Synthesis and spectral characterization of a novel series of methylcinnamate derivatives of 15-crown-5

Article abstract of DOI:10.1002/jhet.90

(Chemical Equation Presented) A series of novel methylcinnamate derivatives of 15-crown-5 have been synthesized. The derivatives of methylcinnamate have been prepared by a synthesis from the corresponding chromenone-crown ether with MeONa/MeOH or KOH, CH₃I, and DMSO as solvent. Novel compounds were characterized by elemental analysis, IR, ¹H NMR, and MALDI-TOF.

Full text of DOI:10.1002/jhet.90

May 2009
Synthesis and Spectral Characterization of a Novel Series of
Methylcinnamate Derivatives of 15-Crown-5
567
¨
Cihan Gu¨ndu¨z, Umit Salan, and Mustafa Bulut*
_
Department of Chemistry, University of Marmara, 34722 Kadikoy-Istanbul, Turkey
*E-mail: mbulut@marmara.edu.tr
Received April 20, 2008
DOI 10.1002/jhet.90
Published online 26 May 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of novel methylcinnamate derivatives of 15-crown-5 have been synthesized. The derivatives
of methylcinnamate have been prepared by a synthesis from the corresponding chromenone-crown ether
with MeONa/MeOH or KOH, CH3I, and DMSO as solvent. Novel compounds were characterized by
1
elemental analysis, IR, H NMR, and MALDI-TOF.
J. Heterocyclic Chem., 46, 567 (2009).
INTRODUCTION
complexes with alkali metal cations [5–8]. d-Lacton ring
of alkyloxy coumarin compounds can be opened using
sodium alkoxide in dry respective alcohol yielding cin-
namate derivatives. Then, the phenolic hydroxyl group
can be alkylated [9,10].
Cinnamic (3-phenylpropenoic) acid analogues are a
fundamental part of plant chemistry. The hydroxylated
cinnamic acids possess antifungal, antibacterial, and par-
asite fighting abilities [1]. In the cinnamic acid mole-
cule, the carboxylic acid group is separated from the ar-
omatic ring by a double bond. Conjugation between the
AC¼¼CA bond gives very interesting electronic struc-
ture to cinnamic acid derivatives.
Because the cinnamic acid analogues show biological
activity, we might expect that the crown ether deriva-
tives of methylcinnamate could also have biological
activity.
This work introduces the preparation and characteriza-
tion of some novel crown ether derivatives of methyl-
cinnamate compounds obtained from respective chrome-
none-crown ethers.
The flavonoid class compound coumarin (2H-chrome-
none) derivatives exist in many plants as free or gluco-
sides. Because of biological activities, which gain im-
portance in recent years, many coumarin derivatives
have been synthesized and took place in literature. Most
important coumarins are the ones that have substituted
in third position. Some coumarins show a perfect fluo-
rescens characteristic in addition to their anticoagulant,
anti-inflammatory, anti-oxidative, anti-aging, and anti-
cancer effects [2,3]. Methyl and acetyl substituents
destroy the activities of coumarins. The beneficial
effects of phenolic antioxidants on health have been
attributed to their antioxidant capacity, particularly their
ability to protect low-density lipoproteins from oxidative
attack [4]. As a result of this, hydroxy coumarin deriva-
tives gain more importance. Particularly, o-dihydroxy-
3-phenylcoumarin shows antioxidant property and the
18-crown-6, 15-crown-5, 12-crown-4 derivatives form
RESULTS AND DISCUSSION
Recent work from our laboratory described general
method for the synthesis of chromenone-crown ethers
[5–8]. 7,8-Dihydroxy-2H-chromenone crown ether deriv-
atives 4a–f were synthesized from the polyethylene
glycol ditosylate or dichloride with corresponding 7,8-
dihydroxy-2H-chromenone derivatives 3a–f, which were
prepared from pyrogallol and D,L-malic acid 2a in the
presence of H2SO4 or 2,3,4-trihydroxybenzaldehyde and
corresponding methoxyphenylacetic acid in NaOAc/
Ac2O mixture 3b–f [5–8]. All these compounds were
purified using column chromatography (silica gel) with
C
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2009 HeteroCorporation

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C. Gu¨ndu¨z, U. Salan, and M. Bulut
568
Vol 46
chloroform. The structures of all synthesized compounds
1
mass spectra confirmed the formation of novel methylcin-
namate derivatives of 15-crown-5 5a–g (Scheme 1).
were identified by elemental analysis, IR, H NMR, 13C
NMR, and mass spectrometry [6–8].
