Nickel/Photoredox-Catalyzed Decarboxylative Coupling of Aryl Bromides with N-Protected Glycine as an Aminomethyl Source

Abstract

Benzylamines are important scaffolds that are ubiquitously found in various bioactive molecules. Among the benzylamine derivatives, primary benzylamines (ArCH₂NH₂) are regarded as valuable building blocks for pharmaceuticals. Herein, we report decarboxylative aminomethylation of aryl bromides with N-protected glycine under nickel/photoredox-catalyzed conditions. The corresponding products can be easily deprotected under acidic conditions to give primary benzylamines.

Key words

benzylamines - aryl bromides - glycine - decarboxylation - aminomethylation - cross-coupling

Publication History

Received: 28 March 2023

Accepted after revision: 23 May 2023

Article published online:
13 July 2023

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• 13 Typical experimental procedure: Aryl bromide 1a (22.2 mg, 0.10 mmol, 1.0 equiv.), N-(tert-butoxycarbonyl)glycine (2a) (25.8 mg, 0.15 mmol, 1.5 equiv.), and Cs₂CO₃ (51.1 mg, 0.15 mmol, 1.5 equiv.) were added to a screw-capped glass tube containing a magnetic stirring bar. The air was removed under vacuum, and the vessel was refilled with N₂ gas three times. A 5 mL DMF solution containing 4CzIPN (2.0 mg, 2.5 μmol, 2.5 mol%), NiCl₂·DME (2.2 mg, 10 μmol, 10 mol%), and 2,2-bipyridine (2.3 mg, 15 μmol, 15 mol%) was added to the vessel and sonicated for 10 min. The mixture was stirred under blue-light irradiation (a 456 nm Kessil lamp was placed 1 cm from the reaction tube) for 18 h. Brine was added to the resulting mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was evaporated. Purification by preparative thin-layer chromatography (ethyl acetate/hexane = 2:1) afforded 3a (13.7 mg, 53%). ¹H NMR (600 MHz, CDCl₃): δ = 8.00 (d, J = 8.2 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 4.90 (br s, 1 H), 4.38 (d, J = 5.8 Hz, 2 H), 3.91 (s, 3 H), 1.47 (s, 9 H). ¹³C NMR (150 MHz, CDCl₃): δ = 166.9, 155.9, 144.3, 129.9, 129.2, 127.2, 79.8, 52.0, 44.4, 28.4. HRMS (ESI): m/z calcd for C₁₄H₁₉NO₄Na [M + Na]⁺: 288.1206; found: 288.1209.