Application of the Nitroaldol (Henry) Reaction for a Two-Step Sequence in the Synthesis of Polyfunctionalized Dihydropyran Derivatives

Abstract

Nitroaldol (Henry) reaction of a variety of nitroalkanes, under neat t-BuOK catalysis, allows a one-pot synthesis of polyfunctionalized tetrahydropyranols which, with CeCl₃·7H₂O/NaI system, dehydrate to dihydropyran derivatives. Thus, the dihydro­pyrans can be obtained in only two steps from nitroalkanes.

Key words

nitroalkanes - nitroaldol (Henry) reaction - dihydro­pyrans - two-step sequence - neat conditions - cerium(III) chloride

References and Notes

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10

General Procedure for the Preparation of Dihydropyrans 5: To a stirred solution of aldehyde 1 (0.186 g, 1.0 mmol) and nitroalkane 2 (1.0 mmol), cooled at 0 °C, t-BuOK (33.6 mg, 0.3 mmol) was added. After 5 min the mixture was stirred at r.t. for 6-9 h (TLC), then treated with 0.5 N HCl (5 mL) and extracted with Et₂O (3 × 10 mL). The combined layers were dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure. To the obtained crude compound 4, dissolved in MeCN (10 mL), cerium(III) chloride heptahydrate (1.5 mmol) and NaI (1.5 mmol) were added and the obtained solution was refluxed for 6-8 h (TLC). The reaction mixture was then treated with 0.5 N HCl (5 mL) and the organic phase was extracted with Et₂O (3 × 10 mL). The organic layer was dried (Na₂SO₄), filtered, evaporated and purified by flash chromatography (hexane-EtOAc, 9:1), yielding the pure dihydropyranols 5.

11

Selected Analytical Data for Compounds 5′a,h,k and 5′′a,h,k: Compound 5a′: waxy solid. IR: 1702, 1638, 1562 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.97 (t, J = 7.3 Hz, 3 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.50-1.61 (m, 1 H), 1.74-1.85 (m, 1 H), 1.88-2.01 (m, 2 H), 2.14 (s, 3 H), 2.20-2.31 (m, 1 H), 2.35-2.44 (m, 1 H), 4.12 (q, J = 7.3 Hz, 2 H), 4.25 (dt, J = 2.6, 9.0 Hz, 1 H), 4.42-4.50 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 10.2, 14.6, 20.1, 20.7, 23.0, 23.1, 60.1, 76.0, 92.3, 101.9, 163.3, 168.1. EIMS (70 eV): m/z = 257, 240, 212, 149, 139, 121, 97, 55, 43 (100), 29. Anal. Calcd for C₁₂H₁₉NO₅ (257.28): C, 56.02; H, 7.44; N, 5.44. Found: C, 56.56; H, 7.68; N, 5.12.
Compound 5a′′: yellow oil. IR: 1706, 1633, 1557 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.55-1.67 (m, 1 H), 1.87-1.95 (m, 1 H), 1.96-2.14 (m, 2 H), 2.17-2.30 (m, 1 H), 2.20 (s, 3 H), 2.40-2.51 (m, 1 H), 4.09-4.17 (m, 3 H), 4.46-4.53 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 10.5, 14.6, 20.1, 20.9, 23.4, 23.5, 60.1, 75.6, 91.5, 102.4, 163.4, 168.2. EIMS (70 eV): m/z = 257, 240, 212, 149, 139, 121, 97, 55, 43 (100), 29. Anal. Calcd for C₁₂H₁₉NO₅ (257.28): C, 56.02; H, 7.44; N, 5.44. Found: C, 56.41; H, 7.71; N, 5.24.
Compound 5h′: waxy solid. IR: 1740, 1703, 1635, 1551 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (t, J = 7.3 Hz, 3 H), 1.28-1.45 (m, 2 H), 1.50-1.77 (m, 4 H), 1.91-2.03 (m, 2 H), 2.15 (s, 3 H), 2.20-2.35 (m, 3 H), 2.37-2.46 (m, 1 H), 3.64 (s, 3 H), 4.14 (q, J = 7.3 Hz, 2 H), 4.21-4.27 (m, 1 H), 4.51-4.58 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.6, 20.1, 20.7, 23.1, 24.3, 25.2, 29.3, 33.7, 51.9, 60.1, 76.0, 90.7, 102.0, 163.3, 168.1, 173.7. EIMS: m/z = 343, 312, 298, 251, 167, 139, 97, 55, 43 (100), 29. Anal. Calcd for C₁₆H₂₅NO₇ (343.37): C, 55.97; H, 7.34; N, 4.08. Found: C, 56.25; H, 7.55; N, 3.91.
Compound 5h′′: yellow oil. IR: 1737, 1706, 1633, 1557 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (t, J = 7.3 Hz, 3 H), 1.30-1.43 (m, 2 H), 1.53-1.75 (m, 4 H), 1.85-1.99 (m, 2 H), 2.19 (s, 3 H), 2.20-2.35 (m, 3 H), 2.40-2.52 (m, 1 H), 3.64 (s, 3 H), 4.08-4.18 (m, 3 H), 4.52-4.58 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.6, 20.1, 20.9, 23.4, 24.4, 25.5, 29.6, 33.7, 51.8, 60.1, 75.7, 89.9, 102.4, 163.3, 168.1, 173.8. EIMS: m/z = 343, 312, 298, 251, 167, 139, 97, 55, 43 (100), 29. Anal. Calcd for C₁₆H₂₅NO₇ (343.37): C, 55.97; H, 7.34; N, 4.08. Found: C, 56.27; H, 7.51; N, 3.87.
Compound 5k′: yellow oil. IR: 1719, 1641, 1556 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (t, J = 7.3 Hz, 3 H), 1.59-1.69 (m, 1 H), 1.98-2.11 (m, 1 H), 2.12-2.35 (m, 9 H), 2.41-2.62 (m, 3 H), 4.15 (q, J = 7.3 Hz, 2 H), 4.27 (dt, J = 2.6, 9.8 Hz, 1 H), 4.56-4.64 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.6, 20.1, 20.6, 23.1, 23.4, 30.3, 38.7, 60.2, 76.0, 89.9, 102.1, 163.2, 168.1, 206.2. EIMS: m/z = 299, 254, 163, 97, 55, 43 (100), 29. Anal. Calcd for C₁₄H₂₁NO₆ (299.32): C, 56.18; H, 7.07; N, 4.68. Found: C, 55.88; H, 6.89; N, 4.79.
Compound 5k′′: yellow oil. IR: 1715, 1631, 1557 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (t, J = 7.3 Hz, 3 H), 1.56-1.67 (m, 1 H), 1.88-1.95 (m, 1 H), 2.10-2.33 (m, 3 H), 2.13 (s, 3 H), 2.17 (s, 3 H), 2.41-2.63 (m, 3 H), 4.12 (q, J = 7.3 Hz, 2 H), 4.16-4.21 (m, 1 H), 4.56-4.62 (m, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.6, 20.1, 21.0, 23.2, 23.4, 30.2, 39.1, 60.1, 75.9, 88.9, 102.4, 163.4, 168.1, 206.6. EIMS: m/z = 299, 254, 163, 97, 55, 43 (100), 29. Anal. Calcd for C₁₄H₂₁NO₆ (299.32): C, 56.18; H, 7.07; N, 4.68. Found: C, 56.45; H, 7.32; N, 4.28.