Synthesis of 4,5,6-trisubstituted 2,3-pyridinediones via Mannich reaction and oxidation-Michael addition of 3-hydroxy-2(1H)-pyridinones

Article abstract of DOI:10.1007/s11164-012-0495-z

4-Substituted 3-hydroxy-2(1H)-pyridinones 2 were prepared by Mannich reaction of 3-hydroxy-2(1H)-pyridinones with secondary amines and formaldehyde. The isolated products were then reacted with aromatic amines in the presence of NaIO₃ as oxidan

Full text of DOI:10.1007/s11164-012-0495-z

Res Chem Intermed (2012) 38:1699–1705
DOI 10.1007/s11164-012-0495-z
Synthesis of 4,5,6-trisubstituted 2,3-pyridinediones
via Mannich reaction and oxidation–Michael addition
of 3-hydroxy-2(1H)-pyridinones
•
Wen Lin Xie Chuang Ping Xiao Ling Xie
•
•
•
Ying Zhou Xue Feng Li Xu Fu Tang
•
•
•
Chun Tao Yuan Ming Hua Qiu
Received: 27 October 2011 / Accepted: 19 January 2012 / Published online: 3 February 2012
Ó Springer Science+Business Media B.V. 2012
Abstract 4-Substituted 3-hydroxy-2(1H)-pyridinones 2 were prepared by Man-
nich reaction of 3-hydroxy-2(1H)-pyridinones with secondary amines and formal-
dehyde. The isolated products were then reacted with aromatic amines in the
presence of NaIO3 as oxidant via oxidation–Michael addition to yield 4,5,6-tri-
substituted-2,3-pyridinediones 3 in good yields (80.2–88.9%). The structures of the
1
products were characterized by H NMR, ESI-MS, and IR, and elemental analysis.
Keywords Pyridinone Á Mannich reaction Á Oxidation Á Michael addition
Introduction
Pyridinones are an interesting class of heterocycles. The pyridinone ring system is
found abundantly in a wide variety of naturally occurring alkaloids and novel
synthetic biologically active molecules [1–3], many of which have biological activity
[4]. For example, 3-hydroxy-2(1H)-pyridinones and 3-hydroxy-4(1H)-pyridinones
are of medicinal interest as bidentate chelators with high affinity for metal-ions in
high oxidation states [5–8]. The specific chelator 1,2-dimethyl-3-hydroxy-4(1H)-
pyridinone, under the name deferiprone, is used clinically for treatment of iron
overload, although toxic effects are now known [9]. The synthesis of less toxic
derivatives and of oligodentate chelators by covalent coupling of these moieties is
currently under investigation by organic chemists. Herein, we report a simple,
convenient two-step synthesis of 4,5,6-trisubstituted 2,3-pyridinediones
3
W. L. Xie (&) Á C. P. Xiao Á L. Xie Á Y. Zhou Á X. F. Li Á X. F. Tang Á C. T. Yuan Á M. H. Qiu
Key Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education,
Hunan Provincial University Key Laboratory of QSAR/QSPR, School of Chemistry and Chemical
Engineering, Hunan University of Science and Technology, Xiangtan 411201, China
e-mail: xwl2003zsu@yahoo.com.cn
123

