Synlett 2019; 30(09): 1048-1052
DOI: 10.1055/s-0037-1611529
© Georg Thieme Verlag Stuttgart · New York

Nickel-Catalyzed β-Carboxylation of Ynamides with Carbon Dioxide

Ryohei Doi
Taichi Okano
Iman Abdullah
Japan Science and Technology Agency (ACT-C / JPMJCR12YM), Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research (B), 2629300).
Further Information

Publication History

Received: 01 April 2019

Accepted after revision: 15 April 2019

Publication Date:
08 May 2019 (online)

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


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.

Supporting Information

  • 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.