Imidazole → TBDMS ether

Participants

Reaction Steps

A solution of N-BOC-4(S)-hydroxy-2-methyl-(L)-proline, methyl ester (Step A, 2.2 g, 8.5 mmol), tert-butyldimethylsilyl chloride (1.8 g, 12 mmol), and imidazole (1.1 g, 17 mmol) in 40 mL of anhydrous DMF was stirred at rt overnight. The reaction mixture was partitioned between Et2O and water, and the product was extracted with Et2O (2×200 mL). The combined extracts were dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in anhydrous CH2Cl2 (15 mL), and was added with 2,6-dimethyllutidine (3.0 mL, 26 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (3.9 mL, 17 mmol) at rt. After stirring for 2 h, the reaction mixture was cooled by an ice-water bath, and was added potassium fluoride (1.4 g, 24 mmol) in 20 mL of water. After stirring at 0° C. for 2 h, the reaction mixture was partitioned between ether and water. The product was extracted with Et2O (3×50 mL), and the organic extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was azeotroped with toluene and was dissolved in CH2Cl2 (10 mL) and THF (10 mL). The solution was cooled with an ice water bath, and was added DIPEA (4.4 mL, 25 mmol), 4-DMAP (0.10 g, 0.85 mmol) and 3-chlorobenzenesulfonyl chloride (2.7 g, 12 mmol). The reaction was allowed to warm to rt overnight. The reaction mixture was concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 4:1 hexane/EtOAc to give the tert-butyldimethylsilyl ether of the title compound, which was used immediately. Thus, to a solution-of the silyl ether in acetonitrile (40 mL) at 0° C. was added aqueous HF (48%, 4 mL), and the reaction was allowed to warm up to rt overnight. The reaction mixture was partitioned between 5 N aqueous NaOH, brine and EtOAc, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness to give the title compound (3.0 g, 96% from the product of Step A).

Provenance & Evidence