HETEROCYCLES

Note | Regular issue | Vol. 78, No. 8, 2009, pp. 2067-2076
Received, 18th February, 2009, Accepted, 1st April, 2009, Published online, 3rd April, 2009.
DOI: 10.3987/COM-09-11685

■ Alkylheteroaromatic-carbonitriles as Building Blocks in Heterocyclic Synthesis: Synthesis of Ethyl 1-Substituted 5-Cyano-4-methyl-6-oxopyridine-3-carboxylates; Versatile Precursors for Polyfunctionally Substituted Isoquinolines and Pyrido[3,4-c]pyridine

Khaled D. Khalil, Hamad M. Al-Matar,* and Mohamed H. Elnagdi

Department of Chemistry, Faculty of Science, Kuwait University, Safat 13060, P.O. Box 5969, Kuwait

Abstract

The title compounds were prepared via reacting diethyl 2-cyano-4-dimethylamino-methylene-3-methylpent-2-enedioic acid 2 with hydrazine hydrate and with ethyl amine. The formed pyridones 3a condensed with dimethylformamide dimethyl acetal to yield the corresponding enamine 4 that could be cyclised into the pyrido[3,4-c]pyridine 5 by reflux in acetic acid in presence of ammonium acetate. The reaction of 3a with elemental sulfur afforded the thienopyridine 6 that reacted readily with electron poor olefins and acetylenes to yield isoquinolines 8, 10 and 11. Compound 3a reacted with benzylidene-malononitrile to yield the isoquinoline 14.

Alkyl heteroaromatic carbonitriles have been extensively utilized as precursors to benzofused heterocycles.1-3 Whereas we have explored potentialities of alkylpyridazinylcarbonitriles as precursors to phthalazines 4-7 and cinnolines,8 Elnagdi et al.9, 10 and Dopp et al.11, 12 have reported on utility of 4-alkyl-coumarinylcarbonitriles as precursors to benzocoumarines. Only very recently Alzaidi et al. 13 and Al-Mousawy et al. 14 have reported on the utility of 3-arylazo-4-methyl -2,6-dioxopyridine-5-carbonitriles as precursors to isoquinolines and pyridopyridazines. In conjunction to our interest in chemistry of alkylazinylcarbonitriles we report here an efficient synthesis of ethyl 1-substituted-5-cyano-4-methyl-6-oxopyridine-3-carboxylates and their utility for synthesis of polyfunctionally substituted isoquinolines and pyrido[3,4-c]pyridines.
Condensing ethyl cyanoacetate with ethyl acetoacetate in refluxing toluene in presence of ammonium acetate following literature procedure15 has afforded (Z)-diethyl 2-cyano-3-methylpent-2-endioate 1. However, the product was highly impure, and consequently we have stirred a mixture of ethyl cyanoacetate and acetoacetic ester in ethanol in presence of potassium carbonate and the product, so formed, proved identical with the product obtained via literature procedure, but was formed in better yield and higher purity that enabled its utility as such for next steps (Scheme 1).

Compound 1 condensed with dimethylformamide dimethyl acetal (DMFDMA) to yield pent-2-endioic acid ester 2 in a good yield (68% yield). The latter reacted with ethylamine in refluxing ethanol to yield the targeted pyridone 3a in 52% yield. The reaction of 2 with hydrazine hydrate afforded the N-aminopyridone 3b in 65% yield. The methyl function in 3a condensed with DMFDMA to yield an enamine 4 (46% yield) that was assigned as trans structure based on presence of two olefinic protons at 5.31 and 6.12 ppm with J = 14.6 Hz; typical for trans olefinic protons. Compound 4 cyclized readily upon reflux in acetic acid in presence of ammonium acetate to yield pyridopyridone 5 in 27% yield (Scheme 1).

Typical to alkylazinylcarbonitriles compound 3a reacted with elemental sulfur in dioxane in presence of piperidine to yield the thienopyridone 6. Compound 6 reacted with acrylonitrile to yield product of 4 + 2 cycloaddition with hydrogen sulfide elimination. In theory both 8 and 9 can be formed. However 1H-NMR revealed protons at 7.15 and 7.64 with J = 8.4 Hz typical for H-5 and H-6 isoquinoline protons. Thus structure 8 was established for this product (Scheme 2).

