Ph3P catalyzed one-pot synthesis of heterocyclic derivatives of biological active curcumin

Article abstract of DOI:10.1002/jhet.808

The natural product curcumin with different biological activity reacts smoothly with electron-deficient acetylenic compounds in the presence of Ph ₃P to produce different new curcumin derivatives which is containing coumarin and furan functiona

Full text of DOI:10.1002/jhet.808

May 2012
Ph3P Catalyzed One-Pot Synthesis of Heterocyclic Derivatives of
Biological Active Curcumin
683
a
a
b
*
Rahebeh Amiri, Parnia Padyab, Firoozeh Chalabian,
and Nasir Ahmad Rajabia
aChemistry Department, Islamic Azad University, Central Tehran Branch, Tehran, Iran
bBiology Department, Islamic Azad University, North Tehran Branch, Tehran, Iran
*
E-mail: rahebeha@hotmail.com
Received July 24, 2010
DOI 10.1002/jhet.808
View this article online at wileyonlinelibrary.com.
The natural product curcumin with different biological activity reacts smoothly with electron–deficient
acetylenic compounds in the presence of Ph3P to produce different new curcumin derivatives which is
containing coumarin and furan functional fragments in moderate yields. The reaction based on the aromatic
electrophilic substitution reaction between phenol moieties of curcumin and vinyltriphenylphosphonium
salts under mild conditions.
J. Heterocyclic Chem., 49, 683 (2012).
INTRODUCTION
under neutral conditions. Furthermore, coumarin and
furan moieties of the synthesized compounds have
long been recognized for their broad spectrum of
applications [18–21].
Curcumin as a turmeric yellow-orange pigment (Cur-
cuma longa) [1–3], is used as a spice in South Asian
cooking and a herbal medicine. It is known to exhibit
different biological activities such as bilious regulating
functions [4,5], reducing cholesterol level [6], anti-
inflammatory [7–9], antiarthritic effects [10] and anti-
oxidant properties [11]. In addition, curcumin inhibits
the proliferation of a variety of tumor cells [12–14], and
it has been shown to be active in both the prevention
and treatment of Alzheimer’s disease [15,16]. Despite
the extensive investigations on the possible medicinal
applications of curcumin have been done, information
about the precise reactions mechanism of this compound
is still scant [17]. The various activities of curcumin can
be related to these factors: the ring substituents, the
enone functionality, the presence of conjugated double
bonds in the aliphatic chain, or the position of the phe-
nolic hydroxyl groups [17]. So, curcumin analogs have
been used in recent studies to examine the effective site
for each property [13]. The present work reports an
operationally convenient reaction between curcumin and
p-deficient acetylenic reagents to show curcumin reactivity
EXPERIMENTAL
Compounds 1, 4, and triphenylphosphine were obtained
from Fluka (Buchs, Switzerland). Curcumin was purchased
from sigma (St. louis, MO). Melting points were measured
on an Electrothermal 9100 apparatus are uncorrected. IR spectra
1
were recorded on a Shimadzu IR-460 spectrometer. H and 13C
spectra were measured with a Bruker DRX-500 AVANCE
instrument with CDCl3 as solvent at 500 and 125.7 MHz,
respectively. Mass spectra were recorded on a Finnigan-Matt
8430 mass spectrometer operating at an ionization potential of
70 eV. Elemental analyses were performed using a Heraeus
CHN-O-Rapid analyzer.
General procedure. To a magnetically stirred solution of
triphenylphosphine (3.14 g, 12 mmol) and dimethoxycurcumin
(1.47 g, 4 mmol) in 1,4-dioxane (10 mL) was added, dropwise,
a mixture of dimethylacetylenedicarboxylate (1.44 mL, 12 mmol)
or methylacetylene carboxylate (1.01 mL, 12 mmol) in
1,4-dioxane at ꢀ5ꢁC over 5 min. The reaction mixture was
then allowed to warm up to room temperature and refluxed for
© 2012 HeteroCorporation

