Microwave-assisted synthesis of novel 2,3-dihydro-4-pyridinones

Article abstract of DOI:10.3390/molecules15118425

Novel 2,3-dihydro-4-pyridinones were synthesized via the reactionof curcumin and primary amines or amine acetates under microwave irradiation. Montmorillonite K-10 was used as a catalyst. Reaction times did not exceed 120 s. The structures of the compounds were established by elemental analysis and from their mass, ¹H- and ¹³C-NMR spectra.

Full text of DOI:10.3390/molecules15118425

Molecules 2010, 15, 8425-8430; doi:10.3390/molecules15118425
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Microwave-Assisted Synthesis of Novel
2,3-Dihydro-4-Pyridinones
Bahjat A. Saeed 1,*, Rita S. Elias 2 and Wisam A. Radhi 1
1
Department of Chemistry, College of Education, University of Basrah, Iraq
2
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basrah, Iraq
* Author to whom correspondence should be addressed; E-Mail: bahjat.saeed@yahoo.com;
Tel.: +964-0780-2410050.
Received: 22 October 2010; in revised form: 9 November 2010 / Accepted: 11 November 2010/
Published: 17 November 2010
Abstract: Novel 2,3-dihydro-4-pyridinones were synthesized via the reaction of curcumin
and primary amines or amine acetates under microwave irradiation. Montmorillonite K-10
was used as a catalyst. Reaction times did not exceed 120 s. The structures of the
1
compounds were established by elemental analysis and from their mass, H- and
13C-NMR spectra.
Keywords: curcumin; microwave-assisted synthesis; Montmorillonite K-10; dihydropyridones
1. Introduction
Dihydropyridones are important intermediates for the synthesis of natural products, particularly
alkaloids, and have been investigated extensively as valuable building blocks for the construction of
piperidines, perhydroquinolines, indolizidines, quinolizidines and other alkaloid ring systems possessing
a wide range of biological and pharmacological properties [1-5]. For their synthesis, the addition of
Grignard reagents to 1-acyl-4-methoxy pyridinium salts has been exploited by Commins [6-10]. Hetero-
Diels-Alder reactions or stepwise, formal [4+2] transformations involving imines have also been
employed [11-13]. Recently they have been synthesized via cyclization of α,β-unsaturated 1,3-diketones
in acidic medium [14] and through catalytic metathesis of o-alkynylanilines and aldehydes [15]. A facile
route to functionalized dihydropyridones has been developed via formal [5C+1N] annulations of
α-alkynoyl ketene-(S,S)-acetals with aliphatic amines [16]. In addition, partial reduction of pyridinium
salts has also been exploited for their synthesis [17]. We previously reported the microwave-assisted

8426
Molecules 2010, 15
formation of 2,3-dihydro-4-pyridinones from curcumin and simple primary amines in the presence of
Montmorillonite K-10 via a transient imine [18-19]. Curcumin is an α,β-unsaturated 1,3-diketone that
constitutes one of the three major components of the Indian herb Curcuma longa [20-21]. In
continuation of our interest in the reactions of unsaturated 1,3-diketones and amines for the synthesis
of dihydropyridones under microwave irradiation, we report herein the microwave-assisted synthesis
of novel dihydropyridones from the reaction of curcumin and primary amines or amine acetates. The
reported compounds had not previously been obtained by conventional methods.
2. Results and Discussion
The dihydropyridones were synthesized by microwave-assisted reaction of curcumin with either
primary amines (n-pentylamine) or amine acetates (all aromatic amines) in the presence of
Montmorillonite K-10 as the catalyst. The experimental procedure involved absorbing the reactants on
Montmorillonite K-10, then irradiating the mixture with microwaves. The product was extracted from
the clay with ethanol and the compounds were separated by column and then by preparative TLC
chromatography. The reaction time was 120 s and the yields ranged from 17 to 28%. Attempts to
enhance the yields by using longer reaction times proved unsuccessful. The dihydropyridones were
synthesized via transient imine mechanism (Scheme 1) and were confirmed by an elemental analysis
and by mass, 1H- and 13C-NMR spectroscopy.
