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Studies on condensation of 1,3-dicarbonyls with malononitrile: Synthesis of 2-pyridinones
⁎Corresponding author. Tel./fax: +98 341 322 2033. hsheibani@mail.uk.ac.ir (Hassan Sheibani)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
A simple and novel method to the chemoselective synthesis of 3-cyano-2-pyridinone derivatives from a Knoevenagel condensation of malononitrile with the carbonyl group of 1,3-dicarbonyls followed by cycloaddition and isomerization, is reported. The reactions occur in ethanol and water at reflux, in the presence of a base catalyst such as triethylamine. This method provides an easy route to prepare 2-pyridinone derivatives in good to excellent yields and in a short experimental time.
Keywords
1,3-Dicarbonyls
Malononitrile
2-Pyridinones
Knoevenagel condensation
Cycloaddition and isomerization
1 Introduction
The development of heterocyclic compounds such as pyridinones is a topic of current interest because of their presence in numerous natural products along with the wide spectrum of physiological activities displayed by this class of compounds (Nagarajan et al., 2003; Fassihi et al., 2009; Manna et al., 1992). It is well known that the 2-pyridinone derivatives are valuable building blocks in natural product synthesis and also a versatile synthon for the synthesis of a variety of other nitrogen-containing heterocyclic compounds, such as β-lactams, quinolizidines, pyridines, piperidines, and indolizidine alkaloids (Elbein and Molyneux, 1981). The diene portion of these molecules can undergo Diels–Alder cycloaddition reactions with dienophiles, or one double bond may act as a dienophile to an added diene (Chou and Chen, 2008). So they have been applied as a key synthetic intermediate to synthesize some complex natural products (Snider and Che, 2004; Chen et al., 2010). A large number of methods have been developed for the synthesis of 2-pyridinones and their derivatives (Torres et al., 2005). The most common strategies involve the construction of the heterocyclic compounds from easily available starting materials. Due to the importance of 2-pyridinone skeleton, to develop new and efficient methodologies for diversely functionalized construction of 2-pyridinone is still highly desired. Organic fluorine compounds have received significant attention in the materials and pharmaceutical sciences due to their unique physical and biological properties such as the increased membrane permeability, enhanced hydrophobic binding and stability against metabolic oxidation (Kuznetsova et al., 2004; Filler et al., 1993; Chambers, 2004; Ryckmanns et al., 2002; Purser and Moore, 2008). The replacement of hydrogen by fluorine in organic molecules has frequently led to dramatic changes in their dipole moments, acidity or basicity of neighboring groups; any of which can affect molecular interactions with receptors or other interacting molecules (Muller et al., 2007). Therefore, the synthesis of fluorinated molecules plays an important role in drug discovery and many pharmaceuticals, such as well known ciprofloxacin, ofloxacin or norfloxacin which all contain fluorine atoms (Albrecht et al., 1994; Song et al., 1997; Popp et al., 1994; Lam et al., 2001). In continuing our previous works on the reaction of 1,3-dicarbonyls with electrophiles such as acyl ketenes (Cantillo et al., 2012; Sheibani et al., 2006a,b; Sheibani et al., 2004), arylidenemalononitrile and the S–S-bond of 2,2’-disulfanediyldianiline (Seifi and Sheibani, 2008; Sheibani et al., 2006a,b), we now turn our attention to the reactivity of malononitrile on the fluorinated-1,3-dicarbonyls to the synthesis of fluorinated-2-pyridinone derivatives. The simplicity and efficient one-pot procedure is one aspect of particular interest, in comparison to the other multi-step methods. On the other hand, readily available starting materials such as malononitrile and fluorinated-1,3-dicarbonyls, shorten experimental times, and high yield of the final products are the other advantages of this method.
2 Results and discussion
In continuing our interest in the synthesis of heterocyclic compounds which contain the 2(1H)-pyridinone skeleton (Abaszadeh et al., 2009; Sheibani et al., 2009), as exhibited in Scheme 1 the 3-cyano-2-pyridinone derivatives (3a–e) were prepared in the reaction of 1,3-dicarbonyl compounds (1a-e) with malononitrile 2 followed by cycloaddition and isomerization in good to excellent yields and in a short experimental time.