Similar to its behavior toward acrylonitrile compound 6 reacted with ethyl propiolate and dimethyl acetylenedicarboxylate to yield 10 and 11 respectively. It is of value report that o-protons in 10 showed coupling value of 8.3 Hz typical for such protons (Scheme 3).

Compound 3a reacted with benzylidene-malononitrile to yield the isoquinoline 14; that was formed, most likely, via 12 and 13 and hydrogen cyanide elimination (Scheme 4).

In conclusion we have developed an easy approach to alkyl pyridinylcarbonitriles and could reveal that these are versatile precursors to polyfunctionally substituted isoquinolines.

EXPERIMENTAL
Melting points were recorded on Gallenkamp apparatus and are uncorrected. Infrared spectra (KBr) were determined on a Perkin-Elmer 2000 FT-IR system. NMR measurements were determined on a Bruker DPX spectrometer, at 600 MHz for 1H NMR and 125 MHz for 13C NMR, in DMSO-d6 as solvent and using TMS as internal standard. Mass spectra were measured on MS 30 and MS 9 (AEI) spectrometers, with EI 70 eV. Elemental analyses were measured by means of LECO CHNS-932 Elemental Analyzer.

Reaction of ethyl acetoacetate with ethyl cyanoacetate:
Metod A: A mixture of ethyl acetoacetate (1.30 g, 10.0 mmol), ethyl cyanoacetate (1.13 g, 10.0 mmol), 0.5 g of acetic acid, 0.2 g of ammounium acetate, and 0.02 g of piperidine was dissolved in 25 mL dry benzene.15 The mixture was refluxed in a flask fitted by azeotropic water separator on an oil bath at 160°C till removing 0.5 mL water were separated. The product was cooled to rt and washed with saturated NaCl solution then with distilled water. The product was obtained by vaccum distillation under 0.3 pressure to give ~ 0.62 g (bp 0.3 120°C, yield: 38%).
Method B: A mixture of ethyl acetoacetate (1.30 g, 10.0 mmol), ethyl cyanoacetate (1.13 g, 10.0 mmol), and 0.5 g of K2CO3 anhydrous dissolved in 50 mL absolute EtOH. The mixture was stirred overnight. The product was washed by water, extracted with chloroform and then dried by anhydrous sodium sulphate. The pure product was obtained by evaporation of CHCl3 and proved identical with the purified product obtained by method A.

(Z)-Diethyl 2-cyano-3-methylpent-2-enedioate (1)
This compound was obtained as a yellow oil (yield: 68%); IR(KBr): υ = 1610.3 (C=C), 1680 (C=O), 1686 (C=O), 2190.29 (CN) cm-1, 1H NMR (DMSO-d6): δ = 1.13 (t, J = 7.0 Hz, J = 7.2 Hz, 6H, two ester CH3), 2.32 (s, 3H, CH3), 3.37 (s, 2H, CH2), 3.95 (q, 2H, J = 7.0 Hz, CH2), 4.24 (q, 2H, J = 7.2 Hz, CH2); 13C NMR (DMSO-d6): δ = 13.7 (CH3 of CO2C2H5), 14.2 (CH3 of CO2C2H5), 15.4 (CH3), 38.8 (CH2), 58.1 (O-CH2), 60.6 (O-CH2), 97.2 (=C(CN)), 116.8 (CN), 165.2 (=C(CH3)), 169.6 (C=O), 170.1 (C=O); MS, m/z (%), 225.1 (M+, 98), 151.0 (100), 123.0 (84). Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N, 6.22. Found: C, 58.61; H, 6.69; N, 6.19.

Reaction of 1 with N,N-dimethylformamide dimethyl acetal (DMFDMA):
A mixture of 1 (2.25 g, 10.0 mmol), and dimethylformamide dimethyl acetal (2.40 g, 20.0 mmol) was dissolved in 25 mL dry xylene. The mixture was refluxed for 5 h, and then cooled to rt then treated with petroleum ether. The solid product, so formed, was collected by filtration and recrystallized from EtOH to give 2.

