Solid-phase microwave assisted synthesis of curcumin analogs

Article abstract of DOI:10.2174/157017812801322417

Turmeric contains three important analogs, curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), collectively called as curcuminoids. Curcumin, the most abundant of these curcuminoids is reported to have antioxidant, anti-inflammatory, neuroprotective, antimicrobial, nematocidal, antimutagenic, anticarcinogenic, antiretroviral and chemopreventive activities. Curcumin (a symmetric β diketone) analogs 3a-e were synthesized from β-diketones and aromatic aldehydes using solid phase microwave irradiation method in presence of boric acid in diethanolamine, acetic acid (1:1) with reduced reaction time and enhanced %yield. Various clays like Alumina (neutral), Silica gel and Montmorillonite K₁₀ were used as solid phase catalysts where alumina was found to be efficient in the synthesis of curcumin analogs.

Full text of DOI:10.2174/157017812801322417

Letters in Organic Chemistry, 2012, 9, 447-450
447
Solid-Phase Microwave Assisted Synthesis of Curcumin Analogs
Dinesh Pore1, Ramesh Alli2, Achanta S.C. Prabhakar1, Rajashekar R. Alavala1, Umasankar
Kulandaivelu1 and Shireesha Boyapati*,1
1Medicinal Chemistry Research Division, Department of Pharmaceutical Chemistry, Vaagdevi College of Pharmacy,
Warangal-506001, Andhra Pradesh, India
2Vaagdevi Institute of Pharmaceutical Sciences, Bollikunta, Warangal, Andhra Pradesh, India
Received August 16, 2011: Revised September 21, 2011: Accepted September 21, 2011
Abstract: Turmeric contains three important analogs, curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin
(BDMC), collectively called as curcuminoids. Curcumin, the most abundant of these curcuminoids is reported to have
antioxidant, anti-inflammatory, neuroprotective, antimicrobial, nematocidal, antimutagenic, anticarcinogenic,
antiretroviral and chemopreventive activities. Curcumin (a symmetric ꢀ diketone) analogs 3a-e were synthesized from ꢀ-
diketones and aromatic aldehydes using solid phase microwave irradiation method in presence of boric acid in
diethanolamine, acetic acid (1:1) with reduced reaction time and enhanced %yield. Various clays like Alumina (neutral),
Silica gel and Montmorillonite K10 were used as solid phase catalysts where alumina was found to be efficient in the
synthesis of curcumin analogs.
Keywords: Aldol condensation, boron-assisted, curcumin analogs, microwave irradiation, regioselective, solid-phase.
INTRODUCTION
been shown to be scavengers of free radicals and reactive
oxygen species (ROS), such as hydroxyl radicals [1],
superoxide radicals, singlet oxygen, peroxyl radicals, and
peroxynitrite, whose production is implicated in the
induction of oxidative stress [1, 6-9].
Curcumin, commonly called diferuloyl methane, is a
hydrophobic polyphenol derived from the rhizome (turmeric)
of the herb Curcuma longa (Zingiberaceae). Turmeric has
been used for thousands of years in ayurvedic and traditional
medicine of Chinese and Indians. In modern days, curcumin
continues to be used as an alternative medicinal agent in
many parts of South East Asia for the treatment of many
ailments such as stomach upset, flatulence, jaundice,
arthritis, sprains, wounds and skin infections.
O
O
MeO
HO
OMe
OH
Curcumin
O
O
Turmeric contains three important analogs, curcumin,
demethoxycurcumin (DMC), and bisdemethoxycurcumin
(BDMC), collectively called the curcuminoids. Structures of
curcuminoids are presented in Fig. (1). Of the three
curcuminoids, curcumin is the most abundant in turmeric,
followed by DMC and BDMC. Commercially available
curcumin mixture contain 77% curcumin, 17% DMC, and
3% BDMC. Chemically, it is a bis-ꢁ, ꢀ-unsaturated ꢀ-
diketone-(1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-
heptadien- 3, 5-dione), that exhibits keto-enol tautomerism
presented in Fig. (2).
MeO
HO
OH
Demothoxycurcumin
O
O
HO
OH
Bisdemothoxycurcumin
Fig. (1). Structures of curcuminoids.