We report herein a general method for the synthesis
of methylcinnamate derivatives of 15-crown-5 from the
respective chromenone-crown ethers. The phenylacrylic
acids have been prepared by a synthesis from the corre-
sponding chromenone-crown ethers with MeONa solu-
tion in MeOH refluxed for 4 h to afford 5a [11–13] or
KOH and DMSO as solvent at 60ꢀC for 3–6 h. The phe-
nolic hydroxyl group was methylated with CH3I to give
desired compounds 5b–g in quantitative yield [14,15].
The structures of all synthesized compounds were iden-
tified by elemental analysis, IR, 1H NMR, and mass
spectrometry. All spectral data confirm the proposed
structures of all of the new compounds 5a–g.
EXPERIMENTAL
The starting chemicals used were of reagent grade. Melting
points were obtained on a Gallenkamp apparatus. Elemental
analysis was performed on a LECO CHNS 92 instrument. 1H
NMR spectra were determined with a Brucker DPX-400, 400
MHz High Performance Digital FT-NMR spectrometer. IR
spectra were recorded as KBr disks in the range of 400–4000
cmꢁ1 on a Schimadzu FTIR-8300 spectrometer. Mass spectra
have been obtained with MALDI-TOF Instruments, model
Bruker Autoflex III.
General procedure for the synthesis of methylcinnamate
derivatives of 15-crown-5 5a–g. The crown ethers 4a–f were
prepared according to the known procedure [5–8]. The typical
procedure for the reaction leading to a series of novel substi-
tuted methylcinnamate 15-crown-5 5a–g is as follows: A solu-
tion of sodium methoxide (28% in MeOH) (4 mmol) was
added to a solution of the crown ether 4a (2 mmol) in dry
MeOH, and the mixture refluxed for 4 h and then the reaction
mixture concentrated and extracted with AcOEt. The organic
layer washed with brine and dried over MgSO4 and evaporated
to give product 5a [11–13]. The crown ethers 4b–f and meth-
ylcinnamate 15-crown-5 5a (1 mmol) were dissolved in
DMSO, and then the KOH (2 mmol) was added to the reaction
mixture and stirred at 60ꢀC for 3–6 h. The reaction could also
be monitored by thin-layer chromatography. CH3I (2.5 mmol)
was then added to the cooled reaction mixture. The reaction
mixture was stirred at ambient room temperature for 2–6 h.
The reaction was followed by thin-layer chromatography. The
resulting mixture was poured into 30–50 mL icy water. The
precipitate was collected by filtration, washed with water, and
dried to give product 5b–g [14,15].
The IR spectra of novel methylcinnamate derivatives
of 15-crown-5 5a–g showed CAH stretching bands at
about 2940 and 2858 cmꢁ1, an a,b-unsaturated ester
carbonyl and double bond in the region 1680–1700,
1600 cmꢁ1, respectively. The bending peaks around
1040–1260 cmꢁ1 showed the structure of CAOAC ether
chain for all new methylcinnamate derivatives.
The cinnamate skeleton was also elucidated by 1H
1
NMR spectra. The H NMR spectrum of compound 5a–
g, which showed triplets for the methylene protons
[AOCH2CH2OA] at d 3.66–4.39, a pair of doublet with
ortho-coupling constants at d 6.54–7.40 ppm (d, J ¼
8.50 Hz, H-6) and d 7.10–7.90 ppm (d, J ¼ 8.50 Hz, H-
5) implied the presence of methylcinnamate derivatives
of 15-crown-5. When the 1H NMR spectra of com-
pounds 7,8-dihydroxy-2H-chromenone derivatives of 15-
crown-5 4a–f and methylcinnamate derivatives of 15-
crown-5 5a–g were compared, one marked difference
lay in the aromatic proton region with a singlet (s, H-3)
was observed in the spectrum of 5a–g at lower field
than 4a–f. And, also peaks at 3.68–3.92 ppm indicated
the presence of AOCH3 groups.
