Lithium diisopropylamide → 1-(4-Trifluoromethyl-6-chloropyrimidin-5-yl)-1-(2-chloro-4-methoxypyrimidin-5-yl)methanol

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Reaction Steps

4-Chloro-6-trifluoromethylpyrimidine (1.10 g, 6.02 mmol) in THF (15 ml) was added to a solution of lithium diisopropyl amide (LDA) (prepared from n-BuLi (3.7 ml, 5.9 mmol, 1.6M in hexanes) added to diisopropylamine (820 ul, 591 mg, 5.84 mmol) in THF (30 ml) at -78° C., allowing to warm to room temperature for 30 minutes, and re-cooling to -78° C.) at -78° C. The solution turned brown and was stirred for 10 minutes. Then 2-chloro-4-methoxypyrimidine-5-carboxaldehyde (0.96 g, 5.56 mmol) in THF (25 ml) was added dropwise and allowed to stir at -78° C. for 1 hour. The solution was quenched at -78° C. with 30% aqueous HOAc, diluted with water and extracted with EtOAc (3 times). The combined extracts were washed with brine (sat.), dried (MgSO4), filtered and concentrated in vacuo to give 1.61 g of crude product. Preparative radial chromatography (SiO2 ; hexane/EtOAc gradient elution) gave 190 mg (21% based on 530 mg of recovered starting material) of 1-(4-trifluoromethyl-6-chloropyrimidin-5-yl)-1-(2-chloro-4-methoxypyrimidin-5-yl)methanol.

Provenance & Evidence