 125.75, 126.03, 127.35,
128.66, 134.25, 138.81, 144.98, 146.16, 178.67. Anal. Calcd for
C15H12ClNO: C, 69.91; H, 4.69; Cl, 13.76; N, 5.43. Found: C, 69.78; H,
4.82; Cl, 13.71; N, 5.28.
4.5. 4-Benzyloxymethylacridin-9(10H)-one (17)
648, 616 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d 2.23 (br s, OH and 1 mol
of complexed H2O together, 3H), 4.01 (s, 3H), 5.00 (s, 2H), 7.01 (t,
J¼8 Hz,1H), 7.29 (t, J¼8 Hz,1H), 7.44 (d, J¼8 Hz,1H), 7.68 (d, J¼8 Hz,
1H), 7.71 (t, J¼8 Hz, 1H), 8.22 (d, J¼8 Hz, 1H), 8.39 (d, J¼8 Hz, 1H);
A mixture of 1660 (4.96 g, 22 mmol), thionyl chloride (48 mL,
0.66 mol), dry DMF (0.7 mL) and dry CHCl3 (250 mL) was stirred at
reflux temperature until the reaction was completed
13C NMR (75.5 MHz, CDCl3)
d 42.29, 64.56, 116.76, 121.89, 121.96,

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I. Mo´czar et al. / Tetrahedron 66 (2010) 350–358
358
33. Kele, P.; Orbulescu, J.; Calhoun, T. L.; Gawley, R. E.; Leblanc, R. M. Tetrahedron
Lett. 2002, 43, 4413–4416.
122.76, 124.62, 127.23, 127.24, 129.55, 134.16, 136.90, 144.48, 145.79,
178.83. Anal. Calcd for C15H13NO2$H2O: C, 70.02; H, 5.88; N, 5.44.
Found: C, 70.10; H, 5.77; N, 5.34.
34. Gawley, R. E.; Pinet, S.; Cardona, C. M.; Datta, P. K.; Ren, T.; Guida, W. C.; Nydick,
J.; Leblanc, R. M. J. Am. Chem. Soc. 2002, 124, 13448–13453.
35. Clapham, B.; Sutherland, A. J. Chem. Commun. 2003, 84–85.
36. Geue, J. P.; Head, N. J.; Ward, A. D.; Lincoln, S. F. Dalton Trans. 2003, 521–526.
37. Jia, L. H.; Guo, X. F.; Liu, Y. Y.; Qian, X. H. Chin. Chem. Lett. 2004, 15, 118–120.
38. Roy, M. B.; Samanta, S.; Chattopadhyay, G.; Ghosh, S. J. Lumin. 2004,106,141–152.
39. Gawley, R. E.; Shanmugasundaram, M.; Thorne, J. B.; Tarkka, R. M. Toxicon 2005,
45, 783–787.
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1273–1279.
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Acknowledgements
Financial support of the Hungarian Scientific Research Fund
(OTKA No. K 62654 and T 46403) is gratefully acknowledged. The
´
authors express their appreciation to Dr. Peter Baranyai for helpful
discussions.
42. Kele, P.; Nagy, K.; Kotschy, A. Angew. Chem., Int. Ed. 2006, 45, 2565–2567.
References and notes
´
43. Kalai, T.; Hideg, K. Tetrahedron 2006, 62, 10352–10360.
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