(E)-Methyl-3-(14-hydroxy-2,3,5,6,8,9,11,12-octahydrobenzo
[b][1,4,7,10,13] pentaoxacyclopentadecin-15-yl)acrylate (5a:
C18H24O8). A solution of sodium methoxide (28% MeOH)
(0.77 mL, 4 mmol) was added to compound 4a (0.672 g, 2
mmol) in MeOH (10 mL), which was reacted as described ear-
lier to afford 5a. Yield: 0.42 g (57%), mp 188–189ꢀC; IR (KBr):
3402, 2939, 2873, 2858, 1681, 1604, 1504, 1458, 1261, 1041
cmꢁ1; H NMR (400 MHz/CDCl3): d 3.66 (t, 4H, J ¼ 4.29 Hz),
1
The IR spectrum of compound 5a, the absorption
band at 3400 cmꢁ1 corresponding to hydroxyl stretching
vibration disappears after its conversion into compound
5b. The rest of spectral data of compound 5a are very
similar to 5b. The IR spectrum of compound 5a and 5b
including the stretching bands around 2947–2858 cmꢁ1
of the CAH stretching frequency, 1701–1681 cmꢁ1of
the carbonyl group, 1623–1604 cmꢁ1 of the benzene
ring, and 1261–1041 cmꢁ1 of the ether chain, respec-
3.68 (s, 3H, OCH3), 3.70 (t, 2H, J ¼ 4.29 Hz), 3.79 (t, 2H, J ¼
4.29 Hz), 3.88 (t, 2H, J ¼ 4.29 Hz), 4.00 (t, 2H, J ¼ 5.46 Hz),
4.20 (t, 2H, J ¼ 4.29 Hz), 4.30 (t, 2H, J ¼ 5.46 Hz), 6.48 (d,
1H, J ¼ 8.97 Hz), 6.55 (d, 1H, J ¼ 15.99 Hz), 7.15 (d, 1H, J ¼
8.58 Hz), 7.90 (d, 1H, J ¼ 15.99 Hz). Anal. Calcd. for
C18H24O8: C, 58.69; H, 6.57. Found: C, 58.45; H, 6.78.
(E)-Methyl-3-(14-methoxy-2,3,5,6,8,9,11,12-octahydrobenzo
[b][1,4,7,10,13] pentaoxacyclopentadecin-15-yl)acrylate (5b:
C19H26O8). A mixture of compound 5a (0.40 g, 1.09 mmol)
and CH3I (0.138 mL, 2.7 mmol) in DMSO was treated as
described earlier to give 5b. Yield: 0.18 g (43%) mp 84–85ꢀC;
IR (KBr): 2947, 2904, 2858, 1701, 1623, 1593, 1496, 1461,
1
tively. The structural assignments are based on the H
NMR coupling constants of the olefinic protons, and
stereochemistry of the 5a and 5b was assigned as trans-
1296, 1261, 1041 cmꢁ1 1H NMR (400 MHz/CDCl3): d 3.74
;
on the basis of the coupling constant value (JHAH
15.99 Hz) with reference to previous data [11].
¼
(t, 8H, J ¼ 5.46 Hz), 3.79 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
3.93 (t, 4H, J ¼ 4.68 Hz), 4.16 (t, 2H, J ¼ 4.29 Hz), 4.18 (t,
2H, J ¼ 5.07 Hz), 6.41 (d, 1H, J ¼ 16.38 Hz), 6.64 (d, 1H, J
¼ 8.58 Hz), 7.23 (d, 1H, J ¼ 8.58 Hz), 7.87 (d, 1H, J ¼ 15.99
The structures of newly synthesized compounds 5a–g
were checked using MS spectrometry. Also MALDI-TOF
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
Synthesis and Spectral Characterization of a Novel Series of
Methylcinnamate Derivatives of 15-Crown-5
569
Scheme 1
Hz); ms: m/z 382 (Mþ), 405 (Mþ þ Naþ), 421 (Mþ þ Kþ).
Anal. Calcd. for C19H26O8: C, 59.68; H, 6.85. Found: C,
59.45; H, 6.78.
z 458 (Mþ), 481 (Mþ þ Naþ), 497 (Mþ þ Kþ). Anal. Calcd.
for C25H30O8: C, 65.49; H, 6.60. Found: C, 64.85; H, 6.75.
