Microwave-assisted synthesis of dihydropyridones from curcumin

Article abstract of DOI:10.1016/j.tetlet.2008.03.064

Dihydropyridones were prepared by microwave-assisted reaction between curcumin and primary amines or their acetates in the presence of Montmorillonite (K-10) as a catalyst. The reaction was complete within a few minutes and the yield depends on the amine used.

Full text of DOI:10.1016/j.tetlet.2008.03.064

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3049–3051
Microwave-assisted synthesis of dihydropyridones from curcumin
Rita S. Elias a, Bahjat A. Saeed b,*, Kawkab Y. Saour c, Najim A. Al-Masoudi d
a College of Pharmacy, University of Basra, Basra, Iraq
b Department of Chemistry, College of Education, University of Basra, Basra, Iraq
c College of Pharmacy, University of Baghdad, Baghdad, Iraq
d Fachbereich Chemie, Universitat Konstanz, Postfach 5560, D-78457 Konstanz, Germany
Received 19 September 2007; revised 26 February 2008; accepted 14 March 2008
Available online 16 March 2008
Abstract
Dihydropyridones were prepared by microwave-assisted reaction between curcumin and primary amines or their acetates in the
presence of Montmorillonite (K-10) as a catalyst. The reaction was complete within a few minutes and the yield depends on the amine
used.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Curcumin; Dihydropyridones; Montmorillonite K-10; Microwave
1. Introduction
absorbing the reactants on Montmorillonite K-10, then
irradiating the mixture with microwaves. The products
were extracted with a suitable solvent. The reaction times
ranged from 50 to 120 s and the yields ranged from 7%
to 41%. The structures of the dihydropyridones (Scheme
1) were confirmed by an elemental analysis and by 1H
NMR, 13C NMR and MS analyses. The products were also
characterized by comparison with 2,3-dihydro-1,2-diphen-
yl-6-(2-phenylethenyl)-4-pyridone that was prepared by
Sugiyama et al.21 from the reaction of 6-methyl-1,2-diphen-
yl-2,3-dihydro-4-pyridone with benzaldehyde.
Dihydropyridones are important intermediates for the
synthesis of natural products, particularly alkaloids, and
many approaches to their synthesis have been devel-
oped.1–5 In general, two main approaches are used for their
preparation (a) from acyclic precursors6–11 and (b) from
pyridines.11,12
Curcumin is a yellow pigment and an active component
of turmeric powder extracted from Curcuma longa L. As
well as being anti-inflammatory, extensive research has
revealed that this polyphenol can both prevent and treat
cancer.13–20
In this work, we report on the synthesis of dihydropyr-
idones from the reaction of curcumin and amines or amine
acetates under microwave irradiation, an approach, that to
our knowledge, has not been previously undertaken.
The dihydropyridones were prepared by microwave-
assisted reaction of curcumin with either primary amines
(in the case of aliphatic amines) or the amine acetate (in
the case of aromatic amines) in the presence Montmorillon-
ite K-10 as a catalyst. The experimental procedure involved
The 1H NMR spectra of the products were characterized
by two singlets for both the OMe and OH groups, while the
spectrum of curcumin22 contained only one singlet for each
of these groups. This indicates that the products are non-
symmetrical in comparison with the symmetric curcumin.
In addition, characteristic signals due to the nitrogen-
containing heterocyclic ring were present.
1
For compound 1 (as an example), the H NMR spec-
trum showed two doublets of doublets at 2.42 ppm
(J = 16 Hz and 4 Hz) and 2.84 ppm (J = 16 Hz and 7 Hz)
due to the two (geminal) methylene protons (3-H) that cou-
pled with each other as confirmed by the HOMO-COSY
spectrum. Further, the HETCOR spectrum indicated that
these protons were attached to the same carbon atom
*
Corresponding author. Tel.: +964 0780 2410050.
E-mail address: bas_chem_dep@yahoo.com (B. A. Saeed).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.064

