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Synlett 2009(14): 2249-2252  
DOI: 10.1055/s-0029-1217719
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Mild Protocol for the Efficient Synthesis of 5,6-Unsubstituted 1,4-Dihydropyridines

Swarupananda Maiti, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax: +34(91)3941822; e-Mail: josecm@farm.ucm.es;
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Publication History

Received 30 April 2009
Publication Date:
29 July 2009 (online)

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Abstract

Treatment of 6-alkoxy-1,4,5,6-tetrahydropyridines with neutral alumina (activity grade I) suspended in refluxing aceto­nitrile, afforded 1,4-dihydropyridines in excellent yields. This method allowed the efficient synthesis of 5,6-unsubstituted dihydropyridines, which are difficult to prepare by traditional methods, from acyclic and readily available precursors.

Key words

eliminations - heterocycles - dihydropyridines - cerium(IV) - Lewis acids

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19

General experimental procedure: To a solution of a suitable primary amine (1.1 mmol) and β-keto ester (1 mmol) in anhydrous MeCN (5 mL) was added CAN (5 mol%). The solution was stirred at room temperature for 30 minutes. To this solution was added a suitable α,β-unsaturated aldehyde (1.1 mmol) in EtOH (3 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with CH2Cl2
(15 mL) and washed with water (3 × 5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. The crude residue was dissolved in MeCN (10 mL) and neutral, grade I activity Al2O3 (5 g) was added. The suspension was heated under reflux for the time specified in Table  [²] . After completion of the reaction (verified by NMR), the mixture was diluted with CH2Cl2 and filtered through a layer of Celite, which was thoroughly washed with boiling CH2Cl2 (50 mL, in several portions). The organic layer was washed with water (5 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The crude residue was purified by column chromatography on neutral Al2O3 (EtOAc-petroleum ether, 98:2 containing 1% Et3N). Characterization data for representative compounds 2 are given below.
Ethyl 1-Butyl-2-methyl-1,4-dihydropyridine-3-carboxylate (2a). Colorless viscous liquid. IR (neat, NaCl): 2960, 2932, 2874, 1681, 1567, 1233, 1178, 1145, 1073 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.29-1.38 (m, 2 H), 1.44-1.56 (m, 2 H), 2.31 (s, 3 H), 3.1 (d, J = 3.5 Hz, 2 H), 3.2 (t, J = 7.2 Hz, 2 H), 4.05-4.13 (m, 2 H), 4.68-4.75 (m, 1 H), 5.67 (d, J = 7.9 Hz, 1 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 14.3, 14.9, 15.8, 20.3, 24.9, 32.7, 50.2, 59.6, 94.9, 104.2, 130.9, 150.9, 169.6. Anal. Calcd for C13H21NO2 (223.3): C, 69.92; H, 9.48; N, 6.27; Found: C, 69.65; H, 9.23; N, 6.12.
Ethyl 1-Butyl-2,4-dimethyl-1,4-dihydropyridine-3-carboxylate (2e). Colorless viscous liquid. IR (neat, NaCl): 2958, 2930, 2872, 1684, 1560, 1232, 1177, 1137, 1088
cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 0.92-0.98 (m, 6 H), 1.27 (t, J = 6.4 Hz, 3 H), 1.33-1.42 (m, 2 H), 1.48-1.59 (m, 2 H), 2.38 (s, 3 H), 3.11-3.23 (m, 1 H), 3.32-3.52 (m, 2 H), 4.07-4.20 (m, 2 H), 4.87 (dd, J = 7.4, 6.2 Hz, 1 H), 5.81 (d, J = 7.4 Hz, 1 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 14.3, 14.9, 16.0, 20.2, 25.3, 28.5, 32.8, 50.2, 59.5, 101.0, 109.2, 129.6, 149.3, 169.7. Anal. Calcd for C14H23NO2 (237.3): C, 70.85; H, 9.77; N, 5.90. Found: C, 70.57; H, 9.50; N, 6.00.
Ethyl 1-Butyl-2-methyl-4-phenyl-1,4-dihydropyridine-3-carboxylate (2k). Light-yellow viscous liquid. IR (neat, NaCl): 2959, 2872, 1682, 1557, 1393, 1230, 1178, 1145, 1078 cm-¹. ¹H NMR (250 MHz, CDCl3): δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.13 (t, J = 7.1 Hz, 3 H), 1.31-1.46 (m, 2 H), 1.55-1.68 (m, 2 H), 2.49 (s, 3 H), 3.21-3.32 (m, 1 H), 3.44-3.56 (m, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 4.60 (d, J = 5.6 Hz, 1 H), 4.96 (dd, J = 5.6, 7.5 Hz, 1 H), 5.91 (d, J = 7.6 Hz, 1 H), 7.15-7.55 (m, 5 H). ¹³C NMR (62.9 MHz, CDCl3): δ = 14.3, 14.7, 16.2, 20.1, 32.7, 40.5, 50.4, 59.5, 99.9, 108.2, 126.3, 127.7 (2 × C), 128.6 (2 × C), 129.3, 149.1, 149.7, 169.6. Anal. Calcd for C19H25NO2 (299.4): C, 76.22; H, 8.42; N, 4.68. Found: C, 75.98; H, 8.31; N, 4.23.