Diethyl 2-Cyano-4-dimethylaminomethylene-3-methyl-pent-2-enedioate (2)
This compound was obtained as pale green solid (yield: 68%); IR(KBr): υ = 1608 ( C=C), 1675 (C=O), 1682 (C=O), 2192.3 (CN) cm-1, 1H NMR (DMSO-d6): δ = 1.2 (t, 6H, J = 7.1 Hz, J = 7.2 Hz, two ester CH3), 2.32 (s, 3H, CH3), 3.23 (s, 6H, N(CH3)2), 4.04 (q, J = 7.1 Hz, J = 7.2 Hz, 4H, 2 O-CH2), 7.28 (s, 1H, CH); 13C NMR (DMSO-d6): δ = 13.3 (aliphatic, CH3), 13.9 (CH3 of CO2C2H5), 14.1 (CH3 of CO2C2H5), 45.2 (2 N-CH3), 59.0 (O-CH2), 59.6 (O-CH2), 98.1 (=C(CN)), 102.1 ( C, B to enamine N), 116.4 (CN), 147.7 (C, α to enamine N), 164.8 (C=O), 166.7 (C=O), 167.0 ( =C-CH3); MS, m/z (%), 280.2 (M+, 98), 235.1 (48), 119.1 (42). Anal. Calcd for C14H20N2O4: C, 59.99; H, 7.19; N, 9.99. Found: C, 59.97; H, 7.16; N, 9.92.

Reaction of 2 with ethylamine and with hydrazine:
A mixture of 2 (2.80 g, 10.0 mmol), and 10.0 mmol of ethylamine (70 wt. % solution in water) or hydrazine hydrate (80 wt. % solution in water) in 25 mL of EtOH was refluxed for 6 h. The solid crude product, so formed, was collected by filtration and purified by recrystallization from EtOH to give 3a and 3b, respectively.

Ethyl 5-cyano-1-ethyl-4-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate (3a)
This compound was obtained as a brown solid (yield: 52%); IR(KBr): υ = 1611 (C=C), 1668 (C=O), 1675 (C=O), 2188.1 (CN) cm-1, 1H NMR (DMSO-d6): δ = 1.04 (t, 3H, J = 7.0 Hz, amide CH3), 1.19 (t, 3H, J = 7.2 Hz, ester CH3), 1.82 (s, 3H, CH3), 3.87 (q, 2H, J = 7.0 Hz, N-CH2), 4.11 (q, 2H, J = 7.2 Hz, O-CH2), 8.51 (s, 1H, pyridine CH); 13C NMR (DMSO-d6): δ = 12.0 (aliphatic, CH3), 13.4 (CH3, ester CH3), 13.8 (CH3, ester CH3), 41.2 ( CH2, N-CH2), 61.3 (CH2, O-CH2), 102.5 ( C, C5, pyridone), 115.4 (=C(CN)), 118.7 (CN), 139.4 (CH, C6, pyridone), 159.2 (C=O, amide), 163.7 (C=O, ester), 164.6 (C, pyridone C-4); MS, m/z (%), 234.1 (M+, 98), 188.1 (54). Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C, 61.49; H, 5.97; N, 11.92.

Ethyl 1-amino-5-cyano-4-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate (3b)
This compound was obtained as a pale brown solid (yield: 65%); IR(KBr): υ = 1609 (C=C), 1665 (C=O), 1671 (C=O), 2184.1 (CN), 3425 (br., NH2) cm-1, 1H NMR (DMSO-d6): δ = 1.19 (t, 3H, J = 7.1 Hz, ester CH3), 2.46 (s, 3H, CH3), 4.13 (q, 2H, J = 7.1 Hz, O-CH2), 4.67 (s, 2H, NH2), , 8.26 (s, 1H, pyridine CH); 13C NMR (DMSO-d6): δ = 12.7 (CH3, pyridine- CH3), 13.4 (CH3, ester CH3), 60.8 (CH2, O-CH2), 100.4 (C, pyridine C-5), 116.3 (=C(CN)), 118.6 (CN), 132.0 (CH, pyridone C-6), 158.4 (C=O, amide), 164.2 (C=O, ester), 167.3 (C, pyridone C-4); MS, m/z (%), 221.1 (M+, 100), 176 (64). Anal. Calcd for C10H11N3O3: C, 54.29; H, 5.01; N, 19.00. Found: C, 54.24; H, 4.96; N, 18.95.

Reaction of 3a with dimethylformamide dimethylacetal:
A mixture of 3a (2.34 g, 10.0 mmol) and (1.8 g, 15.0 mmol) of dimethylformamide dimethyl acetal was dissolved in 25 mL of dry xylene and was refluxed for 6 h, then treated with petroleum ether. The solid product, so formed, was collected by filtration and recrystallized from EtOH to give 4.