1700
W. L. Xie et al.
(Scheme 1) from commercially available starting materials 3-hydroxy-2(1H)-
pyridinone 1 by Mannich and oxidation–Michael addition reaction.
Results and discussion
The 4,5,6-trisubstituted-2,3-pyridinediones were synthesized in good yields by the
oxidation–Michael addition of aromatic amines to 4-substituted-3-hydroxy-2(1H)-
pyridinones in the presence of the oxidant NaIO3 at room temperature. The intermediate
product 4-substituted-3-hydroxy-2(1H)-pyridinones were obtained by Mannich reac-
tion of 3-hydroxy-2(1H)-pyridinones with secondary amines and formaldehyde at
45 °C. The structures of the products formed were supported by results from elemental
analysis and by spectral data (IR, NMR, and MS). The IR spectrum of 3d revealed the
presence of two carbonyl stretching vibration bands at 1,724 and 1,655 cm-1; an
absorption peak at 3,363 cm-1 indicated the presence of N–H stretching vibration. The
mass spectrum of 3d contained a molecular ion peak at m/z 419.3 ([M ? H]?), which
indicates addition of the aromatic amine to the 4-substituted-3-hydroxy-2(1H)-
1
pyridinones. The H NMR spectrum of 3d contained a multiplet in the region d
2.06–2.08 and a broad singlet at d 3.53 resulting from the eight protons of four
methylenes of the morpholine ring, two singlets at d 2.35 and 3.35 from two methyl
protons and methylene protons, several multiplets in the region d 6.77–7.26 from
aromatic protons, and two singlets at d 8.23 and 9.23 assigned to the two NH protons.
The 13C NMR spectrum of the product 3d contained signals from three methylene
carbons at d 50.6, 52.5 and 66.8, and two carbonyl carbons at d 157.8 and 173.7.
A plausible mechanism of the reaction from compound 2 to compound 3 is
outlined in Scheme 2. Compound 2 was first oxidized to an active ortho-quinone
intermediate which then suffers nucleophilic attack by the aromatic amine to give
the Michael adduct. The adduct was, again, oxidized to another active ortho-
quinone intermediate, which then suffered secondary nucleophilic attack by the
aromatic amine to give another Michael adduct intermediate which subsequently
underwent fast oxidation to produce product 3.
R1
R
R
R1
NH2
HN
HN
O
O
OH
O
OH
O
HR, HCHO
N
N
H
NaIO3, CH3OH/H2O
N
H
1
2
3
R1
3a:
3e:
R1=p-CH3O
R1=p-Cl
R1=H
N
O
R1=p-Cl
R=
R=
R=
N
N
N
N
R=
R=
R=
R=
2a:
2b:
2c:
N
R=
R=
R=
3f:
3b:
3c:
3d:
R1=p-CH3
R1=H
N
N
O
O
N
O
3g:
N
R1=p-CH3
O
N
3h:
R1=p-Cl
R=
Scheme 1 Synthetic routes to 4,5,6-trisubstituted 2,3-pyridinediones 3a–h
123

Mannich reaction and oxidation–Michael addition
1701
R
H2N
R
R
H
N
R
R
O
O
R
OH
[O]
H
O
O
[O]
NaIO3
OH
O
N
R
N
O
H
N
H
NH2
N
N
H-
R
2
R
R
R
R
H
N
R
R
H
N
O
O
[O]
N
H
N
OH
N
H
N
O
H
H-
3
Scheme 2 A plausible mechanism of reaction from compound 2 to compound 3
Experimental
Melting points were determined in open capillaries and were uncorrected. IR spectra
were recorded on a PE-2000 spectrometer in KBr pellets and are reported in cm-1
All NMR spectra were recorded on a Bruker AV-II 500 MHz NMR spectrometer,
.
1
operating at 500 MHz for H, and 125 MHz for 13C, TMS was used as an internal
1
reference for H and 13C chemical shifts and CDCl3 was used as solvent. Mass
spectra were collected on a Bruker Esquire electrospray–ion trap instrument.
Elemental analysis was performed with a Perkin–Elmer 240c elemental analysis
instrument. 3-Hydroxy-2(1H)-pyridinone was purchased from Aldrich; other
commercially available materials were purchased from Aladdin-Reagent and
Sinopharm Chemical Reagent, and were used without further purification.
General method for preparation of 4-aminomethyl 3-hydroxy-2-(1H)-
pyridinones 2a–c
Compounds 2a–c were prepared in accordance with a reported procedure [10].
Formaldehyde (37% aqueous solution, 0.155 mL, 2.0 mmol) and the appropriate
secondary amine (3.0 mmol) were stirred together in ethanol (95% 15 mL) for
30 min. This solution was then added slowly to a solution of 3-hydroxy-2-(1H)-
pyridinone (0.222 g, 2.0 mmol) in 95% ethanol which was stirred at 45 °C for 12 h.
The solvent was removed under reduced pressure to yield a crude solid. The
crude product was recrystallized from ethanol–acetone to afford the corresponding
2.
4-Piperidinomethyl-3-hydroxy-2(1H)-pyridinone (2a)
Yield 92.5%, white solid, mp 208 °C (decomp.). IR (KBr, cm-1): 3413, 2912, 2838,
1
1698, 1216, 1105; H NMR (500 MHz, CDCl3) d: 1.44 (br s, 2H), 1.53 (br s, 4H),
123

