Nickel-Catalyzed Synthesis of Benzylamines from (Hetero)aryl Halides and Glycine-Derived N-Hydroxyphthalimide Esters

Dedicated to the late Prof. Keith Fagnou on the 20th anniversary of the start of his academic career.

Abstract

A nickel-catalyzed aminomethylation of aryl or heteroaryl iodides or bromides for the preparation of protected primary benzylamines is reported. This cross-electrophile reductive protocol engages carbamate-protected, glycine-derived N-hydroxyphthalimide (NHP) esters in an efficient decarboxylative cross-coupling in only two hours. The catalyst and NHP ester reagents are commercially available or can be synthesized in one step on a decagram scale with no chromatography.

Key words

cross-electrophile - glycine - hydroxyphthalimide esters - decarboxylative cross-coupling - aminomethylation - benzylamines

• References and Notes

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• 12 N-Boc Benzylamines 2–25; General Procedure A 16 mL threaded reaction tube containing a stirrer bar was capped with a septum, flame-dried under vacuum, and cooled under an inert atmosphere. The tube was charged with the appropriate NHP ester (0.75 mmol, 1.5 equiv), aryl iodide or bromide (0.50 mmol, 1.0 equiv, if solid), [(bipy)₂Ni₂(μ-Cl)₂Cl₂(H₂O)₂] (0.025 mmol, 5.0 mol%), nonactivated Zn flake [4.0 mmol, 8.0 equiv, (–325 mesh)], and 3 Å molecular sieves (20 wt%). The tube was refitted with the septum, evacuated, and backfilled with N₂ (×3), then placed in an ice bath to chill at 0 °C (for aryl iodides). Anhyd DMA (2.5 mL, 0.2 M; cooled to 0 °C for aryl iodides) was added to the reaction tube, followed by Me₃SiCl (1.5 mmol, 3.0 equiv). If the aryl iodide or bromide was a liquid, it was added as a solution during the DMA addition. The mixture was stirred (500 rpm) at 0 °C for 2 h (rt for aryl bromides). The reaction was then quenched with 10% aq K₂CO₃ at 0 °C and the mixture was diluted with CH₂Cl₂ and brine. After extraction, the organics were dried (MgSO₄) and concentrated, and the residue was purified by chromatography. See the Supporting Information for detailed procedures and NMR spectra.
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• 17 Following the conclusion of our work, a complimentary reaction manifold was reported by Dowling (Pfizer), synthesizing tert-butyl {[1-(tetrahydro-2H-pyranyl)-1H-indazol-6-yl]methyl}carbamate (68% yield), tert-butyl (quinolin-3-ylmethyl)carbamate (84% yield), and tert-butyl [4-(morpholinomethyl)benzyl]carbamate (55% yield); see: DeCicco E. M.; Berritt S.; Knauber T.; Coffey S. B.; Hou J.; Dowling M. S. J. Org. Chem. 2023, 88, 12329.