Synthesis of 7,8-dihydroxy-3-(3,4-dihydroxyphenyl)-2H-chromen-2-one derivatives of crown ethers

Article abstract of DOI:10.1002/jhet.17

The novel 1-(3,4-dimethoxyphenyl)-2-(2,3,4-trimethoxyphenyl)acrylonitrile was prepared from the condensation of the mixture of 2,3,4- trimethoxybenzaldehyde and 3,4-dimethoxyphenylacetonitrile in ethanol at 70°C with 20% aqueous sodium hydroxide solution.

Full text of DOI:10.1002/jhet.17

January 2009
Synthesis of 7,8-Dihydroxy-3-(3,4-dihydroxyphenyl)-2H-
chromen-2-one Derivatives of Crown Ethers
105
Cihan G u¨ nd u¨ z and Mustafa Bulut*
_
Department of Chemistry, Marmara University, Kadık o¨ y, 34722 Istanbul, Turkey
*
E-mail: mbulut@marmara.edu.tr
Received December 13, 2008
DOI 10.1002/jhet.17
Published online 6 February 2009 in Wiley InterScience (www.interscience.wiley.com).
The novel 1-(3,4-dimethoxyphenyl)-2-(2,3,4-trimethoxyphenyl)acrylonitrile was prepared from the
condensation of the mixture of 2,3,4-trimethoxybenzaldehyde and 3,4-dimethoxyphenylacetonitrile in
ꢀ
ethanol at 70 C with 20% aqueous sodium hydroxide solution. Cyclization and demethylation of the
acrylacetonitrile was performed using pyridine hydrochloride. The obtained 7,8-dihydroxy-3-(3,4-dihy-
droxyphenyl)-2H-chromen-2-one was reacted with the poly(ethylene glycol) ditosylates in CH CN/alkali
3
carbonate to afford bis-[12]crown-4, -[15]crown-5, and -[18]crown-6 chromenones. The chromatographi-
1
13
cally purified novel chromenone crown ethers were identified by IR, H NMR, C NMR, and MALDI-
TOF mass spectrometry and elemental analysis.
J. Heterocyclic Chem., 46, 105 (2009).
INTRODUCTION
atom, which is contained in the phenyl moiety in cou-
marin arms potentially can participate along with the
other oxygen atoms in the analog crown ether moiety
formed 1:1 complex with a host ion [12–16].
Macrocyclic molecules have attracted much attention
because of their potential use in a variety of chemical
processes, selective complexing agents for earth and
alkaline metal ions, and photoinduced electron transfer
We report here the synthesis of novel bis-[12]crown-
, -[15]crown-5, and -[18]crown-6 derivatives of 7,8-
4
[
1]. Several macrocyclic ethers possessing oxygen
dihydroxy-3-(3,4-dihydroxyphenyl)-2H-chromen-2-one.
dipoles have been synthesized to investigate their alkali
and alkaline-earth cation membrane transport and bind-
ing properties by means of potentiometry, optical spec-
troscopy, as well as NMR spectroscopic methods [2,3].
The ionophores bearing suitable light sensitive moieties
may undergo intermolecular changes at the electronic
level upon cationic interactions of donor oxygen atoms
RESULTS AND DISCUSSION
The synthesis of the precursor compound, 1-(3,
4-dimethoxyphenyl)-2-(2,3,4-trimethoxyphenyl)acrylo-
nitrile (3) was accomplished using Knoevenagel con-
densation reaction [17]. Equal molar amounts of 2,3,
4-trimethoxybenzaldehyde (1) and 3,4-dimethoxyphenyl-
[
2]. Essentially, the fluorescence spectra of fluorogenic
macrocycles is a reliable method to study cationic
recognitions [2,4,5]. Crown ethers have also been
used for chromatographic separations [6,7]. We have
recently synthesized fluorogenic coumarin-[12]crown-4,
ꢀ
acetonitrile (2) in ethanol at 70 C (see Scheme 1) was
reacted with 20% aqueous sodium hydroxide solution.