Curcumin has been shown to exhibit antioxidant [1], anti-
inflammatory [2], neuroprotective, antimicrobial, nema-
tocidal, antimutagenic, anticarcinogenic [3], antiretroviral [4]
and chemopreventive activities. It also has hepatoprotective
and nephroprotective activities, suppresses thrombosis,
protects against myocardial infarction and has hypoglycemic
[5] and antirheumatic properties. The curcuminoids have
O
O
MeO
OMe
HO
OH
O
OH
MeO
HO
OMe
OH
*Address correspondence to this author at the Medicinal Chemistry
Research Division, Department of Pharmaceutical Chemistry, Vaagdevi
College of Pharmacy, Warangal-506001, Andhra Pradesh, India; Tel:
+919848906357; Fax: +91 870-2544949;
E-mails: sirimedchem@yahoo.co.in, sirimedchem@gmail.com
Fig. (2). Keto-enol tautomerism of Curcumin.
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

448 Letters in Organic Chemistry, 2012, Vol. 9, No. 6
Pore et al.
O
O
O
O
O
640 MW, 3-6 min
Solid support
R
R
H
R
3a-e
2
1
Scheme 1. Microwave assisted synthesis of Curcumin analogs on solid-support.
Curcumin is synthesized majorly by the aldol
condensation of ꢀ-diketones and aromatic aldehydes. The
microwave-assisted aldol condensations using boric acid was
already reported to synthesize curcumin [10, 11]. However,
the solid supported microwave synthesis of curcumin with
boron-assisted regioselective aldol condensation is not yet
investigated.
RESULTS AND DISCUSSION
Although curcumin is a simple symmetrical ꢀ- diketone,
its synthesis is complex and involves double aldol
condensation on 2, 4-pentadione (acetyl acetone) (2). Since
C3 of 2, 4-pentadione is more acidic than terminal C1 and C5
- methyl groups, it undergoes Knoevenagel condensation
leading to the formation of side products [22]. To overcome
this condensation, Boron-based protection is reported to
facilitate aldol condensations at C-1 and C-5 of acetyl
acetone. A boron-based reagent such as boric acid, DMF and
diethyl amine and acetic acid acts as Lewis acids with the ꢀ-
diketone systems and consequently reduces the
nucleophilicity of the C-3 position and the reaction occurs
selectively at the terminally active methylenes, resulting in
diarylheptanoids [23].
One of the major current challenges before chemists is to
develop synthetic methods that are less polluting, i.e., to
design clean or ‘green’ chemical transformations. An
important family of catalysts that has received considerable
attention of the synthetic chemist in recent times is derived
from the soil, i.e. clays and zeolites. During microwave
induction of reactions under dry conditions, the reactants
adsorbed on the surface of clay, absorb the microwaves and
accelerate the reaction.
More accessible, convenient and efficient inorganic solid
supports like silica gel, neutral alumina, and montmorillonite
K10 were chosen as catalysts. The organic compounds were
adsorbed on the surface of inorganic oxides which do not
absorb or restrict the transmission of microwaves [24]. These
clays were found to fasten the rate of reaction and thus
decrease the time of reaction by twice.
Clays are solid acidic catalysts which can function as
both Bronsted and Lewis acids in their natural and ion-
exchanged form. Modified smectite clays are very selective
for a wide range of organic transformations [12-16]. Clay
minerals are alluminosilicates and classified as
phyllosilicates, having layered structures comprising
tetrahedral silicate and octahedral aluminate sheets. Higher
acid strength of the catalyst generally leads to greater
catalytic activity, but poorer product selectivity [17-21].
Lewis acidity may persist under dehydrated conditions [21].
Here, the compounds were subjected to 640 MW power
with 10 sec interval leading to the completion of reaction.
Moderate to excellent yields of the desired compounds were
obtained when the reaction mixture was irradiated for 3-6
minutes by microwaves. The yields of the compounds made
in this investigation under microwave-assisted conditions are
consistently higher than those reported under conventional
conditions. The reaction times and % yields of various
curcumin derivatives at varied reaction conditions were
presented in Table 1.