Scheme 1. The mechanism, reaction conditions and prepared compounds.
O
O
MeO
HO
OMe
OH
1
RNH2 or amine acetate
Montmorillonite K-10
MW 800 W
R
O
N
MeO
HO
OMe
OH
O
1
6
2
3
5
MeO
HO
OMe
OH
4
N
R
2
2a= n-pentyl
2b= 3-MeC6H4
2c=diphenyl
2e= 4-EtC6H4
2f=3-FC6H4
2g= 4-OMeC6H4
2d=3,5-diMeC6H3 2h= pyrimidinyl

8427
Molecules 2010, 15
The 1H-NMR spectra of the products showed two singlets within the 8.91-9.04 and
9.38-99.44 ppm ranges assigned to the two OH groups occupying different chemical environments,
1
which proved the asymmetrical structure of the products. In contrast the H-NMR spectrum of
symmetrical curcumin contained only one singlet at 9.79 ppm for the OH group proton. The spectra
are also characterized by a one proton singlet in the 5.01-5.45 ppm range assigned to the H6 vinylic
proton. In addition, two doublets of doublets were also apparent within the 2.40-2.65 ppm
(J ≈ 16 and 4 Hz) and 2.80-3.07 ppm (J ≈ 16 and 7 Hz) range which were assigned to two geminal
protons (C-2) coupled to each other, as was confirmed by the HOMO-COSY spectra. Further, the
HETCOR spectra indicated that these protons were attached to the same carbon atom (C-2) and each
was coupled to the methine proton (3-H), which occurred as a multiplet within the 4.66-5.12 ppm
range. The protons of the methylene group attached to the nitrogen in the N-pentyl substituted compound
were diastereotopic, and appeared as two multiplets at 3.05 and 3.74 ppm. The HETCOR spectrum of
this compound showed that these signals belong to protons connected to the same carbon (C2) which has
13
a signal at 51.5 ppm. C-NMR spectra revealed the C=O signals within the 190.0-187.9 ppm range.
UV-vis spectra (in ethanol) of the products were characterized by a band within the 338-366 nm range,
which was strongly blue-shifted (ca. 60 nm) compared to curcumin whose band appears at 420 nm.
This blue shift reflects the reduction of conjugation in the products due to participation of one of the
olefinic groups of curcumin in the ring-closure to give the corresponding dihydropyridone.
3. Experimental
3.1. General
NMR spectra were recorded on a Bruker 400 MHz spectrometer in deuterated DMSO with
tetramethylsilane as an internal standard. Mass spectra were determined on a Shimadzu GCMS-QP
1000 EX instrument at 70 eV. Melting points were determined in open capillary tubes in a Buchi-510
apparatus. Elemental analyses were performed by Thermo Finnigan CHNS-O analyzer, 1112 series.
3.2. General Method for the Synthesis of Dihydropyridones
The method described by Elias et al. [18] was employed. Curcumin (2 g, 5.4 mmol) and
Montmorillonite K-10 (3 g) were mixed 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 then thoroughly
mixed. The mixture was irradiated in a commercial microwave oven (Samsung 800 MW) for 120 s at
800 W. The reaction protocol includes the irradiation of the reactants for 10 s then cooling to room
temperature and mixing. This was repeated until 120 s of reaction time were accumulated. The extent
of reaction was monitored by TLC using THF/chloroform (30:70) as eluent. On completion, the
mixture was extracted with EtOH (5 × 3 mL). The Montmorillonite was removed by filtration and the
solvent was evaporated. The products were separated by column chromatography (silica gel) using
THF/chloroform (1:5) as eluent. The product fractions were further separated by preparative TLC (silica
gel) using the same eluent. The dihydropyridones were obtained as yellow powders.
