Dehydrogenative Cross-Coupling Reactions of N-Aryl α-Amino Acid Esters with Nitroalkanes for the Synthesis of β-Nitro α-Amino Acid Esters

Abstract

A novel copper-catalyzed dehydrogenative cross-coupling reaction of N-aryl α-amino acid esters with nitroalkanes to give β-nitro α-amino acid esters was developed. Various N-aryl α-amino acid esters reacted smoothly with nitroalkanes to give the desired coupling products in moderate to good yields. The method uses a cheap and simple copper salt as a catalyst and molecular oxygen as an environmentally benign oxidant. A possible mechanism for the dehydrogenative cross-coupling reaction is proposed.

Key words

dehydrogenation - cross-coupling - copper catalysis - amino acid esters - nitroalkanes

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• 8 β-Nitro α-Amino Acid Esters 3; General Procedure Et₃N (2.0 mg, 0.02 mmol) was added to a mixture of CuI (3.8 mg, 0.02 mmol), the appropriate N-aryl glycine ester 1 (0.2 mmol), and nitroalkane 2 (2 mmol) in CH₂Cl₂ (1 mL), and the mixture was stirred at 30 °C under O₂ (1 atm) for 24 h. When the reaction was complete, the mixture was concentrated under vacuum and the residue was purified by column chromatography (silica gel, PE–EtOAc). Ethyl 3-Nitro-N-(4-tolyl)alaninate (3aa) Brown oil; yield: 35.8 mg (71%). ¹H NMR (400 MHz, CDCl₃): δ = 7.03 (d, J = 8.4 Hz, 2 H), 6.60 (dd, J = 6.8, 2.0 Hz, 2 H), 4.87–4.75 (m, 2 H), 4.63–4.58 (m, 1 H), 4.39 (d, J = 8.0 Hz, 1 H), 4.32–4.24 (m, 2 H), 2.25 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.7, 142.9, 130.1, 129.1, 114.2, 75.7, 62.6, 55.4, 20.4, 14.1. HRMS (EI-TOF): m/z [M⁺] calcd for C₁₂H₁₆N₂O₄: 252.1110; found: 252.1107.