Direct Synthesis of α-Amino Amides from N-Alkyl Amines by the Copper-Catalyzed Oxidative Ugi-Type Reaction

Abstract

α-Amino amides can be accessed directly form N-alkyl amines by the isocyanide-compatible oxidative copper-peroxide conditions even in the presence of water. Various functional groups are tolerated in the reaction, leading to the synthesis of various α-amino amides in moderate yield. A plausible mechanism is proposed in which an oxidative Ugi-type three-component pathway is supposed to be involved.

Key words

α-amino amide - isocyanide - Ugi reaction - copper catalysis - multicomponent reaction

References and Notes

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14

Representative Procedure for the Three-Component Reaction
Into an oven-dried flask, N,N-dimethylaniline (1a, 242 mg, 2.0 mmol), 1-(isocyanomethylsulfonyl)-4-methylbenzene (2a, 195 mg, 1.0 mmol), CuCl (10 mg, 0.1 mmol), Ph₃P (26 mg, 0.1 mmol), and TBHP (70% aq, 2.4 mmol) were added at r.t.. Under the protection of N₂, MeCN (5 mL) was added, and the reaction mixture was allowed to react at 80 ˚C for 6 h. After the end of the reaction, the mixture was filtered through a pad of Celite, and the filtrate was concentrated until the solvent was completely removed. The residue was then separated on a silica gel column, and the final product was obtained as a yellow powder (190 mg, 57%). ^¹H NMR (400 MHz, CDCl₃, TMS): δ = 7.72 (d, J = 8.8 Hz, 2 H), 7.29-7.35 (m, 3 H), 7.27 (m, 1 H), 6.89 (t, J = 7.4 Hz, 1 H), 6.68 (d, J = 7.6 Hz, 2 H), 4.69 (d, J = 7.2 Hz, 2 H), 3.75 (s, 2 H), 2.99 (s, 3 H), 2.46 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 170.4, 149.0, 145.6, 133.7, 130.0, 129.5, 128.9, 119.3, 113.4, 59.8, 58.6, 40.1, 21.8. HRMS (EI): m/z calcd for C₁₇H₂₀N₂O₃S [M]⁺: 332.1195; found: 332.1186.