2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-1-pentyl-2,3-dihydropyridin-4(1H)-one
1
(2a). Yield 28%; m.p. 244-246 °C; EI-MS: m/z = 437 (M+); H-NMR δ 0.59 (t, J = 6.0 Hz, 3H,

8428
Molecules 2010, 15
N-(CH2)4-CH3), 1.18 (m, 4H, N-CH2-(CH2)2), 1.49 (m, 2H,N-CH2-CH2), 2.42 (dd, J = 16.0 and 4.0 Hz,
1H, 2-H), 2.84 (dd, J = 16.0 and 7.0 Hz, 1H, 2-H), 3.05 (m, 1H, NCH2),3.74 (s, 4H, NCH2 + OCH3),
3.82 (s, 3H, OCH3), 4.66 (m, 1H,3-H), 5.09 (s, 1H, 6-H), 6.65-7.29 (m, 8H, olefinic + Ar-H), 8.97 (s, 1H,
13
OH), 9.37 (s, 1H, OH); C-NMR δ 13.8, 21.8, 27.3, 28.7, 41.9, 51.5, 55.6, 55.7, 60.5, 95.8, 111.9,
112.3, 115.2, 115.4, 115.5, 119.0, 119.7, 121.7, 123.0, 127.2, 130.2, 131.6, 134.5, 135.3, 137.1, 145.0,
145.8, 146.7, 160.9, 187.9; Anal. Calcd. for C26H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.43;
H, 7.30; N, 3.16.
2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-1-m-tolyl-2,3-dihydropyridin-4(1H)-
one (2b). Yield 19%; m.p. 190 °C; EI-MS: m/z = 457 (M+); 1H-NMR δ 2.22 (s, 3H, Ar-CH3), 2.62 (dd,
J = 16 and 4 Hz, 1H, 2-H), 3.07 (dd, J = 16.0 and 6.0 Hz, 1H, 2-H), 3.70 (s, 3H, OCH3), 3.71 (s, 3H,
OCH3), 5.10 (m, 1H, 3-H), 5.43 (s, 1H, 6-H), 6.29-7.22 (m, 12H, olefinic + Ar-H), 8.96 (s, 1H, OH),
9.41 (s, 1H, OH); 13C-NMR δ 12.7, 17.6, 19.3, 31.2, 42.8, 49.7, 60.3, 95.8, 115.3, 116.0, 118.4, 127.9,
129.2, 129.3, 137.1, 153.4, 157.3, 159.3, 162.2, 189.2; Anal. Calcd. for C28H27NO5: C, 73.51; H, 5.95;
N, 3.06. Found: C, 73.36; H, 6.21; N, 2.86.
1-(biphenyl-4-yl)-2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-2,3-dihydropyridin-
1
4(1H)-one (2c). Yield 16%; m.p. 190 °C; EI-MS: m/z = 519 (M+); H-NMR δ 2.61 (dd, J = 16.4 and
4.4 Hz, 1H, 2-H), 3.04 (dd, J = 16.4 and 6.0 Hz, 1H, 2-H), 3.71 (s, 6H, OCH3), 5.03 (m, 1H, 3-H), 5.40 (s,
1H, 6-H), 6.30 (d, J = 16 Hz, 1H, olefinic-H), 6.85-7.22 (m, 15H, olefinic + Ar-H), 8.98 (s, 1H, OH), 9.46
13
(s, 1H, OH); C-NMR δ 43.1, 55.5, 55.6, 64.3, 98.4, 111.1, 115.2, 115.7, 116.8, 119.1, 119.9, 120.5,
120.9, 126.8, 128.8, 129.1, 130.4, 136.0, 141.5, 143.1, 145.8, 147.7, 148.2, 185.4, 189.1; Anal. Calcd.
for C33H29NO5: C, 76.28; H, 5.63; N, 2.70. Found: C, 77.08; H, 5.80; N, 2.86.
