Synthesis of novel 2,3-dihydro-4-pyridinones from bisdemethoxycurcumin under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2010.08.115

A novel synthesis of 2,3-dihydro-4-pyridinones via the reaction of bisdemethoxycurcumin and primary amines or amine acetates is demonstrated. The structures of the products were established by elemental analysis and from mass, ¹H and ¹³C NMR spectra.

Full text of DOI:10.1016/j.tetlet.2010.08.115

Tetrahedron Letters 51 (2010) 5798–5800
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Tetrahedron Letters
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Synthesis of novel 2,3-dihydro-4-pyridinones from bisdemethoxycurcumin
under microwave irradiation
Bahjat A. Saeed a, , Wisam A. Radhi a, Rita S. Elias b
⇑
a Department of Chemistry, College of Education, University of Basrah, Iraq
b Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basrah, Iraq
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2010
Revised 30 July 2010
Accepted 31 August 2010
Available online 9 September 2010
A novel synthesis of 2,3-dihydro-4-pyridinones via the reaction of bisdemethoxycurcumin and primary
amines or amine acetates is demonstrated. The structures of the products were established by elemental
analysis and from mass, 1H and 13C NMR spectra.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bisdemethoxycurcumin
Microwaves
Montmorillonite K-10
Dihydropyridones
Dihydropyridones are important intermediates for the synthe-
sis of natural products, particularly alkaloids, and have been inves-
tigated extensively as valuable building blocks for the construction
of piperidines, perhydroquinolines, indolizidines, quinolizidines,
and other alkaloid ring systems possessing a wide range of biolog-
ical and pharmacological properties.1–5 For their synthesis, the
addition of Grignard reagents to 1-acyl-4-methoxypyridinium 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 synthesised
novel dihydropyridones from the reaction of bisdemethoxycurcu-
min and primary amines or amine acetates.
The dihydropyridones were synthesized by microwave-assisted
reaction of bisdemethoxy-curcumin with either primary amines
(R = Me, Et or n-Pr) or amine acetates (R = n-Bu, n-pentyl, n-hexyl
or aromatic) in the presence of Montmorillonite K-10 as the cata-
lyst. The experimental procedure involved absorbing the reactants
on Montmorillonite K-10, then irradiating with microwaves. The
product was extracted from the clay with ethanol and the products
were separated by column chromatography and then by prepara-
tive TLC chromatography. The reaction time was 60 s and the
yields ranged from 18% to 38%. Attempts to enhance the yield using
longer reaction times were unsuccessful. The structures of the
dihydropyridones (Scheme 1) were confirmed by elemental analy-
sis and by mass, 1H and 13C NMR spectroscopy.
via cyclization of
a,b-unsaturated 1,3-diketones in acidic med-
ium14 and through catalytic metathesis of o-alkynylanilines and
15
aldehydes.
