Chlorotrimethylsilane → (S)-2-Chloro-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[(2-tetrahydropyranyl)oxy]pyridinepropanoic Acid Methyl Ester

Participants

Reaction Conditions

Reaction Steps

To an amberized flask containing activated Zn dust (0.349 g, 5.51 mmol) under Ar is added THF (2 mL) and 1,2-dibromoethane (0.018 mL, 0.21 mmol). The suspension is brought to reflux for several minutes, cooled to approximately 30° C., and TMSCl (0.17 mL of a 1 M solution in THF) is added. The reaction mixture is stirred at 40±5° C. for 30 min and then is cooled to below rt. A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-iodo-L-alanine methyl ester [93267-04-0] (1.81 g, 5.50 mmol) in 11:7 dimethylacetamide/THF (9.0 mL) is added, and the resulting reaction mixture is stirred at 45° C. for 5 h. The reaction mixture is cooled to below rt, and solid PdCl2(PPh3)2 (0.192 g) is added, followed immediately by addition of a degassed solution of the iodopyridine (0.936 g, 2.76 mmol) in 1:1 THF/dimethylacetamide (5.6 mL). This reaction mixture is stirred for 4 h at 45° C. It is cooled to 0° C., quenched with sat'd aq NH4Cl, and extracted with EtOAc. The combined EtOAc portions are washed with sat'd aq NH4Cl and brine. The EtOAc solution is dried, filtered and concentrated to give a green-yellow colored foam, that upon purification by silica flash chromatography (7:3 hexanes/EtOAc) gives 0.879 g (1.85 mmol, 60%) of the title product: TLC (7:3 hexanes/EtOAc) Rf 0.21; 1H NMR (CDCl3, 300 MHz) d 7.39 (1H), 7.00 (1H), 5.46 (1H), 4.61 (1H), 4.13 (1H), 3.80 (3H), 3.62 (1H), 3.20 (1H), 2.13-1.53 (6H), 1.42 (9H).

Provenance & Evidence