684
R. Amiri, P. Padyab, F. Chalabian, and N. A. Rajabi
Vol 49
Scheme 1. Synthesis of curcumin derivatives 2, 3 and 5, 6.
72 h. The solvent was removed under reduced pressure, and
the residue was purified by Column chromatography (silica
gel, Merck 230–400 mesh) using 1:2:3 CH2Cl2/CHCl3/n-hexane
mixtures as eluent for compounds 2, 3 and CH2Cl2/n-hexane 6:
1 mixture for compounds 5, 6.
(deuterioaceton): d 51.26, 52.38, 52.63, 52.92 and 53.79
(5 OCH3), 100.53 (CH), 111.57 and 115.60 (O—C¼CH2),
115.37 and 116.91 (C¼CH2), 123.84–134.60 (Ar), 160.28,
161.62 and 165.01 (ester C¼O), 186.23 (ketone C¼O).
ms: m/z 618 (M+, 2), 533 (20), 447 (10), 330 (20), 204
(20), 172 (65), 153 (50), 84 (100), 68 (60). Anal. Calcd
for C33H30O12: C, 64.08; H, 4.85. Found: C, 64.0; H, 4.8.
6-(1E,3Z,6E)-3-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-
(methyl-8-methoxy-2-oxo-2H-chromene-4-carboxylate)-5-oxohepta-
1,3,6-triene (2). Yellow powder, 0.65 g (34%), m.p. 271–273ꢁC;
IR (potassium bromide): 3470 (O—H), 1735, 1680 and 1670
(C¼O). 1H NMR (deuteriochloroform): d 3.68, 3.73 and
3.82 (3s, 9H, 3 OCH3), 5.87 (s, 1H, keto-enol CH), 6.84–7.05
Methyl-2-((1E,3Z,6E)-1,7-(methyl-7-methoxybenzofuran-3-
carboxylate)-5-oxohepta-1,3,6-trien-3-yloxy) acrylate (6). Yellow
powder, 0.98 g (40%), m.p. 270–272ꢁC; IR (potassium bromide):
1789, 1725 and 1660 (C¼O). 1H NMR (deuteriochloroform):
d 3.69, 3.70 and 3.71 (3 s, 15H, 5 OCH3), 5.19 and 5.21
(bs, 2H, O—C¼CH2), 5.30 (bs, 1H, CH), 7.05–7.47(s, 10H,
10 CH), 13C NMR (deuteriochloroform) d 65.28, 68.17, and
69.17(5 OCH3), 103.62 (CH), 111.07 and 111.12 (O—C¼CH2),
127.62–133.88 (Ar), 165.43 and 173.32 (ester C¼O), 192.46
(ketone C¼O). ms: m/z 616 (M+, 2), 531 (10), 499 (10), 326
(20), 204 (30), 172 (70), 153 (50), 84 (100), 68 (50). Anal.
Calcd for C33H28O12: C, 64.29; H, 4.54. Found: C, 64. 2; H, 4.5.
3
(d, 4H, JHH = 15 Hz, 4 CH), 7.43–7.83 (m, 6H, 6 CH), 9.87
(s, 1H, PhOH), 10.06 (s, 1H, enol OH); 13C NMR (deuteriochloroform):
d 54.83 (CO2CH3), 66.32 and 67.02 (2 OCH3), 104.08
(keto-enol CH), 124.08–129.11 (Ar), 168.02 (ester C¼O), 170.38
(lactone C¼O), 185.12 (ketone C¼O); ms: m/z 478 (M+, 4), 401
(10), 327(11), 281(20), 207(70), 83 (100), 69 (70); Anal. Calcd.
for C26H22O9: C, 65.27; H, 4.60. Found: C, 65.2; H, 4.5.
6-(1E,3Z,6E)-3-Hydroxy-1,7-bis(methyl-8-methoxy-2-oxo-2H-
chromene-4-carboxylate)-5-oxohepta-1,3,6-triene (3). Yellow
crystals, 0.90 g (47%), m.p. 342–343ꢁC; IR (potassium bromide):
Analyses and spectra.
There have been many studies on
1
the reactions between trivalent phosphorus nucleophiles and
α-β-unsaturated carbonyl compounds in the presence of a
proton-donor source such as a phenol or a CH-acid [22–24].
As curcumin has a relatively simple bis-phenolic structure, we could
represent a route to the synthesis of heterocyclic curcumin
derivatives via the reaction of its phenolic groups with p-deficient
acetylenic reagents in the presence of Ph3P at reflux temperature
(Scheme 1). The structures of products 2, 3 and 4, 5 were deduced
from their elemental analyses and their 1H, 13C NMR, IR, and mass-
spectral data. These compounds displayed molecular ion peaks at
appropriate m/z values. Initial fragmentations involve complete loss
of the side chains and scission of the heterocyclic ring units.
The vinyltriphenylphosphonium salt results from the initial
addition of vinyltriphenylphosphine to the acetylenic com-
pounds and subsequent protonation of the reactive 1:1 adduct
by curcumin. Then, the positively charged ion is attacked by
the conjugate base of the phenol moiety. The product is pre-
sumably produced by intramolecular lactonization of unsatu-
rated diester 2 and 3 (Scheme 2). Compound 3 was isolated as
1724, 1722, and 1675 (C¼O). H NMR (deuteriochloroform):
d 4.18, 4.20, 4.22 and 4.24 (4s, 12H, 4 OCH3), 6.02 (s, 1H,
keto-enol CH), 7.08–7.20 (bs, 4H, 4 CH), 7.52–7.54 (m, 3H, 3CH),