The Knoevenagel reaction is stereoselective and resulted
in the E-product. The precipitated acrylonitrile (3) was
collected by filtration, washed with distilled water, and
dried. The crude product was purified by crystalliza-
tion from ethanol. Then, the ring closure of (3) was
-
[15]crown-5, and -[18]crown-6 derivatives and exam-
ined cation binding effects using steady state fluo-
rescence spectroscopy and reported their cationic
interaction in acetonitrile [5,8–11]. However, the oxygen
V
C
2009 HeteroCorporation

1
06
C. G u¨ nd u¨ z and M. Bulut
Vol 46
Scheme 1
The obtained new coumarino crown ether compounds
will next be examined for their cation binding properties
using fluorescence spectroscopy.
EXPERIMENTAL
The starting chemicals were purchased from Aldrich or
Merck unless otherwise cited. Melting points have been
obtained on a Gallenkamp apparatus and are uncorrected. IR
spectra were obtained from KBr pellets with a Schimadzu
FTIR spectrometer, model 8300. Mass spectra have been
obtained with a MALDI-TOF instrument, model Bruker Auto-
1
flex III. The H NMR spectra have been obtained with a
BRUKER spectrometer, model AVANCE-400 Cpx and TMS
was used as the internal reference. Combustion analyses have
been acquired with a LECO-932 CHN.
Synthesis of 1-(3,4-dimethoxyphenyl)-2-(2,3,4-trimethoxy-
phenyl)acrylonitrile (3). The typical procedure for synthesis
of acrylonitrile (3) is performed according to the literature
[18]. A mixture of 2,3,4-trimethoxybenzaldehyde (1) (4.82 g,
performed with freshly prepared pyridine hydrochloride
ꢀ
at 180 C. The compound, 7,8-dihydroxy-3-(3,4-dihy-
24.59 mmol) and 3,4-dimethoxyphenylacetonitrile (2) (4.34 g,
ꢀ
2
4.59 mmol) in ethanol (100 mL) was heated to 70 C; 20%
droxyphenyl)-2H-chromen-2-one, (4) was washed with
water until neutral, dried, and recrystallized from acetic
acid.
aqueous sodium hydroxide solution was then added dropwise
to the stirred solution until the onset of turbidity. The acryloni-
trile (3) precipitated when the solution was cooled to room
temperature. The precipitate was collected by filtration, washed
with water, and dried. The crude product was purified by
Compound 4 was reacted with poly(ethylene glycol)
ditosylates in the presence of alkali carbonate in CH CN
3
ꢀ
(Scheme 1) to give the 7,8-dihydroxy-3-(3,4-dihydroxy-
recrystallization from ethanol. 6.85 g (78%), mp 114–115 C.
ir (KBr): 2973–2840 (CAH), 2206 (CN), 1583–1403 (C ¼¼ C),
phenyl)-2H-chromen-2-one crown ethers (coumarino
crown ether) 5a, 5b, 5c, respectively.
ꢁ
1 1
1
350–1023 (CAO) cm ; H NMR (400 MHz/CDCl ): d 3.89
3
(
(
6
s, 3H, OCH
s, 3H, OCH
.91 (d, J ¼ 8.2 Hz, 1H), 7.15 (d, J ¼ 2.3 Hz, 1H,), 7.24 (dd,
3
), 3.91 (s, 3H, OCH
3
), 3.92 (s, 3H, OCH
), 6.78 (d, J ¼ 9.0 Hz, 1H),
3
), 3.93
The purification of crown ethers were done by col-
umn chromatography (silica gel-chloroform) to give
pure coumarino crown ethers (5a–5c) in 12–23% yields.
They were soluble in CHCl or CH Cl . The novel com-
3
), 3.95 (s, 3H, OCH
3
J ¼ 8.2 Hz and 2.3 Hz, 1H), 7.72 (s, 1H), 7.96 (d, J ¼ 9.0
þ
þ
3
2
2
Hz, 1H); ms: m/z 355.14 (M ), 356.15 (Mþ1) , 357.15
þ
pounds have been characterized by elemental analysis
1 13
IR, H NMR, C NMR, and MALDI-TOF-MS.