(E)-Ethyl 5-cyano-4-(2-(dimethylamino)vinyl)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (4)
This compound was obtained as a brown solid (yield: 46%); IR(KBr): υ = 1610 (C=C), 1664 (C=O), 1690 (C=O), 2187 (CN) cm-1, 1H NMR (DMSO-d6): δ = 1.32 (t, 3H, J = 7.0 Hz, amide CH3), 1.68 (t, 3H, J = 7.1 Hz, ester CH3), 2.73 (s, 6H, (CH3)2N), 3.24 (q, 2H, J = 7.0 Hz, N-CH2), 4.22 (q, 2H, J = 7.1 Hz, O-CH2), 5.31 (d, 1H, J = 14 Hz, enamine H), 6.72 (d, 1H, J = 14 Hz, enamine H), 8.02 (s, 1H, pyridone C-6); 13C NMR (DMSO-d6): δ = 13.3 (CH3, amide CH3), 13.5 (CH3, ester CH3), 38.6 (CH3, two CH3, (CH3)2N), 41.0 (CH2, N-CH2), 60.7 (CH2, O-CH2), 99.8 (=C(CN)), 104 (CH enamine), 116.3 (C, pyridone C-5), 118.4 (CN), 130.1 (CH, pyridone C-6), 142.0 (CH, =CH-N enamine), 161.4 (C=O, amide), 164.9 (C=O, ester), 169.8 (C, pyridone C-4); MS, m/z (%), 289.1 (M+, 100), 260.1 (19). Anal. Calcd for C15H19N3O3: C, 62.27; H, 6.62; N, 14.52. Found: C, 62.23; H, 6.59; N, 14.47.

Cyclization of enamine 4 in the presence of NH4OAc:
A mixture of enamine 4 (2.89 g, 10.0 mmol), 1 g of ammonium acetate, and 25 mL of glacial acetic acid was refluxed for 5 h, then the crude solid product was neutralized by aqueous sodium carbonate and then the pure product was separated by long column chromatography through silica gel by using 1:3 EtOAc : n-hexane to yield 5.

Synthesis of Ethyl 8-amino-2-ethyl-1-oxo-1,2-dihydro-[2,7]naphthyridine-4-carboxylate (5)
This compound was obtained as a brown solid (yield: 27%); IR(KBr): υ = 1609 (C=C), 1669 (C=O), 1694 (C=O), 3345 (br. NH2) cm-1, 1H NMR (DMSO-d6): δ = 1.29 (t, 3H, J = 7.0 Hz, amide CH3), 1.38 (t, 3H, J = 7.1 Hz, ester CH3), 3.06 (q, 2H, J = 7.0 Hz, N-CH2), 4.26 (q, 2H, J = 7.1 Hz, O-CH2), 5.76 (s, 2H, NH2), 7.29 (d, 1H, J = 8 Hz, aromatic H), 8.32 (d, 1H, J = 8 Hz, aromatic H), 8.56 (s, 1H, aromatic H); 13C NMR (DMSO-d6): δ = 13.1 (CH3, amide CH3), 13.2 (CH3, ester CH3), 40.4 ( CH2, N-CH2), 59.7 (CH2, O-CH2), 110.3, 112.4, 116.2, 134.7, 148.6, 149.2 (aromatic C), 163.0 (C, C=O), 165.2 (C, C-NH2), 165.7 (C=O, ester); MS, m/z (%), 261.2 (M+, 100), 232.2 (32). Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C, 59.73; H, 5.75; N, 16.02.

Reaction of 3a with elemental sulfur:
A mixture of 3a (2.34 g, 10.0 mmol), and 0.5 g of elemental sulfur, 0.2 g of piperidine was dissolved in 25 mL dioxane and then was refluxed for 5 h, the reaction was followed by TLC. The solvent was removed under vacuum and then triturated with water. The solid product, so formed, was purified by crystallization from EtOH to give (6).