1-(3,5-dimethylphenyl)-2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-2,3-
1
dihydropyridin-4(1H)-one (2d). Yield 19%; m.p. 190 °C; EI-MS: m/z = 471 (M+); H-NMR δ 2.18 (s,
6H, Ar-CH3), 2.60 (dd, J = 16.4 and 3.2 Hz, 1H, 2-H), 3.07 (dd, J = 16.4 and 6.4 Hz, 1H, 2-H), 3.70 (s,
3H, OCH3), 3.71 (s, 3H, OCH3), 5.08 (m, 1H, 3-H), 5.42 (s, 1H, 6-H), 6.33 (d, J = 16.0 Hz, 1H,
olefinic-H), 6.70-6.97 (m, 9H, Ar-H), 7.19 (d, J =16.0, 1H, olefinic-H), 8.98 (s, 1H, OH), 9.38 (s, 1H,
13
OH); C-NMR δ 20.8, 42.7, 55.5, 55.6, 64.1, 100.2, 110.9, 111.2, 115.2, 115.7, 118.8, 120.8, 120.9,
122.7, 127.1, 130.1, 136.2, 138.1, 144.5, 145.7, 147.5, 147.7, 148.3, 157.4, 189.5; Anal. Calcd. for
C29H29NO5: C, 73.87; H, 6.20; N, 2.97. Found: C, 74.11; H, 6.04; N, 3.19.
1-(4-ethylphenyl)-2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-2,3-dihydropyridin-
4(1H)-one (2e). Yield 15%; m.p. 190 °C; EI-MS: m/z = 471 (M+); 1H-NMR δ 1.13 (t, J = 6.0 Hz, 3H,
Ar-CH2-CH3), 2.49 (q, J = 6.0 Hz, 2H, Ar-CH2), 2.54 (dd, J = 16.0 and 4.1 Hz, 1H, 2-H), 3.07 (dd,
J = 16 and 6 Hz, 1H, 2-H), 3.71 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 5.07 (m, 1H, 3-H), 5.40 (s, 1H,
6-H), 6.23 (d, J = 15.6 Hz, 1H, olefinic-H), 6.71-7.18 (m, 11H, olefinic + Ar-H), 9.0 (broad, 2H, OH);
13C- NMR δ 15.4, 27.5, 40.1, 42.9, 55.5, 55.6, 64.2, 99.6, 111.0, 111.1, 115.2, 115.8, 118.8, 120.0,
121.4, 125.1, 127.3, 128.3, 130.2, 136.5, 141.2, 142.2, 145.8, 147.6, 148.0, 157.9, 189.3; Anal. Calcd.
for C29H29NO5: C, 73.87; H, 6.20; N, 2.97. Found: C, 73.66; H, 6.32; N, 2.76.

8429
Molecules 2010, 15
1-(3-fluorophenyl)-2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-2,3-dihydropyridin-
1
4(1H)-one (2f). Yield 19%; m.p. 190 °C; EI-MS: m/z = 461 (M+); H-NMR δ 2.68 (dd, J = 16.6 and
4.0 Hz, 1H, 2-H), 3.07 (dd, J = 16.6 and 6.0 Hz, 1H, 2-H), 3.71 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 5.2
(m, 1H, 3-H), 5.47 (s, 1H, 6-H), 6.30 (d, J = 16.1 Hz, 1H, olefinic-H),6.60-7.38 (m, 11H, olefinic + Ar-H),
13
8.95 (s, 1H, OH), 9.36 (s, 1H, OH); C-NMR δ 42.8, 55.6, 64.2, 101.9, 110.9, 111.3, 121.1, 115.7,
118.8, 119.7, 120.5, 121.1, 127.0, 129.8, 130.4, 136.8, 145.8, 146.2, 147.6, 147.8, 148.3, 157.1, 160.8,
163.2, 190; Anal. Calcd. for C28H27NO5: C, 70.27; H, 5.24; N, 3.04. Found: C, 70.36; H, 5.40; N, 2.82.