Synthesis of 3-cyano-2-pyridinone derivatives (3a–e).
Unsymmetrical 1,3-diketones such as 1-phenyl-1,3-butanedione (1c), 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione (1d) and 1,1,1-trifluoropentane-2,4-dione (1e) exist mainly in two enol forms (Scheme 2). Based on the 1H NMR and 13C NMR only one product was obtained from the nucleophilic reaction of malononitrile on the acetyl group of unsymmetrical, 1,3-diketones 1c and 1d, however the reaction of 1,1,1-trifluoropentane-2,4-dione (1e) with malononitrile (2) in the same reaction condition afforded the mixture of 2-pyridinone 3(I)e and 3(II)e in different yields. Quantitative analysis of mixtures is achieved by evaluating the integration peaks of 1H NMR spectrum ((3(II)e: 85% and 3(I)e: 15%)).
Unsymmetrical 1,3-diketones in two enol forms.
On the basis of our results, a plausible mechanism has been proposed for the reactions of 1,3-diketones (1a–e) with malononitrile to yield 3-cyano-2-pyridinone derivatives (3a–e), as shown in Scheme 3. The Knoevenagel reaction occurs via an initial formation of 4-oxo-ylidene malononitrile derivatives (III), from the condensation of malononitrile on the active carbonyl group of 1,3-diketones (1a–e). The second step is followed by intramolecular nucleophilic addition of the hydroxyl group on the cyano (CN) moiety, giving intermediate (IV). The final step is followed by nucleophilic addition of water, cycloaddition, isomerization to afford the 3-cyano-2-pyridinone derivatives (3).
A mechanism for the formation of 3-cyano-2-pyridinone derivatives.
In our investigation it was found that the reaction of dibenzoylmethane 4 with malononitrile 2 in the presence of a little amount of water gave 4-amino-5-benzoyl-6-phenyl-1H-pyridin-2-one 5 as the only product (Scheme 4).
Synthesis of 4-amino-5-benzoyl-6-phenyl-1H-pyridin-2-one (5).
The unexpected formation of the compound 5 can be explained as follows. We believe that the carbonyl group of dibenzoylmethane 4 is not as reactive as the other 1,3-dicarbonyl groups such as compounds (1a–e). It is pertinent to note that the methylene group of dibenzoylmethane 4 is a very reactive nucleophile compared to malononitrile. Therefore it is considered that this reaction proceeds by an initial nucleophilic attack of the β-carbon atom of the enol tautomer of dibenzoylmethane 4 on the nitrile group of malononitrile 2, followed by intramolecular nucleophilic addition of the hydroxyl group to other nitrile groups of intermediate V. Similarly, nucleophilic addition of water on intermediate VI along with cycloaddition, isomerization leads to the formation of 4-amino-5-benzoyl-6-phenyl-1H-pyridin-2-one 5 (Scheme 5).
A mechanism for the formation of 4-amino-5-benzoyl-6-phenyl-1H-pyridin-2-one.
3 Conclusions
In summary, we have developed a simple method to synthesize a series of fluorinated pyridinones via the reaction of 1,3-diketones with malononitrile, the desired products were obtained with up to 85% yields in ethanol at reflux and in short experimental times. Also this methodology offers a different route for the synthesis of 4-amino-5-benzoyl-6-phenyl-1H-pyridin-2-one. Synthesis of 4-amino-2-pyridinone would be achieved because the amine partners can be flexibly varied. Owing to the interest of the amino-2-pyridinone derivatives for the design of biologically relevant compounds.
4 Experimental section
Melting points were measured on a Gallenkamp melting point apparatus and are uncorrected. IR spectra were measured on a Mattson 1000 FT-IR spectrometer. The proton and carbon NMR spectra were recorded with a BRUKER DRX-500 AVANCE spectrometer at 500 and 125.77 MHz, respectively. Mass spectra were recorded on a MS-QP2000A Shimadzu mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer.