Ethyl 3-amino-5-ethyl-4-oxo-4,5-dihydro-thieno[3,4-c]pyridine-7-carboxylate (6)
This compound was obtained as a yellow solid (yield: 55%); IR(KBr): υ = 1610 (C=C), 1664 (C=O, amide), 1690 (C=O, ester), 3350 (br. NH2) cm-1, 1H NMR (DMSO-d6): δ = 1.24 (t, 3H, J = 7.0 Hz, amide CH3), 1.33 (t, 3H, J = 7.1 Hz, ester CH3), 3.08 (q, 2H, J = 7.0 Hz, N-CH2), 4.14 (q, 2H, J = 7.1 Hz, O-CH2), 5.96 (s, 2H, NH2), 6.84 (s, 1H, thiophene H), 8.37 (s, 1H, pyridone H); 13C NMR (DMSO-d6): δ = 13.8 (CH3, amide CH3), 14.4 (CH3, ester CH3), 40.6 ( CH2, N-CH2), 59.2 (CH2, O-CH2), 106.1 (C, pyridone C-5), 123.6 (CH, thiophene CH), 132.8, 133.2, 138.6, 140.5 (aromatic C), 163.2 (C=O, amide), 166.7 (C=O, ester); MS, m/z (%), 266.1 (M+, 100), 237.1 (21). Anal. Calcd for C12H14N2O3S: C, 54.12; H, 5.30; N, 10.52; S, 12.04. Found: C, 54.07; H, 5.24; N, 10.45; S, 11.99.

Cycloaddition reactions of thienopyridine 6 with acrylonitrile, ethyl acrylate, and with dimethyl acetylenedicarboxylate
A mixture of thienopyridine derivative 6 (2.66 g, 10.0 mmol) and 10.0 mmol of acrylonitrile, ethylacrylate or dimethyl acetylenedicarboxylate was dissolved in 25 mL dioxane and then was refluxed for 8 h, the reaction progress was followed by TLC, then the crude product was collected by filtration and purified by recrystallization from EtOH to give pure product 8, 10 and 11, respectively.

Ethyl 8-amino-7-cyano-2-ethyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylate (8)
This compound was obtained as a pale brown solid (yield: 26%); IR(KBr): υ = 1608 (C=C), 1669 (C=O, amide), 1688 (C=O, ester), 2210 (CN), 3300 (br. NH2) cm-1, 1H NMR (DMSO-d6): δ = 2.03 (t, 3H, J = 7.0 Hz, amide CH3), 2.33 (t, 3H, J = 7.2 Hz, ester CH3), 3.98 (m, 4H, J = 7.0 Hz, J = 7.2 Hz, two overlapped CH2), 5.04 (s, 2H, NH2), 7.05 (d, 1H, J = 8.4 Hz, benzene H), 7.67 (d, 1H, J = 8.4 Hz, benzene H), 7.93 (s, 1H, pyridone H); 13C NMR (DMSO-d6): δ = 13.1 (CH3, amide CH3), 13.4 (CH3, ester CH3), 41.2 ( CH2, N-CH2), 61.7 (CH2, O-CH2), 99.2 (C(CN)), 115.8 ( C, pyridone C-5,), 117.4 (CN), 118.6, 119.0, 128.2, 137.7, 140.5, 149.7, 150.3 (aromatic C,s), 162.6 (C=O, amide), 165.4 (C=O, ester); MS, m/z (%), 285.1 (M+, 100), 240.1 (29). Anal. Calcd for C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.11; H, 5.26; N, 14.67.

Diethyl 8-amino-2-ethyl-1-oxo-1,2-dihydroisoquinoline-4,7-dicarboxylate (10)
This compound was obtained as a dark brown solid (yield: 35%); IR(KBr): υ = 1605 (C=C), 1662 (C=O, amide), 1685 (C=O, ester), 1697 (C=O, ester), 3340 (br., NH2) cm-1, 1H NMR (DMSO-d6): δ = 1.43 (t, 3H, J = 7.0 Hz, amide CH3), 2.31 (m, 6H, CH3 and ester CH3, J = 7.1 Hz), 3.08 (m, 4H, two CH2, J = 7.0 Hz), 3.21 (q, 2H, J = 7.1 Hz, CH2), 5.30 (s, 2H, NH2), 7.16 (d, 1H, J = 8.3 Hz, benzene H), 7.87 (d, 1H, J = 8.3 Hz, benzene H), 8.47 (s, 1H, Pyridone H); 13C NMR (DMSO-d6): δ = 13.6 (CH3, amide CH3), 13.8 (CH3, ester CH3), 14.0 (CH3, ester CH3), 40.2 ( CH2, N-CH2), 59.1 (CH2, O-CH2), 61.3 (CH2, O-CH2), 115.4 ( C, pyridone C-5), 116.4, 116.9, 118.2, 128.4, 134.6, 139.3, 147.7 (aromatic C), 162.8 (C=O, amide), 165.4 (C=O, ester), 168.6 (C=O, ester); MS, m/z (%), 332.1 (M+, 100), 258.1 (35). Anal. Calcd for C17H20N2O5: C, 61.44; H, 6.07; N, 8.43. Found: C, 61.42; H, 6.01; N, 8.36.

