Cesium carbonate → 4-[(2-Chloro-5-methylpyrimidin-4-yl)thio]-2-(trifluoromethyl)aniline

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Reaction Conditions

Reaction Steps

A mixture of Pd[PPh3]4 (75 mg, 0.065 mmol) and Cs2CO3 (550 mg, 1.69 mmol) was evacuated and purged with nitrogen. Toluene (12 mL) was then added followed by 4-bromo-2-(trifluoromethyl)aniline (187 μL, 1.33 mmol) and Triisopropylsilanethiol (TIPS-SH) (363 μL, 1.69 mmol). The mixture was heated at 100° C. for 24 h then cooled to room temperature. Saturated aqueous NH4Cl (5 mL) was added then diluted with water and extracted twice with EtOAc. The combined extracts were washed with water, brine then dried (Na2SO4). The solvent was removed under reduced pressure to give the crude TIPS thiophenol as a dark red oil (675 mg). This oil was dissolved in THE (13 mL), 2,4-dichloro-5-methylpyrimidine (190 μL, 1.62 mmol) was added and the solution was cooled to 0° C. Tetrabutyl ammonium fluoride (TBAF) (1.0 M in THF, 2.6 mL, 2.6 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 3 h. Water was added and the mixture was extracted three times with EtOAc. The combined extracts were washed with water, brine then dried (Na2SO4). Solvent removal under reduced pressure and the resulting residue was purified by silica gel chromatography with 30% EtOAc/Petrol as eluent to give 4-[(2-chloro-5-methylpyrimidin-4-yl)thio]-2-(trifluoromethyl)aniline (410 mg, 95%). 1H NMR (CDCl3, 300 MHz) δ 8.07 (d, J=0.9 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.43 (dd, J=8.7, 2.4 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 4.43 (br s, 2H), 2.25 (d, J=0.6 Hz, 3H); LRMS (ESI): m/z calcd for [M+H]+320.0, found 320.2.

Provenance & Evidence