7.69–7.71 (m, 3H, 3 CH), 10.15 (s, 1H, enol OH); 13C NMR
(deuteriochloroform): d 53.69 (2 CO2CH3), 68.16 (2OCH3), 106.62
(keto-enol CH), 126.67–130.87 (Ar), 167.67 (2 ester C¼O), 171.90
(2 lacton C¼O), 187.63 (ketone C¼O). ms: m/z 588 (M+, 2), 503
(20), 458 (35), 352 (50), 281 (30), 207 (80), 83 (100), 69 (70).
Anal. Calcd. for C31H24O12: C, 63.26; H, 4.08. Found: C, 63.2; H,
4.0.
Methyl-2-((1E,3Z,6E)-1-(methyl-2-(2-hydroxy-3-methoxyphenyl)
acrylat)-7-(methyl-7-methoxybenzofuran-3-carboxylate)-5-
oxohepta-1,3,6-trien-3-yloxy) acrylate (5). Yellow powder,
0.90 g (36%), m.p. 323–325ꢁC; IR (potassium bromide): 3323
(O—H), 1773, 1735, 1700, 1680 (C¼O). 1H NMR
(deuterioaceton): d 3.86, 3.88, 3.92, 3.95 and 3.96 (5 s, 15H,
2
5 OCH3), 5.81 and 6.10 (d, 2H, JHH = 4Hz, O—C¼CH2),
6.90 (bs, 1H, CH), 6.97 and 7.04 (bs, 2H, C¼CH2),
7.51–7.97 (m, 9H, 9 CH), 8.75 (s, 1H, PhOH), 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Ph3P Catalyzed One-Pot Synthesis of Heterocyclic Derivatives
of Biological Active Curcumin
685
Scheme 2. Proposed mechanism for the synthesis of compounds 2 and 3.
1
the major product in the reaction. The H NMR spectrum of 2
displayed a characteristic six singlet line identified as three
methoxy (d = 3.68, 3.73 and 3.82) protons, one methyne proton
of keto-enol tautomer (d = 5.87). Phenolic and enol hydroxyl
groups (d = 9.87 and d = 10.06) along with the aromatic
protons, which appear at d = 7.43–7.83. The 13C NMR
spectrum of 2 showed resonances in agreement with the pro-
posed structures. Partial assignment of these resonances is
13C NMR data of structure 2 and 3 were supported by mea-
surement of their IR spectra. Of special interest is the carbonyl
absorption at 1670–1730 cmꢀ1, and the stretching vibration of
the hydroxyl groups are observed around 3400 cmꢀ1
.
As curcumin exists in equilibrium between the diketo and
keto-enol from which especially this phenomenon is strongly
favored by intramolecular H-bonding, when we used methyl
propiolate in aforementioned route, the products of this reaction
(5 and 6) were differentiated. Compound 5 apparently resulted
from the same mechanism but the keto-enol unit of curcumin
treated with the less-hindered vinyltriphenylphosphonium salt,
which underwent a conjugate addition then followed by elimina-
tion of triphenylphosphine. Furthermore, the furan ring closure
given in Experimental section. The H and 13C NMR spectra
1
of 3 are similar to those of 2 except for the phenolic —OH
group, which has been omitted, and the number of 13C NMR
signals of product 3 is reduced because of the molecular sym-
metry. The structural assignments made on the basis of 1H and
Scheme 3. Proposed mechanism for the synthesis of compounds 5 and 6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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R. Amiri, P. Padyab, F. Chalabian, and N. A. Rajabi
Vol 49
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proton for keto-enol system, vinyl (d = 5.81 and 6.10) protons
with a doublet (2JHH = 4 Hz) for enolate moiety and phenolic
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In conclusion, dimethoxy curcumin is a nontoxic, highly
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on its mechanism of action and chemical reactions have been
carried out yet. So, we provide an acceptable method for the syn-
thesis of stable heterocyclic product with variable functionalities
from curcumin and acetylenedicarboxylates or alkyl propiolates
in the presence of triphenylphosphine without any activation or
modification. According to these reactions, the phenolic group
is more reactive than the other sites of curcumin and the enol
functionality of it only reacts with the less hindered substrate.
On the other hand, the one-pot nature of the present procedure
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet