Pd-Catalyzed One-Pot Borylation/Intramolecular Asymmetric Arylation on α-Ketiminoamides: Innovative Approach to Chiral 3-Amino-2-oxindoles

Abstract

3-Amino-2-oxindole derivatives are a common framework found in many natural products and medicinal compounds and thus their synthesis is of significant importance. We report for the first time a one-pot approach for the synthesis of these compounds, using a bory­lation/intramolecular asymmetric arylation sequence starting from ­ortho-bromo-α-ketimino amide derivatives. Pd(OAc)₂ was used as the pre-catalyst along with (R)-BINAP as the chiral source. We successfully obtained a family of 3-phenyl-3-(aryl-amino)-indolin-2-one derivatives (11 in total) with excellent yields (up to 98%) and enantioselectivities of up to 76% ee. The reaction is versatile and tolerant of a wide range of functional groups.

Key words

oxindoles - intramolecular - bis(pinacolate)diboron - palladium - arylation - α-ketimines

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• 18 General Procedure for the Asymmetric Synthesis of Chiral 3-Amino-2-oxindolesIn a Radley’s^® 12 position carousel reactor under a nitrogen atmosphere was added Pd(OAc)₂ (0.0125 mmol, 5 mol%), chiral ligand (0.025 mmol, 10 mol%), and 1,4-dioxane (1 mL). The mixture was stirred for 30 min at room temperature, then the corresponding ortho-bromo-α-ketimino amide substrate 1 (0.25 mmol), B₂Pin₂ (0.28 mmol, 1.1 equiv), KOAc (0.76 mmol), and 1,4-dioxane (1 mL) were added sequentially to the reaction vessel. The reaction was left stirring at 100 °C during 18 h. After cooling to room temperature, the crude mixture was purified by silica gel chromatography using hexane/AcOEt (5:1) as eluent to afford the desired 3-phenyl-3-(aryl-amino)-indolin-2-one derivatives 2.Compound 2a: Pale yellow solid; mp 86.2–87.8 °C. ¹H NMR (400 MHz, CDCl₃) δ = 3.26 (s, CH₃, 3 H), 6.34–6.36 (d, Ar, 2 H, J = 8 Hz), 6.67–6.71 (t, Ar, 1 H, J = 8 Hz), 6.92–6.94 (d, Ar, 1 H, J = 8 Hz), 6.98–7.02 (t, Ar, 2 H, J = 8 Hz), 7.08–7.12 (t, Ar, 1 H, J = 8 Hz), 7.33–7.42 (m, Ar, 5 H), 7.55–7.57 (d, Ar, 2 H, J = 8 Hz). ¹³C NMR (100 MHz, CDCl₃) δ = 26.80, 68.08, 108.90, 115.54, 119.40, 123.32, 125.42, 126.73, 128.73, 129.07, 129.12, 129.51, 130.37, 140.19, 143.28, 145.09, 177.05. FTIR: 1499, 1722, 3055, 3373 cm^–1. ESI-HRMS: m/z calcd for C₂₁H₁₈N₂O: 314.14191; found for C₂₁H₁₈N₂ONa: 337.13113 [M⁺ + Na]. HPLC: Daicel Chiralpak IA column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, 220 nm; t _R = 32.447 min (R, minor), 38.080 min (S, major).
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