1702
W. L. Xie et al.
2.30 (br s, 4H), 3.54 (s, 2H), 6.08 (d, J = 6.5, 1H), 6.75 (d, J = 7.5, 1H), 9.35 (s,
1H); 13C NMR (125 MHz, CDCl3) d: 23.7, 25.6, 53.4, 56.3, 108.1, 122.3, 125.5,
145.6.0, 157.8. ESI-MS: m/z 209.2 (M ? H)?. Anal. Calcd. For C11H16N2O2: C,
63.44; H, 7.74; N, 13.45; Found: C, 63.67; H, 7.68; N, 13.35.
4-Morpholinomethyl-3-hydroxy-2(1H)-pyridinone (2b)
Yield 93.2%, white solid, mp 215 °C (decomp.). IR (KBr, cm-1): 3425, 2917, 2858,
1704, 1226, 1110; 1H NMR (500 MHz, CDCl3) d: 2.07 (br s, 4H), 3.35 (s, 2H), 3.53
(br s, 4H), 6.09 (d, J = 6.5, 1H), 6.79 (d, J = 7.5, 1H), 9.43 (s, 1H); 13C NMR
(125 MHz, CDCl3) d: 51.1, 52.3, 66.7, 109.2, 121.1, 125.5, 145.0, 157.8. ESI-MS:
m/z 211.2 (M ? H)?. Anal. Calcd. For C10H14N2O3: C, 57.13; H, 6.71; N, 13.33;
Found: C, 57.31; H, 6.82; N, 13.42.
4-Pyrrolidinomethyl-3-hydroxy-2(1H)-pyridinone (2c)
Yield 71.3%, white solid, mp 189 °C (decomp.). IR (KBr, cm-1): 3428, 2970, 2845,
1
1708, 1221, 1011. H NMR (500 MHz, CDCl3) d:1.84 (br s, 4H), 2.73 (br s, 4H),
3.67 (s, 2H), 6.11 (d, J = 7.5, 1H), 6.82 (d, J = 8.5, 1H), 9.30 (s, 1H); 13C NMR
(125 MHz, CDCl3) d: 23.9, 50.5, 55.6, 106.7, 122.9, 126.2, 147.1, 157.6. ESI-MS:
m/z 195.2 (M ? H)?. Anal. Calcd. for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42;
Found: C, 61.96; H, 7.35; N, 14.27.
General method for preparation of 4,5,6-trisubstituted 2,3-pyridinediones 3a–h
Sodium iodate (1.386 g, 7.0 mmol) was added to a solution of 3-hydroxy-2(1H)-
pyridinone 2 (0.700 g, 6.3 mmol) in 0.5 mol/L phosphate-buffered saline (35.0 ml,
pH 6.0) and 125 ml methanol. After stirring for 15 min, the appropriate aromatic
amine (12.6 mmol) was then added and the resulting mixture was stirred at room
temperature. The progress of the reaction was monitored by TLC. After completion
of the reaction, water (150 ml) was added, and the precipitate formed was isolated
by filtration. The resulting crude product was purified by column chromatography
on silica gel to afford the corresponding 3.
4-Piperidinomethyl-5,6-di(p-chloroanilino)-2,3-pyridinedione (3a)
Yield 82.6%, yellow solid, mp 145–146 °C. IR (KBr, cm-1): 3431, 3058, 2854,
1
1716, 1654, 1598, 1585, 1494, 1341, 1221, 1011; H NMR (500 MHz, CDCl3) d:
1.49 (br s, 2H), 1.59 (br s, 4H), 2.43 (br s, 4H), 3.59 (s, 2H), 6.76–7.01 (m, 4H),
7.26–7.33 (m, 4H), 8.31 (s, 1H), 9.12 (s, 1H); 13C NMR (125 MHz, CDCl3) d: 23.9,
25.9, 52.7, 53.8, 113.7, 119.8, 123.2, 124.8, 125.7, 128.5, 129.4, 129.8, 136.3,
144.3, 147.4, 156.8, 172.9; MS (ESI) m/z 457.1 (M ? H)?. Anal. Calcd. for
C23H22Cl2N4O2: C, 60.40; H, 4.85; N, 12.25; Found: C, 60.59; H, 4.75; N, 12.17.
123