3050
R. S. Elias et al. / Tetrahedron Letters 49 (2008) 3049–3051
O
O
then stirred for 24 h. The reaction mixture was then irradi-
ated in a commercial microwave oven (Samsung 800 MW)
for 50–120 s at 400 W in the case of the aliphatic amines
and at 800 W in the case of amine acetates. The extent of
the reaction was monitored by TLC using ethanol–chloro-
form 4:96 as an eluent. On completion, the mixture was
extracted with ethanol, Montmorillonite K-10 was filtered
off and the solvent was removed by rotary evaporation.
The products were separated by column chromatography
(silica gel) using a mixture of THF chloroform 1:5 as an
eluent. The product fractions were further purified by a
preparative TLC (silica gel) using ethanol–chloroform
4:96 as an eluent. The dihydropyridones were collected as
yellow, sparingly soluble (in most solvents), powders.
MeO
OMe
OH
HO
RNH2 or amine acetate/
Montmorillonite K-10
MW 400-800 W
R
O
N
MeO
HO
OMe
OH
2.1. Data for ð1Þ
Yellow powder (yield 41%) mp 244–246 °C. EI-MS: m/z
1
381 (M +), CIMS: m/z 382 (M+1)+. H NMR (600 MHz,
O
H
DMSO-d6) d 2.42 (dd, J = 16 and 4 Hz, 1H, 3-H), 2.84
(dd, J = 16 and 7 Hz, 1H, 3-H), 3.05 (s, 3H, N–CH3),
3.74 (s, 3H O–CH3), 3.82 (s, 3H, O–CH3), 4.66 (m, 1H,
2-H), 5.09 (s, 1H, 5-H), 6.65–7.29 (m, 8H, olefinic +
Ar-H), 8.97 (s, 1H, OH), 9.37 (s, 1H, OH). Anal. Calcd
for (381) C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found:
C, 68.88; H, 6.39; N, 3.36.
H
4
5
3
2
H
6
MeO
HO
OMe
1
N
R
OH
1 R= Me
2 R= Et
3 R= n-Pr
5 R= n-hexyl
6 R= benzyl
7 R= phenyl
8 R= p-tolyl
2.2. Data for ð2Þ
4 R= n-Bu
Yellow powder (yield 23%). Mp 218–220 °C. CIMS:
m/z = 396 (M+1)+. 1H NMR (600 MHz, DMSO-d6) d
1.10 (t, J = 6 Hz, 3H, N–CH2–CH3), 2.42 (dd, J = 16 and
4 Hz, 1H, 3-H), 2.80 (dd, J = 16 and 7 Hz, 1H, 3-H),
3.07 (m, 1H, N–CH2), 3.74 (s, 3H, OCH3), 3.80 (m, 1H,
N–CH2), 3.82 (s, 3H, OCH3), 4.73 (m, 1H, 2-H), 5.06 (s,
1H, 5-H), 6.65–7.27 (m, 8H, olefinic + Ar), 8.93 (s, 1H,
OH), 9.36 (s, 1H, OH). Anal. Calcd for (395)
C23H25NO5: C, 69.85; H, 6.37; N, 3.54. Found: C, 69.54;
H, 6.73; N, 3.21.
Scheme 1.
(C-3). Each of these protons was coupled to the methine
proton (2-H), which occurred as a multiplet at 4.66 ppm
as confirmed by the COSY spectrum. The proton spectrum
of 1 also contained a vinylic singlet at 5.09 ppm, which
appeared at 6 ppm in the spectrum of curcumin. The
olefinic protons of the disubstituted alkene and aromatic
protons occurred as a multiplet at 6.65–7.29 ppm, while
in curcumin the alkene protons appeared as two doublets
(4H). The 13C NMR spectrum confirmed the presence of
two OMe groups at 55.3 and 55.5 ppm, and two C–OH
groups at 145.8 and 147.6 ppm. Compounds 2–8 provided
similar spectral data.
In this work, it was demonstrated that the synthesis of
dihydropyridones can be achieved by the direct reaction
of curcumin with amines or amine acetates under micro-
wave irradiation in the presence of Montmorillonite K-10
as a catalyst.
2.3. Data for ð3Þ
Yellow powder (yield 16%), mp 205–207 °C. CIMS:
m/z = 410 (M+1)+. 1H NMR (600 MHz, DMSO-d6) d
0.83 (t, J = 6 Hz, 3H, N–(CH2)2–CH3), 1.55 (m, 2H, N–
CH2–CH2), 2.47 (dd, J = 16 and 4 Hz, 1H, 3-H), 2.83
(dd, J = 16 and 7 Hz, 1H, 3-H), 2.92 (m, 1H, N–CH2),
3.74 (s, 3H, OCH3), 3.77 (m, 1H, N–CH2), 3.82 (s, 3H,
OCH3), 4.74 (m, 1H, 2-H), 5.05 (s, 1H, 5-H), 6.64–7.29
(m, 8H, olefinic + Ar-H), 8.96 (s, 1H, OH), 9.41 (s, 1H,
OH). Calcd for (409) C24H27NO5: C, 70.39; H, 6.64; N,
3.42. Found: C, 69.92; H, 6.90; N, 3.25.
2. Typical procedure for the preparation of dihydropyridones
Curcumin (2 g, 5.4 mmol) and Montmorillonite K-10
(3 g) were mixed thoroughly in a mortar and placed in a
10 mL beaker. The appropriate amount of amine or amine
acetate (5.4 mmol) was added to the mixture, which was
2.4. Data for ð4Þ
Yellow powder (yield 16%), mp 122 °C. CIMS:
m/z = 424 (M+1)+. 1H NMR (600 MHz, DMSO-d6) d