A facile route to functionalized dihydropyridones
has been developed involving formal [5C+1N] annulations of
a
-alkynoyl ketene-(S,S)-acetals with aliphatic amines.16 In addi-
tion, partial reduction of pyridinium salts has been exploited for
their synthesis.17 In this connection, we previously reported the
microwave-assisted formation of 2,3-dihydro-4-pyridinones from
curcumin and simple primary amines in the presence of Montmoril-
lonite K-10 via a transient imine.18 Bisdemethoxycurcumin is an
The 1H NMR spectra of the products showed two characteristic
singlets within the range 8.29–9.82 ppm assigned to the two OH
groups occupying different chemical environments, which proved
the asymmetrical structure of the products. In contrast the 1H
NMR spectrum of symmetrical bisdemethoxycurcumin contained
only one singlet within the same region. In addition, two doublets
of doublets were also apparent at about 2.40 ppm (J ꢀ 16 and 4 Hz)
and 2.80 ppm (J ꢀ 16 and 7 Hz), which were assigned to two gem-
inal 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 range 4.65–5.10 ppm. The protons of
the methylene groups in the N-alkyl-substituted compounds were
a
,b-unsaturated 1,3-diketone that constitutes one of the three
major components of the Indian herb Curcuma longa.19,20 In contin-
uation 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
⇑
Corresponding author
E-mail address: bahjat.saeed@yahoo.com (B.A. Saeed).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.115

B. A. Saeed et al. / Tetrahedron Letters 51 (2010) 5798–5800
5799
O
O
Data for (2a): Yellow powder (yield 38%), mp 254–255 °C. EI-
MS: m/z 321 (M+). 1H NMR (400 MHz, DMSO-d6) d 2.34 (dd,
J = 16.1 and 3.4 Hz, 1H, 2-H), 2.87 (dd, J = 16.1 and 7.2 Hz, 1H, 2-
H), 3.05 (s, 3H, N–CH3), 4.65 (m, 1H, 3-H), 5.10 (s, 1H, 6-H),
6.19–7.70 (m, 10H, olefinic + Ar), 9.41 (s, 1H, OH), 9.82 (s, 1H,
OH). 13C NMR (100 MHz, DMSO-d6) d 189.20, 157.67, 156.80,
142.19, 141.50, 136.81, 129.98, 128.82, 128.46, 127.90, 127.47,
124.87, 118.73, 115.88, 115.36, 99.52, 64.05, 42.88, 27.86. Anal.
Calcd for C20H19NO3: C, 74.57; H, 5.96; N, 4.36. Found: C, 74.83;
H, 5.58; N, 4.40.
1
HO
OH
RNH2 or amine acetate
Montmorillonite K-10
MW 400-800 W
R
Data for (2b): Yellow powder (yield 32%), mp 227–228 °C. EI-
MS: m/z 335 (M+). 1H NMR (400 MHz, DMSO-d6) d 1.09 (t,
J = 6 Hz, 3H, N–CH2–CH3), 2.35 (dd, J = 16 and 3.6 Hz, 1H, 2-H),
2.81 (dd, J = 16 and 6.8 Hz, 1H, 2-H), 3.08 (m, 1H, N–CH2), 3.75
(m, 1H, N–CH2), 4.71 (m, 1H, 3-H), 5.06 (s, 1H, 6-H), 6.70–7.77
(m, 10H, olefinic + Ar), 8.29 (s, 1H, OH), 9.48 (s, 1H, OH). 13C
NMR (100 MHz, DMSO-d6) d 189.21, 157.64, 156.67, 142.18,
141.19, 136.19, 129.38, 129.03, 128.32, 127.97, 127.49, 127.20,
124.92, 118.75, 115.88, 115.24, 99.47, 64.03, 42.88, 27.51, 15.33.
Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C,
75.38; H, 6.36; N, 4.02.
Data for (2c): Yellow powder (yield 26%), mp 221–222 °C. EI-
MS: m/z 349 (M+). 1H NMR (400 MHz, DMSO-d6) d 0.80 (t,
J = 6 Hz, 3H, N–CH2–CH2–CH3), 1.52 (m, 2H, N–CH2–CH2), 2.26
(dd, J = 16 and 3.6 Hz, 1H, 2-H), 2.83 (dd, J = 16 and 6.8 Hz, 1H, 2-
H), 3.09 (m, 1H, N–CH2), 3.73 (m, 1H, N–CH2), 4.70 (m, 1H, 3-H),
5.02 (s, 1H, 6-H), 6.67–7.48 (m, 10H, olefinic + Ar), 8.29 (s, 1H,
OH), 9.48 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6) d 186.68,
157.60, 157.01, 143.00, 141.51, 136.20, 129.14, 129.01, 128.25,
127.86, 127.52, 127.26, 124.81, 116.81, 115.72, 115.36, 99.12,
64.13, 42.67, 30.50, 26.68, 16.74. Anal. Calcd for C22H23NO3: C,
75.62; H, 6.63; N, 4.01. Found: C, 75.88; H, 6.56; N, 4.12.