Mannich reaction and oxidation–Michael addition
1703
4-Piperidinomethyl-5,6-di(p-methylanilino)-2,3-pyridinedione (3b)
Yield 88.1%, red solid, mp:139–140 °C. IR (KBr, cm-1): 3445, 3023, 2943, 2851,
1720, 1654, 1589, 1512, 1431, 1380, 1339, 1271, 1107; 1H NMR (500 MHz,
CDCl3) d: 1.44 (br s, 2H), 1.52–1.53 (m, 4H), 2.30 (br s, 4H), 2.34 (s, 6H), 3.52 (s,
2H), 6.67 (m, 2H), 7.01–7.26 (m, 6H), 8.22 (s, 1H), 9.21 (s, 1H); 13C NMR
(125 MHz, CDCl3) d: 20.8, 20.9, 23.9, 25.9, 52.6, 53.5, 114.5,119.7, 123.3, 128.2,
129.1, 130.4, 134.8, 135.4, 136.1, 140.6, 147.2, 157.1, 172.9. ESI-MS: m/z 417.4
(M ? H)?. Anal. Calcd. for C25H28N4O2: C, 72.09; H, 6.78; N, 13.45; Found: C,
72.23; H, 6.87; N, 13.29.
4-Piperidinomethyl-5,6-dianilino-2,3-pyridinedione (3c)
Yield 85.2%, red solid, mp:135.6–136.8 °C. IR (KBr, cm-1): 3428, 3047, 2933,
2848, 1721, 1650, 1591, 1581, 1498, 1429, 1380, 1338, 1270, 1203, 1013; 1H NMR
(500 MHz, CDCl3) d: 1.45 (br s, 2H), 1.55 (br s, 4H), 2.34 (br s, 4H), 3.56 (s, 2H),
7.12–7.16 (m, 2H), 7.32–7.37 (m, 8H), 8.23 (s, 1H), 9.22 (s, 1H); 13C NMR
(125 MHz, CDCl3) d: 23.8, 25.8, 52.8, 53.4, 113.5, 119.7, 123.1, 124.8, 125.5,
128.6, 129.3, 129.8, 136.1, 144.1, 147.3, 156.1, 172.8; ESI-MS: m/z 389.1
(M ? H)?. Anal. Calcd. For C23H24N4O2: C, 71.11; H, 6.23; N, 14.42; Found: C,
71.34; H, 6.12; N, 14.29.
4-Morpholinomethyl-5,6-di(p-methylanilino)-2,3-pyridinedione (3d)
Yield 85.7%, yellow solid, mp:159.2–160.8 °C. IR (KBr, cm-1): 3363, 3236, 2917,
2858, 1724, 1655, 1569, 1515, 1405, 1304, 1220, 1110; 1H NMR (500 MHz,
CDCl3) d: 2.06–2.08 (m, 4H), 2.35 (s, 6H), 3.35 (s, 2H), 3.53 (br s, 4H), 6.77-6.79
(m, 2H), 7.06–7.26 (m, 6H), 8.23 (s, 1H), 9.23 (s, 1H); 13C NMR (125 MHz,
CDCl3) d: 20.8, 20.9, 50.6, 52.5, 66.8, 113.1, 115.5, 120.0, 124.6, 128.9, 130.6,
135.7, 136.2, 141.4, 144.7, 155.1, 157.8, 173.7. ESI-MS: m/z 419.3 (M ? H)?.
Anal. Calcd. For C24H26N4O3: C, 68.88; H, 6.26; N, 13.39; Found: C, 69.03; H,
6.35; N, 13.46.
4-Morpholinomethyl-5,6-di(p-methoxylanilino)-2,3-pyridinedione (3e)
Yield 88.9%, yellow crystals, mp 103–104 °C. IR (KBr, cm-1): 3424, 3290, 2952,
1713, 1645, 1571, 1508, 1458, 1291, 1246, 1112, 1035; 1H NMR (500 MHz,
CDCl3) d: 2.08–2.12 (m, 4H), 3.31 (s, 2H), 3.54 (br s, 4H), 3.82 (s, 6H), 6.86–7.15
(m, 8H), 8.25 (s, 1H), 9.28 (s, 1H); 13C NMR (125 MHz, CDCl3) d: 30.9, 50.3, 52.6,
55.5, 66.9, 112.5, 113.5, 115.3, 121.8, 126.6, 131.6, 136.8, 141.3, 144.9, 155.3,
157.7, 157.8, 173.8; MS (ESI) m/z 451.3 (M ? H)?. Anal. Calcd. for C24H26N4O5:
C, 63.99; H, 5.82; N, 12.44; Found: C, 64.10; H, 5.93; N, 12.53.
123

