Heteropoly Acids Catalyzed Direct Mannich Reactions: Three-Component Synthesis of N-Protected β-Amino Ketones

Abstract

Heteropoly acids efficiently catalyzed one-pot three-component Mannich reactions of aryl aldehydes, aryl ketones, and carbamates at ambient temperature and afforded the corresponding N-protected β-amino ketones in good to excellent yields. This method provides a novel and improved modification of three-component Mannich reactions in terms of a wide scope of aldehydes, ketones and carbamates, economic viability and reusability.

Key words

heteropoly acids - one-pot - Mannich reaction - N-protected β-amino ketones

References and Notes

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16

Typical Procedure for the Synthesis of N-Protected β-Amino Ketones To a solution of HPAs (5 mol%) in MeCN (1.0 mL) were added ethyl carbamate (1.5 mmol), benzaldehyde (1.0 mmol), and acetophenone (2.0 mmol) successively at r.t. After the mixture was stirred for 24 h, a sat. aq NaHCO₃ solution (5 mL) and brine (5 mL) were added, and the mixture was extracted with EtOAc. The organic phase was dried (anhyd Na₂SO₄) and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified by silica gel chromatography and gave the desired product.
Compound 4d: mp 96-97 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.89 (d, J = 7.4 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 2 H), 7.20 (t, J = 8.0 Hz, 1 H), 6.76-6.93 (m, 3 H), 5.70 (br s, 1 H), 5.25 (dd, J ₁ = 6.0 Hz, J ₂ = 13.6 Hz, 1 H), 4.08 (dd, J ₁ = 7.0 Hz, J ₂ = 14.1 Hz, 2 H), 3.77 (s, 3 H), 3.65 (m, 1 H), 3.40 (dd, J ₁ = 5.8 Hz, J ₂ = 16.7 Hz, 1 H), 1.20 (t, J ₁ = 6.7 Hz, J ₂ = 14.0 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 197.8, 159.8, 155.9, 143.2, 136.7, 133.3, 129.7, 128.7, 128.1, 118.6, 112.7, 112.4, 60.9, 55.2, 51.7, 44.0, 14.6. ESI-HRMS: m/z calcd for [C₁₉H₂₁NO₄ + Na]⁺: 350.3641; found: 350.3638.
Compound 4j: mp 116-117 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.24 (s, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 7.4 Hz, 2 H), 7.73 (d, J = 7.2 Hz, 1 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.44-7.50 (m, 3 H), 5.99 (br s, 1 H), 5.38 (dd, J ₁ = 5.6 Hz, J ₂ = 13.0 Hz, 1 H), 4.09 (dd, J ₁ = 7.0 Hz, J ₂ = 14.2 Hz, 2 H), 3.72-3.75 (m, 1 H), 3.50 (dd, J ₁ = 5.4 Hz, J ₂ = 17.4 Hz, 1 H), 1.23 (t, J ₁ = 6.4 Hz, J ₂ = 14.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 197.3, 156.0, 148.5, 144.0, 136.3, 133.8, 132.9, 129.5, 128.8, 128.1, 122.4, 121.4, 61.3, 50.9, 43.5, 14.5. ESI-HRMS: m/z calcd for [C₁₈H₁₈N₂O₅ + Na]⁺: 365.3358; found: 365.3460.
Compound 4s: mp 81-82 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.86 (d, J = 7.7 Hz, 2 H), 7.52 (t, J = 7.1 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 2 H), 7.19-7.31 (m, 6 H), 6.88 (t, J = 7.7 Hz, 2 H), 6.75 (dd, J ₁ = 2.2 Hz, J ₂ = 8.2 Hz, 1 H), 5.86 (br s, 1 H), 5.28 (dd, J ₁ = 6.2 Hz, J ₂ = 13.1 Hz, 1 H), 5.05-5.10 (m, 2 H), 3.74 (s, 3 H), 3.65 (m, 1 H), 3.39 (dd, J ₁ = 5.2 Hz, J ₂ = 16.5 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 197.8, 159.8, 155.7, 136.7, 136.5, 133.4, 129.7, 128.7, 128.5, 128.1, 118.6, 112.8, 112.4, 66.8, 55.2, 51.8, 44.0. ESI-HRMS: m/z calcd for [C₂₄H₂₃NO₄ + Na]⁺: 412.4335; found: 412.4330.
Compound 4w: mp 143-144 °C. ¹H NMR (600 MHz, CDCl₃): δ = 8.15 (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 7.6 Hz, 2 H), 7.34-7.54 (m, 10 H), 6.08 (br s, 1 H), 5.40 (d, J = 6.2 Hz, 1 H), 5.10-5.15 (m, 2 H), 3.73-3.76 (m, 1 H), 3.49 (dd, J ₁ = 4.6 Hz, J ₂ = 17 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 197.3, 155.7, 148.8, 147.1, 136.2, 133.9, 128.8, 128.3, 127.0, 123.8, 51.2, 43.2. ESI-HRMS: m/z calcd for [C₂₃H₂₀N₂O₅ + Na]⁺: 427.4052; found: 427.4055