Data for (2d): Yellow powder (yield 26%), mp 207–208 °C. EI-
MS: m/z 363 (M+). 1H NMR (400 MHz, DMSO-d6) d 0.83 (t, J = 6 Hz,
3H, N–(CH2)3–CH3), 1.25 (m, 2H, N–(CH2)2–CH2), 1.50 (m, 2H, N–
CH2–CH2), 2.32 (dd, J = 16 and 3.5 Hz, 1H, 2-H), 2.83 (dd, J = 16 and
6.8 Hz, 1H, 2-H), 2.96 (m, 1H, N–CH2), 3.77 (m, 1H, N–CH2), 4.70
(m, 1H, 3-H), 5.04 (s, 1H, 6-H), 6.70–7.76 (m, 10H, olefinic + Ar),
8.30 (s, 1H, OH), 9.51 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6) d
181.71, 160.39, 159.59, 156.75, 151.80, 137.08, 129.39, 129.27,
127.46, 118.08, 115.79, 115.19, 95.58, 60.25, 49.70, 42.81, 31.34,
19.24, 13.62. Anal. Calcd for C23H25NO3: C, 76.01; H, 6.93; N, 3.85.
Found: C, 75.81; H, 6.59; N, 4.02.
Data for (2e): Yellow powder (yield 23%), mp 107–108 °C. EI-
MS: m/z 377 (M+). 1H NMR (400 MHz, DMSO-d6) 0.59 (t, J = 6 Hz,
3H, N–(CH2)4–CH3), 1.18 (m, 4H, N–CH2–(CH2)2), 1.49 (m, 2H, N–
CH2–CH2), 2.26 (dd, J = 16.1 and 3.4 Hz, 1H, 2-H), 2.80 (dd,
J = 16.1 and 7 Hz, 1H, 2-H), 2.90 (m, 1H, N–CH2), 3.74 (m, 1H, N–
CH2), 4.66 (m, 1H, 3-H), 5.01 (s, 1H, 6-H), 6.55–7.47 (m, 10H, ole-
finic + Ar), 8.30 (s, 1H, OH), 9.51 (s, 1H, OH). 13C NMR (100 MHz,
O
N
HO
OH
O
H
1
H
6
2
3
5
4
N
H
R
HO
OH
2
2a= Me
2b= Et
2c= n-Pr
2d= n-Bu
2e= n-pentyl
2f= n-hexyl
2g= benzyl
2h= Ph
2i=3-FC6H4
2j=4-EtC6H4
Scheme 1. The mechanism, reaction conditions and prepared compounds.
diastereotopic, especially those directly attached to the nitrogen
atoms. The N–CH2-protons occurred as two distinct signals within
the ranges 2.90–4.14 and 3.73–4.18 ppm. This was confirmed by
HOMO-COSY and HETCOR spectroscopy. The 13C NMR spectra re-
vealed the C@O signals within the range 181.71–189.80 ppm. The
UV–vis spectra (ethanol) of the products were characterized by a
band within the range 334–342 nm, which was strongly blue-
shifted (ca. 70 nm) compared to the starting material which ap-
peared at 418 nm. This blue shift reflects the reduction of conjuga-
tion in the products due to participation of one of the olefinic
groups of bisdemethoxycurcumin in the ring-closure to give the
corresponding dihydropyridone.
For the synthesis of the dihydropyridones the method described
by Elias et al.18 was employed with minor modifications. Typically,
bisdemethoxycurcumin (2 g, 6.5 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 (6.5 mmol) was
added to the mixture, which was then thoroughly mixed. The mix-
ture was irradiated in a commercial microwave oven (Samsung
800 MW) for 60 s at 400 W (for amines) and 800 W (for amine ace-
tates). The extent of reaction was monitored by TLC using THF/
chloroform (30:70) as the eluent. On completion, the mixture
was extracted with EtOH (5 Â 3 mL). The Montnorillonite was re-
moved by filtration and the solvent was evaporated. The products
were separated by column chromatography (silica gel) using THF/
chloroform (1:5) as the eluent. The product fractions were further
separated by preparative TLC (silica gel) using the same eluent. The
dihydropyridones were obtained as yellow powders.