(Mþ2) .
Synthesis of 7,8-dihydroxy-3-(3,4-dihydroxyphenyl)-2H-
chromen-2-one (4). A mixture of the acrylonitrile (3) (6.85 g,
19.24 mmol) and freshly prepared pyridine hydrochloride
The IR spectra of 3 showed absorption bands at 2840
ꢁ
1
and 2973 cm for the CAH stretching. The characteris-
tic band of the nitrile group (CN), benzene ring (C ¼¼ C),
ꢀ
(
11.11 g, 96.20 mmol) was heated for 2 h at 180 C; the cooled
solution was treated with water. The precipitated coumarin
was washed with water until neutral, dried, and recrystallized
and methoxy group (OCH ) appeared at 2206, 1583–
3
ꢁ
1
403, 1350–1023 cm , respectively. The IR spectrum
ꢀ
ꢀ
1
from acetic acid. 4.6 g (83%), mp 295 C (lit: 297 C [19]); ir
(KBr): 3560–3328 (ArAOH), 1681 (C ¼¼ O), 1618–1535
of 4 showed a characteristic band for the hydroxyl group
ꢁ
1 1
(C ¼¼ C), 1311–1109 (CAO) cm ; H NMR (400 MHz/DMSO-
(
(
OH), carbonyl group (C ¼¼ O), benzene ring (C ¼¼ C), and
ꢁ
1
,
d ): d 6.71 (d, J ¼ 8.5 Hz, 1H), 6.85 (d, J ¼ 8.5 Hz, 1H),
6
CAO) 3560–3328, 1681, 1618–1535, 1311–1109 cm
6
1
9
.95 (dd, J ¼ 8.5 Hz and 2.0 Hz 1H), 7.15 (d, J ¼ 8.5 Hz,
H), 7.22 (d, J ¼ 2 Hz, 1H), 7.95 (s, 1H), 9.05 (br-s, 1H),
.12 (br-s, 1H), 9.40 (br-s, 1H), 9.95 (br-s, 1H).
respectively.
1
The H NMR spectra of 5a–5c showed characteristic
signals for etheral (AOACH ACH AOA) protons at d
2
2
General procedure for the synthesis of 7,8-dihydroxy-
-(3,4-dihydroxyphenyl)-2H-chromen-2-one crown ethers
3
.85–4.48 ppm, each a triplet. In addition, the chemical
shifts of the aromatic protons are observed at d 6.86–
.81 ppm.
3
(5a–5c). The typical procedure for the cyclization reaction
leading to macrocyclic ethers (5a–5c) is as follows. A mixture
of 4 (5 mmol), poly(ethylene glycol) ditosylate (10 mmol),
and metal carbonate (20 mmol) was dissolved in 60 mL
7
13
The C NMR spectrum of 5a–5c showed expected
signals for aromatic, carbonyl, and etheral carbons at d
09.83–140.63, 160.46–173.90, 69.06–75.17 ppm,
CH
heated for 35–40 h at 80–85 C. The solvent was distilled.
Diluted HCl was added to the residue and the mixture was
3
CN in a 100-mL reaction flask. The reaction mixture was
ꢀ
1
respectively. Also the MALDI-TOF-MS and elemental
analysis confirmed the formation of coumarino crown
ether derivatives.
extracted with CHCl
extracts were washed with water, dried over CaCl
3
(3 ꢂ 50 mL). The combined organic
2
, and the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2009
Synthesis of 7,8-Dihydroxy-3-(3,4-dihydroxyphenyl)-2H-chromen-2-one
Derivatives of Crown Ethers
107
0
CHCl
3
solution evaporated in vacuo. Chromatography of the
crude products (silica gel 60, Merck) with chloroform gave
7.17 (dd, J ¼ 8.7 Hz and 2 Hz, 1H, H-6 ), 7.29 (d, J ¼ 2 Hz,
0
3
13
1H, H-2 ), 7.67 (s, 1H, H-4); C NMR (100 MHz, CDCl /
pure coumarino crown ethers (5a–5c).