4.1 General procedure for the preparation of 3-cyano-2-pyridinones (3a–e)
A mixture of β-dicarbonyl 1a–e (2 mmol), malononitrile 2 (2 mmol) and triethylamine (0.2 ml) in ethanol (20 mL) was refluxed with stirring for 15 min (the progress of the reaction being monitored by TLC and used hexane/ethyl acetate as an eluent). When the reaction was completed as indicated by TLC, the crude product 3a–e was precipitated from the reaction mixture by cooling, and the solid was filtered and recrystallized with ethanol to get the pure product.
4.2 General procedure for the preparation of 4-amino-5-benzoyl-6-phenyl-1H-pyridin-2-one (5)
A mixture of dibenzoylmethane 4 (2 mmol) and malononitrile 2 (2 mmol), in CH2Cl2 (20 mL) was refluxed with stirring for 15 min (the progress of the reaction being monitored by TLC and used hexane/ethyl acetate as an eluent). Then 2 ml H2O was added to the mixture reaction and refluxed with stirring for 10 min. When the reaction was completed as indicated by TLC, the crude product 5 was precipitated from the reaction mixture by cooling, and the solid was filtered and recrystallized with ethanol to get the pure product.
4.3 Spectral data for selected compounds
4.3.1 1,2-Dihydro-4,6-dimethyl-2-oxopyridine-3-carbonitrile (3a)
Yield: 95%. m.p. 276–278 °C (decompose); IR (KBr, νmax/cm−1): 3341 (NH), 2216 (CN), 1670 (C⚌O), 1620, 1580 (C⚌C); 1H NMR (500 MHz, DMSO-d6): 8.40 (s, 1H, NH), 6.07 (s, 1H), 2.34 (s, 3H, CH3), 2.23 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6): 160.87 (C⚌O), 159.75 (C6), 150.84 (C4), 115.79 (CN), 115.40 (C3), 106.31 (C5), 20.65, 18.25 (2 CH3); MS (m/z): 148 (M+) (100), 120 (35), 119 (80), 105 (20). Anal. Calcd. For C8H8N2O: C, 64.72; H, 5.46; N, 18.97%. Found: C, 64.85; H, 5.44; N, 18.91.
4.3.2 4,6-Bis(trifluoromethyl)-1,2-dihydro-2-oxopyridine-3-carbonitrile (3b)
Yield: 85%. m.p. 123–125 °C; IR (KBr, νmax/cm−1): 3340 (NH), 2216 (CN), 1660 (C⚌O), 1620, 1580 (C⚌C); 1H NMR (500 MHz, DMSO-d6): 8.89 (s, 1H, NH), 6.24 (s, 1H); 13C NMR (125 MHz, DMSO-d6): 155.40 (C4), 150.23 (C⚌O), 135.75 (C6), 112.59 (q, 1JC-F, 284.25 Hz, CF3), 112.44 (q, 1JC-F, 276.25 Hz, CF3), 110.21 (C3), 110.12 (CN), 108.31 (C5); MS (m/z): 256 (M+) (5), 251 (70), 198 (100), 182 (60), 117 (10), 93 (10), 75 (10), 69 (50).
4.3.3 1,2-Dihydro-4-methyl-2-oxo-6-phenyl pyridine-3-carbonitrile (3c)
Yield: 92%; m.p. 285 °C (decompose); IR (KBr, νmax/cm−1): 3255 (NH), 2212 (CN), 1617 (C⚌O), 1590, 1492 (C⚌C); 1H NMR (500 MHz, DMSO-d6): 12.43 (s, 1H, NH), 7.69–7.41 (m, 5H, Ar), 6.63 (s, 1H), 2.40 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6): 162.26 (C⚌O), 161.13 (C6), 151.32 (C4), 133.00, 131.90, 129.79, 128.33, 116.80 (C3), 115.12 (CN), 107.91 (C5), 21.62 (CH3); MS (m/z): 210 (M+) (5), 196 (80), 185 (20), 171 (10), 134 (20), 95 (100), 77 (40), 45 (60). Anal. Calcd. For C13H10N2O: C, 74.27; H, 4.79; N, 13.32%. Found: C, 74.35; H, 4.74; N, 13.37.