In the present study, we designed a novel, green solid-
phase synthetic method (Scheme 1) for the preparation of
curcuminoids (3) using the microwave irradiation and
various clays like Alumina (neutral), Silica gel and
Montmorillonite K10 as catalysts. Several analogs of
curcumin were prepared (3a-e) from various substituted
aromatic aldehydes (1) using the novel method.
Table 1. Reaction Times and % Yield of Synthesized Compounds (3a-f)
O
O
R
R
Reaction Time (min)
% yielda
Silica
Compound
Code
Substitution R
Alumina
Silica
Montmorillonite K10
Alumina
Montmorillonite K10
3a
3b
3c
3d
3e
H
2.5
2.6
2.3
2.8
2.2
5.8
5.6
5.8
5.2
5.3
5.2
5.8
5.6
5.6
4.8
89
92
87
85
95
68
74
72
69
73
82
86
76
72
76
2-OH
3-OCH3
4-OCH3
4-Cl
aIsolated yields after column chromatography.

Solid-Phase Microwave Assisted Synthesis of Curcumin Analogs
Letters in Organic Chemistry, 2012, Vol. 9, No. 6
449
NMR spectra revealed that the compounds exist in enol
form in solution. The H-bonded hydroxyl proton of the enol
form expected in highly desheilded region (>ꢀ 13) was seen;
the active methine (-COCHCO-) of the diketo tautomer was
observed. Elemental analyses of these compounds were with
in +0.4 range from the calculated value.
309 (19.3), and 310 (3.9); Elemental analysis (cal/obser) C
74.01/74.06, H 5.23/5.21, O 20.76/20.73.
1, 7-Bis (3-methoxyphenyl) hept-1, 6-diene-3, 5-dione (3c)
Reddish brown gummy solid; C21H20O4; IR (cm-1, KBr):
3628 (enolic OH), 1720.24 (C=O), 1645.65 (C=C); 1H NMR
(400MHz, CDCl3, ꢀppm): 15.0 (s, 1H, enolic -OH), 7.66 (s,
1H, CH=C), 7.46 (s, 2H, Ar-H), 7.44 (s, 2H, Ar-H), 7.39 (d,
2H, Ar-H), 7.03 (s, 1H, CH=C), 6.95 (d, 2H, Ar-H), 6.85 (s,
1H, CH=C), 6.7 (s, 1H, CH=C), 6.65 (s, 1H, CH=C), 3.869
(s, 6H, 2-OCH3). MS (EI) 70eV, m/z (rel. intensity): 336
(M+, 100), 337 (23.7), and 338 (3.9); Elemental analysis
(cal/obser) C 74.98/74.92, H 5.99/5.99, O 19.03/19.66.
The enhanced yields and reduction in time with alumina
may be attributed to the acidic nature of alumina. The good
reaction conditions with K10 clay may be due to bulky
organic alkyl ammonium ion which carries out ion exchange
reactions with inorganic exchangeable cations between the
clay unit layers, leading to the increase of the distance
between the clay layers.
1, 7-Bis (4-methoxyphenyl) hept-1, 6-diene-3, 5-dione (3d)
Reddish brown gummy solid; C21H20O4; IR (cm-1, KBr):
3638 (enolic OH), 1705 (C=O), 1640 (C=C); 1H NMR
(400MHz, CDCl3, ꢀppm): 15.0 (s, 1H, enolic OH), 7.84 (d,
4H, Ar-H), 7.66 (s, 1H, CH=C), 7.03(s, 1H, CH=C), 7.0 (d,
4H, Ar-H), 6.85 (s, 1H, CH=C), 6.7 (s, 1H, CH=C), 6.65 (s,
1H, CH=C), 3.8 (s, 6H, 2-OCH3); MS (EI) 70eV, m/z (rel.
intensity): 336 (M+, 100), 337 (23.5), and 338 (2.7);
Elemental analysis (cal/obser) C 74.98/74.83, H 5.99/5.96, O
19.03/19.21.
EXPERIMENTAL
Melting points were recorded on an electro-thermal
apparatus and are uncorrected. Column chromatography
purifications were carried using silica gel (230-400 mesh)
obtained from Silicycle.1H NMR spectra were obtained
using a Bruker 400-MHz spectrophotometer in CDCl3, and
chemical shift values are expressed in ꢀ values (ppm)
relative to tetramethylsilane (TMS) as internal standard.