TMS) d: 69.06, 69.21, 69.36, 69.44, 69.68, 69.82, 70.55,
70.60, 70.67, 70.78, 70.84, 70.90, 70.94, 70.97, 71.01, 71.12,
71.18, 71.27, 71.39, 73.24, 110.62, 113.61, 114.57, 116.14,
121.78, 122.88, 124.97, 128.18, 136.19, 139.34, 148.63,
1
4-(2,3,5,6,8,9-Hexahydrobenzo[b][1,4,7,10]tetraoxacyclo-
dodecin-12-yl)-5,6,8,9-tetrahydro-2H-[1,4,7,10]tetra-oxa-
cyclododeca[2,3-h]chromen-15(3H)-one (5a; C27
Compound 4 (1.5 g, 5.2 mmol), Na CO (2.2 g, 21 mmol),
tri(ethylene glycol) ditosylate (4.8 g, 10 mmol) in CH CN
60 mL) was reacted as described earlier to afford light yellow
30
H O10).
þ
2
3
152.38, 152.45, 154.75, 173.90 ; ms: m/z 690.2 (M ), 713.18
þ
þ
3
(MþNa) , 629.16 (MþK) . Anal. Calc. for C35
46
H O14: C,
(
60.86; H, 6.71. Found: C, 60.36; H, 6.81.
ꢀ
1
solid 5a, 0.6 g (22%), mp 126–128 C; H NMR (400 MHz/
CDCl
(
3
): d 3.85 (t, J ¼ 4Hz, 4H), 3.95 (t, J ¼ 4Hz, 4H), 3.97
Acknowledgment. The authors thank the Research Foundation
of Marmara University, Commission of Scientific Research Pro-
ject (BAPKO) [FEN-C-DPR-041007-0203] and the Scientific
and Technical Research Council of Turkey (TUBITAK)
[107T347].
t, J ¼ 4Hz, 4H), 4.21 (t, J ¼ 4Hz, 4H), 4.23 (t, J ¼ 4Hz,
0
4
H), 4.40 (t, 4Hz, 4H), 6.86 (d, J ¼ 8.7 Hz, 1H, H-5 ), 7.01
(
(
d, J ¼ 8.5 Hz, 1H, H-6), 7.19 (d, J ¼ 8.7 Hz, 1H, H-5), 7.31
0
dd, J ¼ 8.5 Hz and 1.5 Hz, 1H, H-6 ), 7.37 (d, J ¼ 1.5 Hz,
0
13
H, H-2 ), 7.69 (s, 1H, H-4); C NMR (100 MHz, CDCl /
1
3
TMS): d 69.75, 69.87, 70.31, 70.34, 70.51, 70.87, 71.18,
7
1
1
5
5
1.32, 71.66, 72.16, 72.23, 75.17, 111.06, 115.02, 117.74,
18.97, 123.17, 124.53, 126.25, 129.14, 136.26, 139.75,
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þ
47.72, 150.37, 151.25, 155.12, 160.46; ms: m/z 513.94 (M ),
þ
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30
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[
.88. Found: C, 62.97; H, 5.68.
4
41.
1
7-(2,3,5,6,8,9,11,12-Octahydrobenzo[b][1,4,7,10,13]penta-
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[
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1
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¨
0
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13
1
6
7
1
1
6
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þ
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38 12
31
¨
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¨
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46
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¨
¨
_
¨
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2
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ditosylate (3.52 g, 7 mmol) in CH CN (60 mL) reacted as
3
[
described earlier to afford light yellow solid 5c, 0.28 g (12%),
ꢀ
1
mp: 95 C; H NMR (400 MHz/CDCl
3
): d 3.92 (t, J ¼ 4Hz,
1
995, 71, 2117.
4
H), 3.95 (t, J ¼ 4Hz, 4H), 3.97 (t, J ¼ 4Hz, 4H), 4.02 (t,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet