Accessing Aliphatic Amines in C–C Cross-Couplings by Visible Light/Nickel Dual Catalysis

chem 49703 0

Accessing Aliphatic Amines in C–C Cross-Couplings by Visible Light/Nickel Dual Catalysis  第1张

A general aminoalkylation of aryl halides was developed, overcoming intolerance of free amines in nickel-mediated C–C coupling. This transformation features broad functional group tolerance and high efficiency. Taking advantage of the fast desilylation of α-silylamines upon single-electron transfer (SET) facilitated by carbonate, α-amino radicals are generated regioselectively, which then engage in nickel-mediated C–C coupling. The reaction displays high chemoselectivity for C–C over C–N bond formation. Highly functionalized pharmacophores and peptides are also amenable.


Table 1. Optimization and Control Studiesa

Accessing Aliphatic Amines in C–C Cross-Couplings by Visible Light/Nickel Dual Catalysis  第2张

entry[PC]mol % [PC]/[Ni]additiveyield (%)b
1[Ru]3:100
2[Ir]3:10trace
34CzIPN3:10trace
44CzIPN3:10K2CO3 (3 equiv)15
54CzIPN5:2K2CO3 (3 equiv)99
6cK2CO3 (3 equiv)0
7d4CzIPNK2CO3 (3 equiv)0
8e4CzIPN5:2K2CO3 (3 equiv)0

aPerformed with α-silylamine 1a (1.5 equiv), para-bromobenzonitrile (0.1 mmol) in THF (0.1 M) under blue LED irradiation at rt for 20 h. 3 mol % photocatalyst [PC] and 10 mol % [Ni] are added when the [PC]/[Ni] ratio is 3:10, while 5 mol % [PC] and 2 mol % [Ni] are added when the [PC]/[Ni] ratio is 5:2.
bYields determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
cNo [PC].
dNo [Ni].

eNo light.

Accessing Aliphatic Amines in C–C Cross-Couplings by Visible Light/Nickel Dual Catalysis  第3张




In conclusion, a user-friendly and versatile route toward the aminomethylation of functionalized (het)aryl halides under mild reaction conditions is reported. This protocol features a protecting-group-free synthetic strategy for the preparation of secondary arylmethylamines. This aminomethylation can be further extended to the synthesis of tertiary amines. The commercial availability of (het)aryl halides as well as the low, uniform oxidation potentials of α-silylamines allow the incorporation of diverse radical architectures from commodity chemicals while retaining high functional group tolerance.


General Procedure for Aminomethylation of Aryl Halides
To an 8 mL reaction vial equipped with a stirrer bar was added 4CzIPN (11.8 mg, 5 mol %), Ni(dtbbpy)Br2 (2.9 mg, 2 mol %), (hetero)aryl bromide (0.3 mmol, 1.0 equiv), α-silylamine (0.45 mmol, 1.5 equiv) and K2CO3 (124.4 mg, 0.9 mmol, 3.0 equiv). The reaction vessel was sealed with a cap containing a TFE-lined silicone septum and cooled to 0 °C in an ice-water bath. Then it was evacuated and backfilled with argon three times. After that, degassed THF (3 mL) was added, and the vessel was removed from the ice-water bath and further sealed with Parafilm®. The vessel was then placed in a sonicator for 3 min and irradiated with blue LEDs (470 nm, ~10 W, at a distance of ~ 2 cm). When judged complete (typically within 20 h), 5 mL of acetone was added, and the crude material was passed through a pad of Celite® and eluted with another 5 mL of acetone. The filtrate was concentrated under reduced pressure and purified by SiO2 column chromatography.


doi.org/10.1021/acs.orglett.1c01207

标签: photoredox

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