1704
W. L. Xie et al.
4-Morpholinomethyl-5,6-di(p-chloroanilino)-2,3-pyridinedione (3f)
Yield 87.7%, yellow crystals, mp:113.5–114.9 °C. IR (KBr, cm-1): 3444, 3242,
2958, 2867, 1725, 1651, 1574, 1514, 1487, 1410, 1317, 1115, 1089, 1012; 1H NMR
(500 MHz, CDCl3) d: 2.17–2.20 (m, 4H), 3.44 (s, 2H), 3.58 (br s, 4H), 6.78–7.39
(m, 8H), 8.32 (s, 1H), 9.37 (s, 1H); 13C NMR (125 MHz, CDCl3) d: 51.3, 52.5, 66.8,
114.5, 121.5, 125.2, 128.6, 130.1, 130.9, 131.4, 138.0, 141.3, 142.4, 144.9, 154.8,
173.6; MS (ESI) m/z 459.5 (M ? H)?. Anal. Calcd. for C22H20Cl2N4O3: C, 57.53;
H, 4.39; N, 12.20; Found: C, 57.65; H, 4.45; N, 12.08.
4-Morpholinomethyl-5,6-dianilino-2,3-pyridinedione (3g)
Yield 80.9%, yellow crystals, mp:128–129 °C. IR (KBr, cm-1): 3422, 3285, 3059,
1
2932, 1724, 1645, 1569, 1509, 1449, 1308, 1115; H NMR (500 MHz, CDCl3) d:
2.08–2.10 (m, 4H), 3.39 (s, 2H), 3.53 (br s, 4H), 6.86–7.44 (m, 10H), 8.35 (s, 1H),
9.34 (s, 1H); 13C NMR (125 MHz, CDCl3) d: 50.9, 52.5, 66.9, 113.7, 120.1, 124.5,
125.8, 125.9, 128.5, 130.0, 139.0, 141.1, 144.1, 144.6, 155.1, 173.8; MS (ESI) m/
z 391.1 (M ? H)?. Anal. Calcd. for C22H22N4O3: C, 67.68; H, 5.68; N, 14.35;
Found: C, 67.82; H, 5.75; N, 14.47.
4-Pyrrolidinomethyl-5,6-di(p-chloroanilino)-2,3-pyridinedione (3h)
Yield 80.2%, yellow crystals, mp:113.5–114.9 °C. IR (KBr, cm-1): 3354, 3263,
2970, 2845, 2791, 1728, 1650, 1573, 1511, 1412, 1341, 1314, 1086, 1011. 1H NMR
(500 MHz, CDCl3) d:1.82 (br s, 4H), 2.71 (br s, 4H), 3.66 (s, 2H), 6.92–6.94 (m,
2H), 7.26–7.331 (m, 6H), 8.33 (s, 1H), 9.35 (s, 1H); 13C NMR (125 MHz, CDCl3) d:
23.2, 50.4, 53.2, 114.9, 121.2, 122.0, 122.8, 124.7, 128.9, 129.4, 130.5, 138.1,
144.8, 147.7, 155.6, 171.7; ESI-MS: m/z 443.6 (M ? H)?. Anal. Calcd. for
C22H20Cl2N4O2: C, 59.60; H, 4.55; N, 12.64; Found: C, 59.76; H, 4.68; N, 12.56.
Conclusion
A facile and novel synthesis of 4,5,6-trisubstituted-2,3-pyridinediones was accom-
plished by oxidation–Michael addition of aromatic amines to 4-substituted-3-
hydroxy-2(1H)-pyridinones, which were obtained in good yields by Mannich reaction
of 3-hydroxy-2(1H)-pyridinones with secondary amines and formaldehyde. Simplic-
ity of operation, high yields, and easy work-up are the key advantages of this method.
Acknowledgments We are grateful for financial support from the Key Laboratory of Theoretical
Chemistry and Molecular Simulation of Ministry of Education (no. LKF0905) and the science and
technology project of Hunan Province (no. 2011SK3122).
References
1. J.W. Daly, J. Nat. Prod. 61, 162 (1998)
2. P.A.O. Lunkett, Nat. Prod. Rep. 11, 581 (1994)
123

Mannich reaction and oxidation–Michael addition
1705
3. M. Balasubramanian, J. G. Keay, in Comprehensive Heterocyclic Chemistry II, vol. 5 eds. by A.R.
Katritzky, C.W. Rees, E.F.V. Scriven (Pergamon Press, Oxford, 1996) pp. 245–252
4. M. Abaszadeh, H. Sheibani, K. Saidi, J. Heterocyclic. Chem 46, 96 (2009)
5. M. Streater, P.D. Taylor, R.C. Hider, J. Porter, J. Med. Chem. 33, 1749 (1990)
6. P.S. Dobbin, R.C. Hider, A.D. Hall, P. Taylor, P. Sarpong, J.B. Porter, G. Xiao, J. Med. Chem. 36,
2448 (1993)
7. O. Shalev, T. Repka, A. Goldfarb, L. Grinberg, A. Abrahamov, N.F. Olivieri, E.A. Rachmilewitz,
R.P. Hebbel, Blood 86, 2008 (1995)
8. J.J. Molenda, M.M. Jones, D.S. Johnston, E.M. Walker, D. Cannon, J. Med. Chem. 37, 4363 (1994)
9. A.G. Osborne, L. Jackson, P.D. Taylor, Spectrochim. Acta. Port A 49, 1703 (1993)
10. A. Nakamura, S. Kamiya, Chem. Pharm. Bull. 16, 1466 (1968)
123