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A Systematic Study on Knoevenagel Reaction and Nazarov Cyclization of Less Reactive Carbonyl Compounds Using Rare Earth Triflates and Its Applications
A Systematic Study on Knoevenagel Reaction and Nazarov Cyclization of Less Reactive Carbonyl Compounds Using Rare Earth Triflates and Its Applications
Journal of the Korean Chemical Society. 2011. Dec, 55(6): 1000-1006
Copyright © 2011, The Korean Chemical Society
  • Received : June 29, 2011
  • Accepted : October 17, 2011
  • Published : December 20, 2011
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About the Authors
A. Ilangovan
ilangovanbdu@yahoo.com
S. Muralidharan
S. Maruthamuthu
Corrosion Protection Division, Central Electro Chemical Research Institute, Karaikudi-630 006, India

Abstract
A systematic study of Knoevenagel reaction and Nazarov cyclization was made on variety of less reactive carbonyl compounds such as β-ketoesters, 1,3-diketones and cyclic active methylene compounds using Yb(OTf) 3 as the catalyst. Recycling study confirms reusability of the catalyst without much loss of activity.
Keywords
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EXPERIMENTAL
All yields reported were based on isolated compounds. TLC separations were carried out on silica gel plates with UV indicator from Aldrich; visualization was by UV fluorescence or by staining with iodine vapor. IR spectra were recorded on a FT-IR Bruker Vector 22 Infrared spectrophotometer using KBr disks. NMR spectra were recorded on FT-NMR Bruker 400/200 MHz spectrometer as CDCl 3 solutions with TMS as internal reference.
- General Experimental Procedure for the Synthesis of Substituted Alkenes
To a mixture of an aromatic aldehyde (5.0 mmol) and active methylene compound (5.5 mmol), Yb(OTf) 3 (0.5 mmol) was added and the resulting reaction mixture was heated at 80–85 ℃ in an oil bath for required time. The progress of the reaction was monitored by thin layer chromatography (TLC, silica gel, hexane: ethyl acetate, 8:2). After completion of the reaction, the reaction mixture was diluted by adding ethyl acetate (10 mL) and washed with water (2×5 mL) and brine solution (5 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane-EtOAc, 8.5:1.5) to afford the substituted olefin in very good yield. All the new products obtained were fully characterized by spectroscopic methods such as IR, 1 H NMR, 13 C NMR and mass spectroscopy. If the compound is already known in the literature, IR, and 1 H NMR values are given, compared with the spectral data already known, and a suitable reference is also mentioned.
- 2-(4-Methoxybenzylidene)malononitrile (3a)
The reaction was carried out according to the general experimental procedure using 4-methoxybenzaldehyde (250 mg, 1.836 mmol), malononitrile (145 mg, 2.197 mmol) and Yb(OTf) 3 (114 mg, 0.184 mmol). Conditions: 80-85 ℃, 2 h. The title compound 3a was obtained (330 mg, 98%) as a solid, mp 114-116 ℃. The spectral data for the compound 3a was in agreement with the values already reported in the literature.
1 H NMR (400 MHz, DMSO) d 3.88 (s, 3H, -O CH 3 ), 7.19 (m, 2H, ArH), 7.97 (m, 2H, ArH) and 8.40 (s, 1H, Ar CH =). IR (KBr) 2224, 1605, 1571, 1513, 1370, 1319, 1279, 1185, 1022, 834 cm -1 .
- 2-(4-Methoxy-benzylidene)-malonic acid diethyl ester (3i)
The reaction was carried out according to the general procedure using 4-methoxy benzaldehyde (100 mg, 0.735 mmol), diethyl malonate (129 mg, 0.808 mmol) and Yb(OTf) 3 (52 mg, 0.074 mmol) conditions: 80-85 ℃, 6 h. The title compound 3i was obtained (171 mg, 84%) as an oily mass. The spectral data of the compound 3i was in agreement with the values reported in the literature.
1 H NMR (400 MHz, CDCl 3 ) δ 1.20 (t, J =7.2 Hz, 3H, -CH 2 CH 3 ), 1.25 (t, J =7.2 Hz, 3H, -CH 2 CH 3 ), 3.44 (s, 3H, -O CH 3 ), 4.26 (m, J =7.2, 16.4 Hz, 4H, - CH 2 CH 3 ), 7.49 (m, 4H, ArH), 7.72 (s, 1H, Ar CH =). IR (KBr) 2982, 1723, 1628, 1448, 1375, 1255, 1196 cm -1 .
- 2-Cyano-3-(3,4,5-trimethoxy-phenyl)-propionic acid ethyl ester (4)
The reaction was carried out 2-cyano-3-(3,4,5-trimethoxyphenyl)-acrylic acid ethyl ester (250 mg, 0.860 mmol), Hantzsch ester (240 mg, 0.950 mmol), and silica (2.5 g) in presence of toluene (5 mL) at reflex condition for 5 h. The title compound 4 was obtained (275 mg, 94%). The spectral data of the compound 4 was in agreement with the values reported in the literature.