2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-1-(4-methoxyphenyl)-2,3-
dihydropyridin-4(1H)-one (2g). Yield 17%; m.p. 190 °C; EI-MS: m/z = 473 (M+). 1H-NMR δ 2.65 (dd,
J = 16.0 and 4.0 Hz, 1H, 2-H), 3.08 (dd, J = 16.0 and 6.0 Hz, 1H, 2-H), 3.71 (s, 6H, 2 × OCH3), 3.72
(s, 3H, OCH3), 5.07 (m, 1H, 3-H), 5.42 (s, 1H, 6-H), 6.29 (d, J = 16.0 Hz, 1H, olefinic-H), 6.60-7.22 (m,
13
11H, olefinic + Ar-H), 8.93 (s, 1H, OH), 9.40 (s, 1H, OH); C-NMR δ 40.0, 42.7, 55.6, 55.7, 64.8,
99.7, 111.0, 111.4, 115.3, 115.8, 119.0, 120.0, 121.2, 125.5, 127.5, 128.2, 130.4, 136.5, 141.2, 142.6,
146.0, 147.7, 148.3, 157.9, 189.5; Anal. Calcd. for C28H27NO5: C, 71.02; H, 5.75; N, 2.96. Found: C,
72.21; H, 5.60; N, 2.67.
2-(4-hydroxy-3-methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-1-(pyrimidin-4-yl)-2,3-dihydropyridin-
1
4(1H)-one (2h). Yield 18%; m.p. 190 °C; EI-MS: m/z = 445 (M+); H-NMR δ 2.65 (dd, J = 16.2 and
4.1 Hz, 1H, 2-H), 3.08 (dd, J = 16.2 and 6.0 Hz, 1H, 2-H), 3.71 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
5.06 (m, 1H, 3-H), 5.46 (s, 1H, 6-H), 6.29 (d, J = 16.0 Hz, 1H, olefinic-H),6.67-7.47 (m, 11H, olefinic
13
+ Ar-H), 9.06 (s, 1H, OH), 9.46 (s, 1H, OH); C-NMR 42.9, 55.6, 55.7, 64.6, 101.8, 110.9, 111.4,
121.3, 116.0, 118.8, 119.4, 120.7, 121.8, 125.6, 127.1, 130.6, 136.7, 146.4, 147.7, 148.1, 148.4, 158.1,
161.0, 163.7, 164.4, 190.0; Anal. Calcd. for C25H273NO5: C, 67.02; H, 5.20; N, 9.43. Found: C, 67.64;
H, 5.29; N, 9.63.
4. Conclusions
In conclusion, this work has demonstrated the positive role of microwave irradiation in the
synthesis of dihydropyridones from the reaction of curcumin and simple amines which could not be
performed under traditional heating conditions.
References
1. Kuethe, J.T.; Commins, D.L. Tandem Diels-Alder cyclization/aromatization reactions of 5-vinyl-
1-acyl-2-aryl-2,3-dihydropyridones. Tetrahedron Lett. 2004, 69, 4179-4182.
2. Commins, D.L.; Sahn, J.J. A six-step asymmetric synthesis of (+)-hyperaspine. Org. Lett. 2005, 7,
5227-5228.
3. Saeed, B.A.; Saour, K.Y.; Elias, R.S.; Xiaodi D. Crystal structure of 2-(4-hydroxy-3-
methoxyphenyl)-6-(4-hydroxy-3-methoxystyryl)-1-methyl-2,3-dihydropyridine-4(1H)-one by x-
ray powder diffraction. Am. J. Appl. Sci. 2010, 7, 916-919.
4. Avenoza, A.; Busto, J.H.; Cativiela, C.; Corazana, F.; Peregrina, J.M.; Zurbano, M.M.
Asymmetric Hetero Diels-Alder as an access to Carbacephams. J. Org. Chem. 2002, 67, 598-601.

8430
Molecules 2010, 15
5. Saeed, B.A.; Saour, K.Y.; Elias, R.S.; Al-Masoudi, N.A.; La Cola, P. Antitumor and quantitative
structure activity relationship study for dihydropyridones derived from curcumin. Am. J. Immun.
2010, 6, 7-10.
