Synthesis of trans-3-Substituted Cyclohexylamines via Brønsted Acid Cata­lyzed and Substrate-Mediated Triple Organocatalytic Cascade Reaction

Abstract

We report a new organocatalytic cascade reaction. A combination of the amine substrate with a catalytic amount of a Brønsted acid merges enamine and iminium catalysis with Brønsted acid catalysis in a new organocatalytic cascade reaction. We found that the aniline substrate itself in combination with a catalytic amount of PTSA·H₂O can function as an aminocatalyst accomplishing an aldol condensation-conjugate reduction cascade, which ­terminates in a Brønsted acid catalyzed reductive amination incorporating the amine substrate into the final product. This transformation furnishes trans-3-substituted cyclohexyl amines in good yields and good diastereoselectivities.

organocatalytic cascade reaction - substrate co-catalyzed - 3-substituted cyclohexyl amine - organocatalysis

References and Notes

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13

Typical Procedure: To a Schlenk tube was added 2,6-dione 1 (0.2 mmol), p-ethoxyphenyl amine 2 (0.3 mmol), Hantzsch ester 3 (0.45 mmol) and PTSA·H₂O (2 mg, 0.01 mmol), and then charged with argon, followed by adding MS 5 Å (50 mg) and anhyd toluene (0.5 mL). The mixture was stirred at 40 °C for 24-72 h. To determine the ratio of trans- to cis-product, 20 µL of the reaction mixture was taken for GC-MS analysis, or 0.2 mL of crude mixture for ¹H NMR analysis. The sample for analysis and the rest were emerged together for column chromatography purification using hexane-EtOAc (96:4) or CH₂Cl₂ as eluent. Compound trans-4a was obtained as colorless liquid (0.144 mmol, 72%) after chromatography with hexane-EtOAc (96:4). ¹H NMR (300 MHz, CDCl₃): δ = 0.91 (d, J = 6.4 Hz, 3 H), 0.99-1.10 (m, 1 H), 1.27-1.37 (m, 1 H), 1.36 (t, J = 6.9 Hz, 3 H), 1.47-1.78 (m, 7 H), 3.20-3.50 (s, br, 1 H), 3.56-3.60 (m, 1 H), 3.95 (q, J = 6.9 Hz, 2 H), 6.53-6.58 (m, 2 H), 6.74-6.79 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 15.05, 20.52, 21.69, 27.13, 30.54, 33.98, 38.96, 48.54, 64.17, 114.60, 115.88, 141.68, 151.04. MS (EI): m/z (%) = 233 (100) [M⁺], 234 (14) [M + H]⁺, 190 (40), 108 (39), 176 (32), 204 (22), 137 (18), 97 (10). HRMS (EI): m/z calcd for C₁₅H₂₄NO [M + H]⁺: 234.1852; found: 234.1852.

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