DMSO-d6) d 184.16, 160.27, 159.32, 157.02, 152.41, 137.07,
129.31, 129.20, 127.88, 118.08, 116.02, 115.21, 95.62, 60.24,
49.70, 42.83, 31.16, 19.25, 17.63, 12.67. Anal. Calcd for
C
24H27NO3: C, 76.36; H, 7.21; N, 3.71. Found: C, 75.98; H, 7.47;
N, 3.68.
Data for (2f): Yellow powder (yield 18%), mp 100–101 °C. EI-MS:
m/z 391 (M+). 1H NMR (400 MHz, DMSO-d6) d 0.77 (t, J = 6 Hz, 3H,
N–(CH2)5–CH3), 1.20 (m, 6H, N–CH2–(CH2)3), 1.51 (m, 2H, N–CH2–
CH2), 2.34 (dd, J = 16.2 and 3.8 Hz, 1H, 2-H), 2.83 (dd, J = 16.2 and
7.2 Hz, 1H, 2-H), 2.96 (m, 1H, N–CH2), 3.76 (m, 1H, N–CH2), 4.70
(m, 1H, 3-H), 5.04 (s, 1H, 6-H), 6.70–7.48 (m, 10H, olefinic + Ar),
8.35 (s, 1H, OH), 9.57 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6)
d 187.76, 160.39, 159.06, 156.62, 136.96, 129.50, 129.27, 127.50,
126.41, 118.44, 115.66, 115.16, 95.65, 60.22, 49.88, 42.32, 30.77,
29.03, 25.56, 21.91, 16.23. Anal. Calcd for C25H29NO3: C, 76.70; H,
7.47; N, 3.58. Found: C, 77.08; H, 7.28; N, 3.44.

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B. A. Saeed et al. / Tetrahedron Letters 51 (2010) 5798–5800
Data for (2g): Yellow powder (yield 18%), mp 139–140 °C. EI-
156.67, 142.18, 141.19, 136.19, 129.38, 129.03, 128.32, 127.97,
127.49, 127.20, 124.92, 119.75, 115.88, 99.47, 64.03, 42.88, 27.51,
15.33. Anal. Calcd for C27H25NO3: C, 78.81; H, 6.12; N, 3.40. Found:
C, 79.04; H, 6.02; N, 3.68.
In conclusion, we have synthesized new dihydropyridones
through the direct reaction of an a,b-unsaturated 1,3-diketone(bis-
demethoxycurcumin) with amines or amine acetates under micro-
wave irradiation in the presence of Montmorillonite K-10 as the
catalyst.