6. Comins, D.L.; Zhang, Y.; Joseph, S.P. Enatiopore N-acyldihydropyridones as synthetic
intermediates: Asymmetric synthesis of benzomorphans. J. Org. Chem. 1999, 1, 657-659.
7. Comins, D.L.; Kueth, J.T.; Hong, H.; Lakner, F.J. Diastereoselective addition of prociral metallo
enolates to chiral 1-acylpyridinium salts. J. Am. Chem. Soc. 1999, 121, 2651-2651.
8. Comins, D.L.; Ollinger, G.C. Inter- and intra molecular Horner-Wadsworth-Emmos reactions of
5-(dirthoxyphosphoryl)-1-acyl-2-alkyl(aryl)-2,3-dihydropyridones. Tetrahedron Lett. 2001, 42,
4115-4118.
9. Young, D.W.; Comins, D.L. Tandem directlithiations of N-Boc-1,2-dihydropyridine toward
highly functionalized 2,3-dihydro-4-pyridones. Org. Lett. 2005, 7, 5661-5664.
10. McCall, W.S.; Grillo, T.A.; Comins, D.L. N-acyldihydropyridones as synthetic intermediates. A
sterioselective synthesis of acyclic amino alcohols containing multiple chiral centers. J. Org.
Chem. 2008, 73, 9744-9751.
11. Waldman, H.; Braun, M. Asymmetric tandem Mannich-Michael reactions of amino acid ester
imines with Danishefsky’s diene. J. Org. Chem. 1992, 57, 4444-4451.
12. Huang, Y; Rawal, V.H. Hetero Diels-Alder reactions of 1-amino-3-siloxy-1,3-butadienes under
strictly thermal additions. Org. Lett. 2000, 2, 3321-3323.
13. Alaimo, P.J., O’Brien, R.; Johanson, A.W.; Slauson, S.R.; O’Brien, J.M. Sustainable synthetic
methods: domino construction of dihydropyridin-4-ones and β-amino esters in aqueous ethanol.
Org. Lett. 2008, 10, 5111-5114.
14. Mc Donald, F.K., Burnell, D.J. 2,3-dihydro-4H-pyran-4-ones and 2,3-dihydro-4-pyridinones by
cyclizations of α,β-unsaturated 1,3-diketones. J. Org. Chem. 2009, 74, 6973-6979.
15. Saito, A.; Kasai, J.; Odaira, Y.; Fukaya, H.; Hanzawa, Y. Synthesis of 2,3-dihydroquinolin-4(1H)-
ones through catalytic metathesis of o-alkynylanilines and aldehydes. J. Org. Chem. 2009, 74,
5644-5647.
16. Dong, D.; Bi, X.; Liu, Q.; Cong, F. A novel synthesis strategy of functionalized 2,3-dihydro-4-
pyridones. Chem. Commun. 2005, 3580-3582.
17. Donhoe, T.J.; Conolly, M.J.; Walton, L. Regioselective nucleophilic addition to pyridinium salts:
A new rout to substituted dihydropyridones. Org. Lett. 2009, 11, 5562-5565.
18. Elias, R.S.; Saeed, B.A.; Saour, K.Y.; Al-Masoudi, N.A. Microwave assisted synthesis of
dihydropyridones derived from curcumin. Tetrahedron Lett. 2008, 49, 3049-3051.
19. Saeed, B.A.; Radhi, W.A.; Elias, R.S. Synthesis of novel 2,3-dihydro-4-pyridinones from
bisdemethoxycurcumin under microwave irradiation. Tetrahedron Lett. 2010, 51, 2798-2880.
20. Portes, E.; Gardart, C.; Castellan, A. A comparative study on the antioxidant properties of
tetrahydrocurcuminoids and curcuminoids. Tetrahedron 2007, 63, 9092-9099.
21. Scotter, M.J. Synthesis and chemical characterization of curcuminoides coloring principles for
their potential use as HPLS standards for the determination of curcumin color in food. J. Food
Sci. Tech. 2009, 42, 1345-1351.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).