A Mild and Efficient Method for Copper-Catalyzed Ullmann-Type N-Arylation of Aliphatic Amines and Amino Acids

Abstract

An efficient and general protocol for copper-catalyzed N-arylation of aliphatic amines and amino acids has been developed using aryl iodides under mild conditions (coupling temperature at 25-35 °C). For the N-(o-nitrophenyl) amino acid derivatives, ­subsequent reduction of the nitro group in the presence of tin(II) chloride resulted in 3,4-dihydroquinoxalin-2(1H)-one derivatives in good yields.

copper-catalyzed - aliphatic amine - amino acid - Ullmann reaction

References and Notes

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15

Synthesis of Ligands Ligands L ^¹ -L ⁴ were prepared according to the reported procedures.^18,19 General Procedure A: Coupling of Aryl Iodides with Amines: A flask was charged with CuI (19 mg, 0.1 mmol), ligand (0.2 mmol), K₃PO₄ (424 mg, 2 mmol), and any remaining solid (amine and/or aryl halide). The flask was evacuated and backfilled with nitrogen. Aryl iodide (1 mmol, if liquid) and amine (1.5 mmol, if liquid), and DMF (1.0-1.5 mL) were added to the flask under a nitrogen atmosphere. The mixture was allowed to stir under the nitrogen atmosphere at the shown temperature for the indicated period of time (see Table [2] ). After completion of the reaction, the mixture was diluted with EtOAc, the solution was filtered, and the inorganic salts were removed. The solvent in the filtrate was removed with the aid of a rotary evaporator, and the residue was purified by column chromatography on silica gel using PE-EtOAc (30:1 → 20:1) as eluent to provide the desired product (3). N -Benzyl-4-methylbenzenamine (3j): yield: 76%; yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.26-7.33 (m, 5 H), 6.95-6.98 (d, J = 7.89 Hz, 2 H), 6.52-6.55 (d, J = 7.89 Hz, 2 H), 4.28 (s, 2 H), 2.22 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 146.1, 139.8, 129.9, 129.5, 128.7, 127.6, 127.3, 126.9, 113.1, 48.8, 20.6. HRMS (EI): m/z [M⁺] calcd for C₁₄H₁₅N: 197.1204; found: 197.1213.
General Procedure B: Coupling of Aryl Iodides with Amino Acids: The procedure is similar to the general procedure A. K₃PO₄ (3.0 mmol) was used as the base. After completion of the reaction (about 12 h), H₂O (5 mL) and Et₂O (5 mL) were added to the solution. The resulting solution was partitioned into two phases, the aqueous phase was separated, and the organic fraction was extracted with 5% NaOH (3 ¥ 10 mL). The combined aqueous phase was neutralized to pH 4 with 20% HCl, and extracted with Et₂O (3 ¥ 20 mL). The resulting organic fraction was dried over MgSO₄. After removal of the solvent, the residue was purified by column chromatography on silica gel using PE-EtOAc-MeOH (30:10:3) as eluent to provide the target product (5). 2-(4-Chlorophenylamino)-4-methylpentanoic Acid (5c): yield: 87%; yellow solid; mp 132-135 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.07-7.10 (d, J = 8.94 Hz, 2 H), 6.56-6.59 (d, J = 8.94 Hz, 2 H), 3.80-3.8.3 (t, J = 5.82 Hz, 1 H), 3.82 (br s, 1 H), 1.76-1.80 (m, 1 H), 1.56-1.63 (m, 2 H), 0.92-0.95 (d, J = 6.50 Hz, 3 H), 0.86-0.89 (d, J = 6.54 Hz, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 176.0, 149.5, 129.1, 120.0, 114.2, 54.7, 41.4, 24.9, 23.3, 22.2. HRMS (EI): m/z [M + H]⁺ calcd for C₁₂H₁₇ClNO₂: 242.0948; found: 242.0953.
General Procedure C: Preparation of 3,4-Dihydroquinoxalin-2 (1 H )-one Derivatives: Tin(II) chloride (0.99 g) was added to N-(o-nitrophenyl) amino acid 5 (0.5 mmol) in MeOH (10 mL), and the mixture was refluxed for 9 h. The solution was cooled to r.t., and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (40 mL) and distilled H₂O (30 mL), and then the solution was adjusted to pH 10-11 with 1 N NaOH. The organic phase was separated, and the aqueous phase was extracted with EtOAc (40 mL). The combined organic phase was dried over MgSO₄. After removal of the solvent, the residue was purified by column chromatography on silica gel using Et₂O-EtOAc-MeOH (40:8:2) as eluent to provide the target product (6). 3-Benzyl-3,4-dihydroquinoxalin-2 (1 H )-one (6a): yield: 78%; yellow oil. ¹H NMR (300 MHz, DMSO-d ₆): d = 10.24 (s, 1 H), 7.19-7.26 (m, 5 H), 6.70-6.75 (m, 3 H), 6.57-6.59 (t, J = 8.58 Hz, 1 H), 5.82 (s, 1 H), 3.99-4.04 (m, 1 H), 2.87-2.93 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆): d = 167.4, 138.0, 134.1, 130.2, 128.6, 126.7, 126.2, 123.3, 118.1, 115.1, 114.2, 57.4, 38.1. HRMS (EI): m/z [M + H]⁺ calcd for C₁₅H₁₅N₂O: 239.1184; found: 239.1193.

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