1 H NMR (400 MHz, CDCl 3 ) δ 1.22 (t, J =7.2 Hz, 3H, -CH 2 CH 3 ), 3.12 (m, J =5.6, 13.6 Hz, 2H, Ar-CH 2 ), 3.64 (t, J =5.6, 1H, ArCH 2 -CH-), 3.76 (s, 3H, -O CH 3 ), 3.78 (s, 6H, 2-O CH 3 ), 4.19 (q, J =7.2, 14. Hz, 2H, - CH 2 CH 3 ), 6.42 (s, 2H, ArH). IR (KBr) 2942, 2253, 1743, 1592, 1509, 1463, 1245, 1127, 1005, 851 cm -1 .
- 2-(2-Chloro-benzylidene)-3-oxo-butyric acid ethyl ester (7d)
The reaction was carried out according to the general procedure using 2-chloro benzaldehyde (100 mg, 0.711 mmol), ethylacetoacetate (102 mg, 0.783 mmol) and Yb(OTf) 3 (50 mg, 0.071 mmol) conditions: 80-85 ℃, 15 h. The crude product was purified by column chromatography (silica gel, hexane: ethyl acetate. 9:1). First eluted was unreacted starting material 1d (40 mg, 40%). Second eluted was the title compound 7d was obtained (54 mg, 57%, yield calculated based on the recovered starting material) as an oilic mass. The spectral data of the compound 7d was in agreement with the values reported in the literature.
1 H NMR (400 MHz, CDCl 3 ) δ 1.17 (t, J =7.2 Hz, 3H, -CH 2 CH 3 ), 2.42 (s, 3H, -CO CH 3 ), 4.24 (q, J =7.6, 14.0 Hz, 2H, - CH 2 CH 3 ), 7.35 (m, 4H, ArH). 7.85(s, 1H, Ar CH =). IR (KBr) 1724, 1669, 1618, 1468, 1439, 1376, 1239, 1200 cm -1 .
- 3-(4-Nitrobenzylidene)pentane-2,4-dione (7f)
The reaction was carried out according to the general experimental procedure using 4-nitrobenzaldehyde (250 mg, 1.650 mmol), acetyl acetone (182 mg, 1.820 mmol) and Yb(OTf) 3 (103 mg, 0.165 mmol). Conditions: 80-85℃, 18 h. The title compound 7f was obtained (131 mg, 34%) as a clear oilic mass. The spectral data for the compound 7f was in agreement with the values already reported in the literature.
1 H NMR (400 MHz, CDCl 3 ) δ 2.23 (s, 3H, -CO CH 3 ), 2.39 (s, 3H, -CO CH 3 ), 3.76 (s, 3H, -O CH 3 ), 7.43 (s, 1H, Ar CH =), 7.48 (d, 2H, ArH), 8.17 (d, 2H, ArH). IR (KBr) 1709, 1653, 1595, 1518, 1345, 1237, 1172, 858 cm -1 .
- 5-(4-Hydroxy-3-methoxybenzylidene)pyrimidine-2,4,6 (1H,3H,5H)-trione (13c)
The reaction was carried out according to the general experimental procedure using vaniline (250 mg, 1.645 mmol), barbituric acid (210 mg, 1.645 mmol) and Yb(OTf) 3 (102 mg, 0.165 mmol). Conditions: 80-85 ℃, 5 h. The title compound 13c was obtained (415 mg, 96%) as a solid, mp 309-311 ℃. The spectral data for the compound 13c was in agreement with the values already reported in the literature.
1 H NMR (400 MHz, DMSO) δ 3.82 (s, 3H, -O CH 3 ), 6.89 (d, 1H, ArH), 7.79 (m, 1H, ArH), 8.21 (s, 1H, Ar CH =), 8.47 (d, 1H, ArH), 10.56 (s, 1H, -OH), 11.13 (s, 1H, -NH), 11.26 (s, 1H, -NH). IR (KBr) 3456, 3195, 3130, 3052, 2847, 1729, 1692, 1657, 1542, 1498, 1398, 1299, 1273, 1255, 1178, 1136, 1024, 851, 791, 516 cm -1 .
- 2,2-Dimethyl-5-(4-methoxybenzylidene)-1,3-dioxane-4,6-dione (14b)
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The reaction was carried out according to the general experimental procedure using 4-methoxybenzaldehyde (250 mg, 1.836 mmol), meldrumsacid (317 mg, 2.201 mmol) and Yb(OTf) 3 (115 mg, 0.185 mmol). Conditions: 80-85 ℃, 4.5 h. The title compound 14b was obtained (320 mg, 67%) as a solid, mp 127-129 ℃. The spectral data for the compound 14b was in agreement with the values already reported in the literature.
1 H NMR (400 MHz, DMSO) δ 1.72 (s, 6H, -CH 3 ), 3.87 (s, 3H, -O CH 3 ) 7.09 (d, 2H, ArH), 8.22 (d, 2H, ArH), 8.30 (s, 1H, Ar CH =).
IR (KBr) 3101, 2997, 2840, 1747, 1714, 1574, 1514, 1429, 1391, 1203, 1171, 1019, 933, 837, 798 cm -1 .
Acknowledgements
Council of Scientific and Industrial Research (CSIR), New Delhi is gratefully acknowledged for financial support (Grant No.: 80(0067)/07/EMRII, dt. 02-11-2007) and Senior Research Fellowship to SM. We are grateful to the DST-FIST for the use of 400 MHz NMR facility at the School of Chemistry, Bharathidasan University.
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