4.3.4 4-(Trifluoromethyl)-1,2-dihydro-2-oxo-6-(thien-2-yl)pyridine-3-carbonitrile (3d)
Yield: 88%; m.p. 205–208 °C; IR (KBr, νmax/cm−1): 3404 (NH), 2237 (CN), 1641 (C⚌O), 1592, 1567 (C⚌C); 1H NMR (500 MHz, DMSO-d6): 8.90 (s, 1H, NH), 7.83 (d, 1H, 3JH-H = 5.03 Hz, CH), 7.72 (d, 1H, 3JH-H = 3.67 Hz, CH), 7.20–7.18 (m, 1H, Ar), 7.08 (s, 1H). 13C NMR (125 MHz, DMSO-d6): 160.40 (C4), 155.68 (C⚌O), 143.77 (C6), 136.04, 131.84, 131.31, 129.49, 122.74 (q, 1JC-F, 273.25 Hz, CF3), 114.37 (C3), 114.12 (CN), 98.18 (C5); MS (m/z): 270 (M+) (8), 246 (15), 193 (20), 148 (40), 106 (80), 91 (100), 77 (20), 57 (85). Anal. Calcd. For C11H5F3N2OS: C, 48.89; H, 1.86; N, 10.37%. Found: C, 52.59; H, 1.88; N, 14.17.
4.3.5 Trifluoromethyl-methyl-2-oxopyridine-3-carbonitrile (3e)
Yield: 90%; m.p. 160 °C (decompose); IR (KBr, νmax/cm−1): 3354 (NH), 2237 (CN), 1666 (C⚌O), 1617, 1567 (C⚌C); MS (m/z): 202 (M+) (10), 188 (70), 163 (30), 134 (15), 109 (100), 95 (60), 45 (40). Anal. Calcd. For C8H5F3N2O: C, 47.54; H, 2.49; N, 13.86%. Found: C, 48.40; H, 2.48; N, 14.01. 6-Trifluoromethyl-1,2-dihydro-4-methyl-2-oxopyridine-3-carbonitrile (3(I)e): 1H NMR (500 MHz, DMSO-d6): 13.35 (s, 1H, NH), 6.64 (s, 1H), 2.28 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6): 161.36 (C⚌O), 151.15 (C4), 146.86 (C6), 124.10 (q, 1JC-F, 262.5 Hz, CF3), 115.89 (C3), 114.27 (CN), 102.44 (C5), 21.91 (CH3). 4-(trifluoromethyl)-1,2-dihydro-6-methyl-2-oxopyridine-3-carbonitrile (3(II)e): 1H NMR (500 MHz, DMSO-d6): 8.36 (s, 1H, NH), 7.12 (s, 1H), 2.38 (s, 3H, CH3); 13C NMR (125 MHz, DMSO-d6): 157.75 (C4), 154.49 (C⚌O), 146.61 (C6), 121.50 (q, 1JC-F, 274.50 Hz, CF3), 115.85 (C3), 114.19 (CN), 101.34 (C5), 20.41 (CH3).
4.3.6 4-Amino- 5-benzoyl-6-phenyl-1H-pyridin-2-one (5)
Yield: 88%; m.p. 290 °C; IR (KBr, νmax/cm−1): 3478, 3344, 3304 (NH, NH2), 1720 (Ph-C⚌O), 1641 (NH-C⚌O), 1617, 1592 (C⚌C); 1H NMR (500 MHz, DMSO-d6): 10.31 (s, 1H, NH), 8.90 (s, 2H, NH2), 7.40–6.025 (m, 10H, Ar), 5.93 (s, 1H); 13C NMR (125 MHz, DMSO-d6): 197.10 (Ph-C⚌O), 160.53 (NH-C⚌O), 158.44 (C4), 147.93 (C6), 136.13, 133.72, 130.02, 129.74, 129.48, 129.28, 128.85, 128.81, 124.86 (C5), 109.07 (C3); MS (m/z): 290 (M+) (15), 261 (18), 221 (10), 146 (8), 105 (80), 91 (15), 77 (100), 58 (25), 51 (35). Anal. Calcd. For C19H13N3O2: C, 72.37; H, 4.16; N, 13.33%. Found: C, 72.02; H, 3.98, N, 13.05.
Acknowledgements
The authors express appreciation to the Shahid Bahonar University of Kerman Faculty Research Committee for its support of this investigation.
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