Ethyl 6,7-dimethyl 8-amino-2-ethyl-1-oxo-1,2-dihydroisoquinoline-4,6,7-tricarboxylate (11)
This compound was obtained as a dark brown solid (% yield = 24); IR(KBr): υ = 1600 (C=C), 1667 (C=O, amide), 1678 (C=O, ester), 1685 (C=O, ester), 1688 (C=O, ester), 3340 (br., NH2) cm-1, 1H NMR (DMSO-d6): δ = 1.20 (t, 3H, J = 7.0 Hz, amide CH3), 1.32 (t, 3H, J = 7.2 Hz, ester CH3), 3.68 (s, 6H, two CH3), 3.94 (q, 2H, J = 7.0 Hz, N-CH2), 4.26 (q, 2H, J = 7.2 Hz, O-CH2), 5.13 (s, 2H, NH2), 7.84 (s, 1H, aromatic H), 8.63 (s, 1H, pyridone H); 13C NMR (DMSO-d6): δ = 13.5 (CH3, amide CH3), 14.8 (CH3, ester CH3), 41.9 (CH2, N-CH2), 54.2 (CH3, two ester CH3), 61.3 (CH2, O-CH2), 116.4 (C, pyridone C-5), 118.2, 118.5, 124.6, 128.0, 136.6, 139.3, 148.2 (aromatic C), 162.9 (C=O, amide), 166.1 (C=O, ester), 168.4 (C=O, ester), 168.6 (C=O, ester); MS, m/z (%), 376.1 (M+, 100), 213.1 (14). Anal. Calcd for C18H20N2O7: C, 57.44; H, 5.36; N, 7.44. Found: C, 57.40; H, 5.31; N, 7.36.

Reaction of 3a with benzylidene-malononitrile:
A mixture of pyridone 3a (2.34 g, 10.0 mmol), and (1.54 g, 10.0 mmol) of benzylidenemalononitrile, 25 mL of EtOH in the presence of piperidine was refluxed for 4 h, then the crude product formed upon cooling was collected by filtration and purified by recrystallization from EtOH to give pure product 14.

Ethyl 8-amino-7-cyano-2-ethyl-1-oxo-6-phenyl-1, 2-dihydroisoquinoline-4-carboxylate (14)
This compound was obtained as a brown solid (yield: 68%); IR(KBr): υ = 1600 (C=C), 1668 (C=O), 1684 (C=O), 2191 (CN), 3350 (br., NH2) cm-1, 1H NMR (DMSO-d6): δ = 1.21 (t, 3H, J = 7.0 Hz, amide CH3), 1.65 (t, 3H, J = 7.1 Hz, ester CH3), 3.87 (q, 2H, J = 7.0 Hz, N-CH2), 4.29 (q, 2H, J = 7.1 Hz, O-CH2), 5.37 (s, 1H, NH2), 7.65 (m, 6H, aromatic), 8.37 (s, 1H, pyridone C-6); 13C NMR (DMSO-d6): δ = 13.2 (CH3, amide CH3), 13.7 (CH3, ester CH3), 40.2 ( CH2, N-CH2), 62.3 (CH2, O-CH2), 100.4 (=C(CN)), 115.1 (C, pyridone C-5), 115.7 (CH, aromatic), 117.4 (CN), 118.6, 126.4, 132.2, 135.7, 138.6, 142.2, 149.6 (aromatic C), 163.2 (C=O, amide), 168.8 (C=O, ester); MS, m/z (%), 361.2 (M+, 98), 77.1 (34). Anal. Calcd for C21H19N3O3: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.76; H, 5.26; N, 11.57.

ACKNOWLEDGEMENTS
The support of the University of Kuwait received through research grant no. Sc 04/06 and the facilities of ANALAB and SAF (grant nos. GS01/01, GS01/03, GS03/01) are gratefully acknowledged.

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