MgCl₂-Catalyzed α-Amination of α-Alkyl-β-ketoesters via Oxidative N-Acylnitroso Aldol Reaction with Hydroxamic Acids

Abstract

A practical method for α-amination of α-alkyl-β-keto­esters using hydroxamic acids is described. In this protocol, an oxidative N-acylnitroso aldol reaction is catalyzed by magnesium chloride in the presence of the oxidant tert-butyl hydroperoxide.

Key words

amination - α-alkyl-β-ketoesters - catalysis - magnesium chloride - acylnitroso

• References and Notes

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• 15 General Experimental Procedure for the MgCl₂-Catalyzed α-Amination of α-Alkyl-β-ketoesters TBHP (5–6 M in decane, 0.48 mmol) was added dropwise to a mixture of β-ketoesters 1 (0.48 mmol), hydroxamic acids 2 (0.40 mmol), and MgCl₂ (3.8 mg, 0.040 mmol) in MeCN (2 mL). The reaction was stirred at 40 °C for the indicated time; reaction completion was confirmed based on the disappearance of hydroxamic acids (Table 2). Then the reaction mixture was cooled to r.t., quenched with aq NaHSO₃ solution and extracted with CH₂Cl₂ three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and then concentrated in vacuo. The residue was purified by column chromatography to afford amination product 3. This General Experimental Procedure was carried out using 1a (69.2 mg, 0.48 mmol) and 2a (53.2 mg, 0.40 mmol). The reaction mixture was stirred for 34 h at 40 °C and purified by silica gel chromatography using PE– CH₂Cl₂–EtOAc (4:1:0.75) as eluent to give product 3a (94.3 mg, 85%) as a colorless oil. The structure of 3a was identified by comparison of its ¹H NMR and ¹³C NMR spectra with the reported data in ref. 8. See the Supporting Information for experimental details and characterization data for all new compounds.

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• 17 Chiral HPLC analysis conditions for 3a: Chiralcel AD-H column (0.46 cm × 25 cm), hexanes–i-PrOH (97:3), flow rate = 1.0 mL/min, λ = 210 nm, t _R 1 = 16.4 min, t _R 2 = 19.8 min.