MS: m/z 397 (M+). 1H NMR (400 MHz, DMSO-d6) d 2.38 (dd,
J = 16 and 3.6 Hz, 1H, 2-H), 2.82 (dd, J = 16 and 7.1 Hz, 1H, 2-H),
4.14 (s, 1H, N–CH2), 4.18 (s, 1H, N–CH2), 4.68 (m, 1H, 3-H), 5.16
(s, 1H, 6-H), 6.19–7.25 (m, 15H, olefinic + Ar), 8.46 (s, 1H, OH),
9.39 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6) d 188.08, 160.45,
158.69, 156.68, 138.50, 137.25, 129.32, 129.09, 128.69, 128.22,
127.59, 127.22, 126.60, 118.58, 115.55, 115.24, 96.19, 60.40,
53.05, 42.66. Anal. Calcd for C26H23NO3: C, 78.57; H, 5.83; N,
3.52. Found: C, 78.78; H, 5.68; N, 3.31.
Data for (2h): Yellow powder (yield 21%), mp 129–130 °C. EI-
MS: m/z 383 (M+). 1H NMR (400 MHz, DMSO-d6) d 2.66 (dd,
J = 16.1 and 3.6 Hz, 1H, 2-H), 3.08 (dd, J = 16.1 and 6.4 Hz, 1H, 2-
H), 5.10 (m, 1H, 3-H), 5.38 (m, 1H, 6-H), 6.70–7.48 (m, 15H, ole-
finic + Ar), 8.35 (s, 1H, OH), 9.57 (s, 1H, OH). 13C NMR (100 MHz,
References and notes
1. Kuethe, J. T.; Commins, D. L. J. Org. Chem. 2004, 69, 5219.
2. Huang, S.; Commins, D. L. Chem. Commun. 2000, 569.
3. Kuethe, J. T.; Commins, D. L. Org. Lett. 2000, 2, 588.
4. Avenoza, A.; Busto, J. H.; Cativiela, C.; Corazana, F.; Peregrina, J. M.; Zurbano, M.
M. J. Org. Chem. 2002, 67, 598.
DMSO-d6)
d 187.19, 158.62, 157.13, 142.61, 138.78, 129.18,
128.38, 127.92, 125.08, 120.13, 119.51, 116.24, 99.86, 64.09,
42.78. Anal. Calcd for C25H21NO3: C, 78.31; H, 5.52; N, 3.65. Found:
C, 78.76; H, 5.58; N, 3.57.
5. Commins, D. L.; Goehring, R. R.; Joseph, S. P.; O’Connor, S. J. Org. Chem. 1990, 55,
2574.
6. Commins, D. L.; Hong, H. J. Org. Chem. 1993, 58, 5035.
7. Comins, D. L.; Hong, H. J. Am. Chem. Soc. 1993, 115, 8851.
8. Commins, D. L.; Fulp, A. B. Org. Lett. 1999, 1, 1031.
9. Young, D. W.; Commins, D. L. Org. Lett. 2005, 7, 5661.
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12. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321.
13. Alaimo, P. J.; O’Brien, R., III; Johanson, A. W.; Slauson, S. R.; O’Brien, J. M.; Tyson,
E. L.; Marshall, A. L.; Ottinger, C. E.; Chacon, G. J.; Wallace, L.; Paulino, C.;
Connel, S. Org. Lett. 2008, 10, 5111.
14. McDonald, F. K.; Burnell, D. J. J. Org. Chem. 2009, 74, 6973.
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Data for (2i): Yellow powder (yield 19%), mp 141–142 °C. EI-MS:
m/z 401 (M+). 1H NMR (400 MHz, DMSO-d6) d 2.34 (dd, J = 16.4 and
3.6 Hz, 1H, 2-H), 2.83 (dd, J = 16.4 and 6 Hz, 1H, 2-H), 4.70 (m, 1H,
3-H), 5.04 (s, 1H, 6-H), 6.70–7.48 (m, 14H, olefinic + Ar), 8.40 (s, 1H,
OH), 9.59 (s, 1H, OH). 13C NMR (100 MHz, DMSO-d6) d 189.80,
159.08, 156.99, 156.62, 146.24, 146.13, 136.43, 130.50, 129.12,
129.05, 127.56, 126.30, 121.03, 119.96, 115.75, 115.28, 112.21,
111.87, 111.65, 101.38, 63.92, 42.86. Anal. Calcd for C25H20FNO3:
C, 74.80; H, 5.02; N, 3.49. Found: C, 74.56; H, 5.10; N, 3.25.
Data for (2j): Yellow powder (yield 20%), mp 131–132 °C. EI-MS:
m/z 411 (M+). 1H NMR (400 MHz, DMSO-d6) d 1.12 (t, 3H, N–CH2–
CH3), 1.62 (m, 2H, N–CH2), 2.51 (dd, J = 16 and 3.7 Hz, 1H, 2-H),
3.09 (dd, J = 16 and 7.2 Hz, 1H, 2-H), 5.06 (m, 1H, 3-H), 5.39 (s,
1H, 6-H), 6.19–7.21 (m, 14H, olefinic + Ar), 8.38 (s, 1H, OH), 9.55
(s, 1H, OH). 13C NMR (100 MHz, DMSO-d6) d 189.21, 157.64,
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