Methyl-3-(14-methoxy-2,3,5,6,8,9,11,12-octahydrobenzo[b]
[1,4,7,10,13]pentaoxacyclopentadecin-15-yl)-2-(4-methoxy-
phenyl)acrylate (5d: C26H32O9). Compound 4d (0.221 g, 0.5
mmol), KOH (0.056 g, 1 mmol), and CH3I (0.068 mL 1.25
mmol) in DMSO (5 mL) were reacted as described earlier to
give 5d. Yield: 0.058 g (24%) mp 76–77ꢀC; IR (KBr): 2923,
Methyl-3-(14-methoxy-2,3,5,6,8,9,11,12-octahydrobenzo[b]
[1,4,7,10,13]pentaoxacyclopentadecin-15-yl)-2-phenylacrylate
(5c: C25H30O8). A mixture of compound 4c (0.206 g, 0.5
mmol) and KOH (0.056 g, 1 mmol) in DMSO (5 mL) was
heated, then treated with CH3I (0.068 mL 1.25 mmol), reacted,
and then worked up as described earlier to afford 5c. Yield:
0.044 g (19%) mp 82ꢀC; IR (KBr): 2947, 2904, 2858, 1701,
2858, 1728, 1600, 1454, 1292, 1110, 1033 cmꢁ1 1H NMR
;
(400 MHz/CDCl3): d 3.72 (t, 8H, J ¼ 5.04 Hz), 3.73 (s, 3H,
OCH3), 3.85 (s, 6H, OCH3), 3.90 (t, 4H, J ¼ 5.50 Hz), 4.21
(t, 4H, J ¼ 5.07 Hz), 6.59 (d, 1H, J ¼ 8.58 Hz), 7.00 (d, 1H,
J ¼ 8.58 Hz), 7.20 (d, 2H, J ¼ 7.80 Hz), 7.36 (d, 2H, J ¼
7.80 Hz), 8.05 (s, 1H); ms: m/z 488 (Mþ), 511 (Mþ þ Naþ),
527 (Mþ þ Kþ). Anal. Calcd. for C26H32O9: C, 63.92; H,
6.60. Found: C, 62.78; H, 6.45.
1623, 1593, 1461, 1261, 1041 cmꢁ1 1H NMR (400 MHz/
;
CDCl3) :d 3.78 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.98 (t,
8H, J ¼ 4.68 Hz), 4.08 (t, 4H, J ¼ 4.60 Hz), 4.18 (t, 4H, J ¼
4.60 Hz), 6.90 (dd, 2H, J ¼ 8.97 and 2.34 Hz), 6.97 (dd, 1H,
J ¼ 8.97 and 2.34 Hz), 7.10 (d, 1H, J ¼ 8.58 Hz), 7.40 (dd,
2H, J ¼ 8.58), 7.90 (d, 1H, J ¼ 8.58 Hz), 7.98 (s, 1H); ms: m/
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
C. Gu¨ndu¨z, U. Salan, and M. Bulut
570
Vol 46
4H, J ¼ 4.29 Hz), 4.23 (t, 2H, J ¼ 4.29 Hz), 4.398 (t, 2H, J
¼ 4.68 Hz), 6.85 (d, 1H, J ¼ 8.97 Hz), 6.90 (br s, 2H), 7.19
(d, 1H, J ¼ 8.58 Hz), 7.70 (s, 1H); ms: m/z 573 (Mþ þ Naþ).
Anal. Calcd. for C28H36O11: C, 61.30; H, 6.61. Found: C,
61.01; H, 6.75.
Methyl-2-(3,4-dimethoxyphenyl)-3-(14-methoxy-2,3,5,6,8,9,
11,12-octahydrobenzo[b][1,4,7,10,13]pentaoxa-cyclopentadecin-
15-yl)acrylate (5e: C27H34O10). Compound 4e (0.236 g, 0.5
mmol), KOH (0.056 g, 1 mmol), and CH3I (0.068 mL 1.25
mmol) in DMSO (5 mL) were treated as described earlier to
give 5e. Yield: 0.044 g (17%) mp 91–92ꢀC; IR (KBr): 2923,
2858, 1728, 1600, 1454, 1292, 1110, 1033 cmꢁ1 1H NMR
;
Acknowledgment. The authors thank the Research Foundation
of Marmara University, Commission of Scientific Research Pro-
ject (BAPKO) [FEN-BGS-120707-0149] and [FEN-C-DPR-
041007-0203].
(400 MHz/CDCl3): d 3.83 (s, 3H, OCH3), 3.90 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.94 (t, 4H,
J ¼ 4.29 Hz), 3.98 (t, 4H, J ¼ 4.29 Hz), 4.14 (t, 2H, J
¼4.29 Hz), 4.20 (t, 2H, J ¼ 5.46 Hz), 4.23 (t, 2H, J ¼ 4.29
Hz), 4.38 (t, 2H, J ¼ 4.68 Hz), 6.59 (d, 1H, J ¼ 8.97 Hz),
6.85 (dd, 1H, J ¼ 8.77 and 2.73 Hz), 6.92 (br d, 1H, J ¼
8.19 Hz), 7.19 (d, 1H, J ¼ 8.58 Hz), 7.28 (d, 1H, J ¼ 1.95
Hz), 7.69 (s, 1H); ms: m/z 518 (Mþ), 541 (Mþ þ Naþ), 557
(Mþ þ Kþ). Anal. Calcd. for C27H34O10: C, 62.54; H, 6.61.
Found: C, 61.45; H, 6.88.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet