Nickel-Catalyzed β-Carboxylation of Ynamides with Carbon Dioxide

^◊ Current address: Department of Chemistry, Faculty of Mathematic and Natural Sciences, Universitas Indonesia, Depok 16424, Indonesia

Abstract

A nickel-catalyzed β-selective hydrocarboxylation of ynamides to give protected dehydro-β-amino acids was developed. The key to exclusive β-selectivity was the use of diethylzinc as a reductant in the presence of a magnesium salt. The reaction was conducted with bis(acetylacetonato)nickel(II) instead of costly and sensitive bis(1,5-cyclooctadiene)nickel(0). In addition, the optimized ligand was inexpensive 1,5-cyclooctadiene. Investigation of the substrate scope revealed that both nitrogen and alkyne substituents have marked effects on the reaction efficiency. We obtained experimental clues that indicated the formation of a vinylzinc intermediate that forms a C–C bond with CO₂.

Key words

ynamides - hydrocarboxylation - carbon dioxide - nickel catalysis - β-amino acids

• References and Notes


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• 14 β-Aminoalkenoate Esters 2a–n; General Procedure A Schlenk flask equipped with a rubber septum and a stirring bar was charged with Ni(acac)₂ (5.1 mg, 0.02 mmol) and MgBr₂ (110 mg, 0.6 mmol) under N₂ and cooled to 0 °C. A solution of the appropriate ynamide 1 (0.2 mmol) in NMP (2 mL) and COD (24 μL, 0.2 mmol) were both added from syringes. The vessel was degassed by a freeze–pump–thaw cycle, and CO₂ was introduced by using a balloon. A 1 M solution of ZnEt₂ in toluene (0.6 mL, 0.6 mmol), at the same temperature, was added and the mixture was heated to 50 °C for 1 h. When the starting material had disappeared (TLC), the solution was cooled in an ice bath, and the reaction was quenched with 3 M aq HCl. The aqueous layer was separated and extracted with Et₂O, and the combined organic layer was washed sequentially with H₂O and brine, dried (Na₂SO₄), and concentrated. The residue was dissolved in 1:4 MeOH–Et₂O and treated with TMSCHN₂, with careful monitoring by TLC. The resulting solution was concentrated and purified by column chromatography. Methyl (2E)-2-Butyl-3-{(tert-butyl)[(4-methylphenyl)sulfonyl]amino}acrylate (2h) Prepared as a colorless oil from ynamide 1h (61.5 mg, 0.2 mmol) by following the general procedure; yield: 57.4 mg (78%). ¹H NMR (400 MHz, CDCl₃, r.t.): δ = 7.65 (2 H, d, J = 8.5 Hz), 7.25 (2 H, d, J = 4.0 Hz), 6.74 (1 H, s), 3.76 (3 H, s), 2.39 (3 H, s), 2.22 (2 H, t, J = 7.9 Hz), 1.30 (9 H, s), 1.24–1.19 (4 H, m), 0.83 (3 H, t, J = 7.2 Hz).13C NMR (100 MHz, CDCl₃, r.t.): δ = 167.6, 143.3, 140.2, 138.3, 134.1, 129.5, 129.4, 127.7, 115.2, 61.6, 51.9, 29.6, 29.4, 27.2, 23.2, 21.5, 13.8. HRMS (EI): m/z [M + Na] calcd for C₁₉H₂₉NNaO₄S: 390.1715; found: 390.1714. For additional procedures and characterization data, see the Supporting Information.