R. S. Elias et al. / Tetrahedron Letters 49 (2008) 3049–3051
3051
0.83 (t, J = 6 Hz, 3H, CH2–CH3), 1.26 (m, 2H, CH2–CH3),
2.8. Data for ð8Þ
1.52 (m, 2H, N–CH2–CH2), 2.44 (dd, J = 16 and 4 Hz, 1H,
3-H), 2.82 (dd, J = 16 and 7 Hz, 1H, 3-H), 2.98 (m, 2H, N–
CH2), 3.73 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.72 (m,
1H, 2-H), 5.05 (s, 1H, 5-H), 6.67–7.27 (m, 8H, ole-
finic + Ar-H), 8.93 (s, 1H, OH), 9.37 (s, 1H, OH). Anal.
Calcd for (423) C25H29NO5: C, 70.90; H, 6.90; N, 3.31.
Found: C, 70.77; H, 7.22; N, 2.92.
Yellow powder (yield 14%) mp 190 °C. EI-MS: m/z =
1
457 (M+). H NMR (300 MHz, DMSO-d6) d 2.26 (s, 3H,
Ar-CH3), 2.65 (dd, J = 16 and 4 Hz, 1H, 3-H), 3.08 (dd,
J = 16 and 6 Hz, 1H, 3-H), 3.71 (s, 3H, OCH3), 3.72 (s,
3H, OCH3), 5.08 (s, 1H, 2-H), 5.42 (s, 1H, 5-H), 6.29 (d,
J = 16 Hz, 1H, olefinic-H), 6.60–7.22 (m, 11H, olefinic +
Ar-H), 8.96 (s, 1H, OH), 9.41 (s, 1H, OH). Anal. Calcd
for (457) C28H27NO5: C, 73.51; H, 5.95; N, 3.06. Found:
C, 73.36; H, 6.21; N, 2.86.
2.5. Data for ð5Þ
Yellow powder (yield 7%) mp 130 °C. CIMS: m/z = 452
(M+1)+. 1H NMR (250 MHz, DMSO-d6) d 0.78 (t,
J = 6 Hz, 3H, CH2–CH3), 1.21 (m, 6H, (CH2)3–CH3),
1.56 (m, 2H, N–CH2–CH2), 2.40 (dd, J = 16 and 4 Hz,
1H, 3-H), 2.82 (dd, J = 16 and 7 Hz, 1H, 3-H), 2.99 (m,
2H, N–CH2), 3.74 (s, 3H, OCH3), 3.80 (s, 3H, OCH3),
4.71 (m, 1H, 2-H), 5.05 (s, 1H, 5-H), 6.65–7.24 (m, 8H, ole-
finic + Ar-H). The OH protons could not be seen in the
spectrum of this compound. Anal. Calcd for (452)
C27H33NO5: C, 71.82; H, 7.37; N, 3.10. Found: C, 71.92;
H, 7.69; N, 2.85.
References and notes
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2.6. Data for ð6Þ
Yellow powder (yield 13%) mp 128 °C. CIMS:
m/z = 458 (M+1)+. 1H NMR (250 MHz, DMSO-d6) d
2.40 (dd, J = 16 and 4 Hz, 1H, 3-H), 2.82 (dd, J = 16
and 7 Hz, 1H, 3-H), 3.71 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 4.20 (s, 2H, N–CH2), 4.72 (m, 1H, 2-H), 5.18 (s,
1H, 5-H), 6.71–7.37 (m, 13H, olefinic + Ar-H), 9.00 (s,
1H, OH), 9.43 (s, 1H, OH). Anal. Calcd for (457)
C28H27NO5: C, 73.51; H, 5.95; N, 3.06. Found: C, 73.08.;
H, 6.22; N, 2.87.
2.7. Data for ð7Þ
Yellow powder (yield 13%) mp 111 °C. EI-MS:
m/z = 443 (M) +. H NMR (300 MHz, DMSO-d6) d 2.60
1
(dd, J = 16 and 4 Hz, 1H, 3-H), 3.00 (dd, J = 16 and
6 Hz, 1H, 3-H), 3.70 (s, 3H, OCH3), 3.71 (s, 3H, OCH3),
5.08 (m, 1H, 2-H), 5.42 (s, 1H, 5-H), 6.70–7.36 (m, 13H,
olefinic + Ar-H). The OH protons could not be seen in
the spectrum of this compound. Anal. Calcd for (443)
C27H25NO5: C, 73.12; H, 5.68; N, 3.16. Found: C, 72.98;
H, 5.93; N, 2.92.