Mannich Reaction of Imines and Silyl Enol Ethers Induced by Radical Cation Salts: Synthesis of β-Amino Ketones

Abstract

Mannich reaction of imines and sily enol ethers induced by radical cation salts was investigated and a series of β-amino ketones were synthesized. Reverse diastereoselectivity was obtained in the reactions of imines and silyl enol ethers of pentan-2-one and pentan-3-one, respectively, which was rationalized by quantum mechanical calculations. A single electron-transfer mechanism was proposed in which the imine radical cation acts as an electrophilic species in this transformation.

Key words

Mannich reaction - radical cation salts - imines - silyl enol ether - β-amino ketones

References and Notes

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General Procedure for TBPA ⁺ -Induced Reaction of 1a and 2a
An anhyd CH₂Cl₂ solution (20 mL) of imine (1a, 1 mmol) and silyl enol ether (2a, 2 mmol) was added dropwise to a stirred solution of a catalytic amount of TBPA⁺ (0.05 mmol) suspended in anhyd CH₂Cl₂ (20 mL) at ambient temperature. The reaction completed within 60 min monitored by TLC. After simple column chromatographic purification (silica gel, hexane-acetone = 10:1) gave the pure product 3a.
Representative Spectral Data of the Products
Compound 3a: ^¹H NMR (400 MHz, CDCl₃): δ = 3.39-3.54 (m, 2 H), 4.55 (br, NH, 1 H), 5.00 (t, J = 6.4 Hz, 1 H), 6.56 (d, J = 8.8 Hz, 2 H), 6.66 (t, J = 7.2 Hz, 1 H), 7.09 (t, J = 8.0 Hz, 2 H), 7.21-7.28 (m, 2 H), 7.30-7.36 (m, 2 H), 7.42-7.46 (m, 3 H), 7.48-7.58 (m, 1 H), 7.91 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 46.3, 54.8, 113.8, 117.7, 126.3, 127.3, 128.2, 128.7, 128.8, 129.1, 133.4, 136.7, 143.0, 147.0, 198.2. MS (EI): m/z (%) = 301 (3.1), 280 (20.2), 209 (15.7), 208 (100), 207 (96.0), 182 (19.6), 131 (37.9), 105 (40.4), 103 (39.0), 77 (80.2). ESI-HRMS: m/z calcd for C₁₇H₁₈N₂O₃ + H: 302.1539; found: 302.1543.

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Representative Spectral Data of the Products Compound syn -4r: ^¹H NMR (400 MHz, CDCl₃): δ = 0.86 (t, J = 7.2 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.99-2.00 (m, 1 H), 2.25-2.35 (m, 1 H), 3.01-3.08 (m, 1 H), 4.43 (d, J = 4.4 Hz, 1 H), 5.10 (br, NH, 1 H), 6.37 (d, J = 8.8 Hz, 2 H), 7.12 (d, J = 8.8 Hz, 2 H), 7.19-7.31 (m, 5 H). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 7.1, 15.6, 36.5, 51.7, 60.5, 108.7, 114.8, 126.3, 127.5, 128.7, 131.7, 141.1, 145.9, 215.4. MS (EI):
m/z (%): 347 (6.1), 345 (6.0), 262 (92.6), 260 (100), 216 (9.4), 184 (12.1), 182 (14.2), 157 (7.4), 155 (7.8), 117 (11.6). ESI-HRMS: m/z calcd for C₁₈H₂₀BrNO + H⁺: 346.0801; found: 346.0807.
Compound anti-4r: ^¹H NMR (400 MHz, CDCl₃): δ = 0.93 (t, J = 7.2 Hz, 3 H), 1.09 (d, J = 7.2 Hz, 3 H), 2.31-2.36 (m, 2 H), 3.98-3.01 (m, 1 H), 4.44 (br, NH, 1 H), 4.59 (d, J = 5.6 Hz, 1 H), 6.36 (d, J = 8.8 Hz, 2 H), 7.13 (d, J = 9.2 Hz, 2 H), 7.24-7.33 (m, 5 H). ^¹³C NMR (100.6 MHz, CDCl₃): δ = 7.5, 11.5, 35.6, 52.0, 59.2, 109.4, 115.2, 126.8, 127.5, 128.7, 131.7, 140.5, 145.9, 213.4. MS (EI): m/z (%): 347 (3.7), 345 (3.9), 262 (92.5), 260 (100), 184 (11.5), 182 (13.1), 157 (12.4), 155 (12.4), 117 (28.4), 57 (71.4). ESI-HRMS: m/z calcd for C₁₈H₂₀BrNO + H⁺: 346.0801; found: 346.0806.

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Crystallographic data for the structure analysis have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 779685 for syn-4r and CCDC 779686 for anti-4r.