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

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.

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

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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.