Reaction progress was monitored by analytical thin-layer
chromatography (TLC) on precoated glass plates (silica gel
60 F254 plate), and the spots were visualized by ultraviolet
(UV) light. The structures of novel compounds were
identified by infrared spectra obtained from Thermo Nicolet
Nexus 670 spectrometer and EI-MS spectra obtained from
CEC 21-110B sector instrument. CHN analyses were
recorded on a Vario EL analyzer.
1, 7-Bis (4-chlorophenyl) hept-1, 6-diene-3, 5-dione (3e)
Reddish brown gummy solid; C19H14Cl2O2; IR (cm-1,
KBr): 3648 (enolic OH), 1708 (C=O), 1660 (C=C); 1H
NMR (400MHz, CDCl3, ꢀppm): 15.0 (s, 1H, enolic OH),
7.82 (d, 4H, Ar-H), 7.66 (s, 1H, CH=C), 7.51 (d, 4H, Ar-H),
7.03 (s, 1-H, CH=C), 6.7 (s, 1H, CH=C), 6.85 (s, 1H,
CH=C), 6.65 (s, 1H, CH=C); MS (EI) 70eV, m/z (rel.
intensity): 344 (M+, 100), 346 (66.5), 345 (20.7), 347 (21.9);
Elemental analysis (cal/observed)
4.09/4.04, O 9.27/9.25.
C
66.10/66.25,
H
General Procedure for Synthesis of Compounds (3a-e)
10 mmole of acetyl acetone is reacted with 22 mmole of
various aromatic aldehydes in the presence of boric acid (10
mmoles) and diethyl amine: acetic acid (1:1) were subjected
to microwave irradiation in the presence of various catalysts
like Alumina (neutral), Silica gel and Montmorillonite K10
clay with 10s pulse at 640 MW, resulting in a reddish yellow
viscous liquid which, upon purification by column
chromatography, yielded reddish brown gummy solid.
CONCLUSION
A series of curcuminoid analogs (3a-e) was synthesized
on the solid support using microwave irradiation with boron
assisted regioselectivity. Among the used clays, Alumina
fastened the reaction and reduced the reaction times twice
when compared with others. All the reported compounds had
given the best yields with greater purity.
1, 7-Diphenylhept-1, 6-diene-3, 5-dione (3a)
Reddish brown gummy solid; C19H16O2; IR (cm-1, KBr):
3625 (enolic OH), 1708.24 (C=O), 1660.65 (C=C); 1H NMR
(400MHz, CDCl3, ꢀppm): 15.0 (br, 1H, enolic -OH), 7.66 (s,
1H, CH=C), 7.26–7.49 (m, 10H, Ar-H), 7.03 (s, 1H, CH=C),
6.85 (s, 1H, CH=C), 6.7 (s, 1H, CH=C), 6.65 (s, 1H, CH=C);
MS (EI) 70eV, m/z (rel. intensity): 276 (M+, 100), 277
(21.5), and 278 (2.7); Elemental analysis (cal/obser) C
82.58/82.54, H 5.84/5.86, O 11.58/11.60.
CONFLICT OF INTEREST
Declared none.
ACKNOWLEDGEMENT
Authors acknowledge the Secretary and Correspondent,
at Viswambhara Educational Society, for his encouragement
and also for providing facilities.
1, 7-Bis (2-hydroxyphenyl) hept-1, 6-diene-3, 5-dione (3b)
Reddish brown gummy solid; C19H16O4; IR (cm-1, KBr):
3630 (enolic OH), 1705.24 (C=O), 1670 (C=C); 1H NMR
(400MHz, CDCl3, ꢀppm) 15.0 (s, 1H, enolic -OH), 7.93 (s,
1H, CH=C), 7.13 (m, 2H, Ar-H), 6.97 (m, 2H, Ar-H), 6.92
(s, 1H, CH=C), 6.86 (s, 1H, CH=C), 6.84 (s, 1H, CH=C)
6.77-6.7 (m, 4H, Ar-H), 6.68 (s, 1H, CH=C), 4.11 (q, 2H,
Ar-OH). MS (EI) 70eV, m/z (rel. intensity): 308 (M+, 100),
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