Robust Buchwald-Hartwig Amination Enabled by Ball-Milling

An operationally simple mechanochemical method for the Pd catalysed Buchwald-Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein.

S3 quantities of internal standard (mesitylene) against known quantities of substrate and product: The quantity of an analyte was then calculated according to the following equation: S4

Experimental Procedures General Method 1: mechanochemical Buchwald-Hartwig amination
To a 15 mL stainless steel jar (Form-Tech Scientific) was added a stainless steel ball of mass 12 g, sand (0.338 g), potassium tert-butoxide (2 mmol, 0.224 g), aryl halide (1 mmol), amine (1.2 mmol) and Pd-PEPPSI-IPent (0.01 mmol, 0.008 g) under air atmosphere. The milling jar was then closed and the mixture was milled at 30 Hz for 3 hours. After the desired reaction time, the black solid mixture was scratched out using spatula and the jar was raised with EtOAc (10 mL) twice. Then the mixture was filtered and concentrated under reduced pressure.
(1) To obtain the 1 H NMR yield, mesitylene (0.5 mmol, 70 μL) and CDCl3 (5 mL) were added to the reaction mixture. Then approximately 1 mL sample of this mixture was taken for 1H NMR analysis. The yield was calculated relative to mesitylene (internal standard).
(2) To obtain the isolated yield, the crude reaction mixture was purified by silica gel flash chromatography using the noted solvent systems.

General Method 2: conventional solution method under air
To a 50 mL round bottom flask a stir bar, potassium tert-butoxide (2 mmol, 0.224 g) and Pd-PEPPSI-IPent (0.01 mmol, 0.008 g) were added. Then a premixed solution of the desired solvent (10 mL), chlorobenzene (1 mmol, 0.113 g), morpholine (1.2 mmol, 0.105 g) and the internal standard mesitylene (0.5 mmol, 0.060 g) was injected into the flask via syringe. The reaction was stirred at room temperature under air. The reaction was analyzed by GC by talking an aliquot (~50 μL) and passing it through a pipette containing a small plug of silica gel using diethyl ether as eluent. The GC yield was calculated relative to mesitylene (internal standard).

IPr imidazolium chloride
The title compound was prepared using a method modified from the literature. 2 IPr (0.753 g, 2 mmol) and methoxy(methyl)chloride (3.220 g, 40 mmol) were added to a glass vial.

Pd-PEPPSI-IPr
The title compound was prepared using a method modified from the literature. 3

IPr(BIAN) imidazolium chloride
The title compound was prepared using a method modified from the literature. 2

Pd-PEPPSI-IPr (BIAN)
The title compound was prepared using a method modified from the literature. 5

N-Boc vortioxetine (30)
The titled compound was prepared using General Method 1.

tert-butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate hydrobromide/ Vortioxetine hydrobromide (31)
N-Boc vortioxetine (0.275 g, 0.7 mmol, ) was dissolved in 2 mL methanol and slowly added 0.2 mL 48 wt% HBr (aq.) followed by heating to reflux for 2 hours. Then the mixture was cooled to room temperature then the solvent was removed by evaporation. After the addition of diethyl ether (2 mL), the mixture was stirred at room temperature for 2 h before leaving the mixture in the freezer overnight. Filtration and washing with 5 mL diethyl ether to produce brownish solid. Then the brownish solid was dried under high vaccum (0.215 g, 81%