methyl thiane-4-carboxylate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of CH3CN (48.7 mmol, 2.54 mL) in 10 mL of THF was added dropwise to a solution of nBuLi (48.7 mmol) in 15 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of methyl tetrahydro-2H-thiopyran-4-carboxylate (24.3 mmol, 3.90 g) in 10 mL of THF was added dropwise and the resulting reaction mixture was stirred at −78° C. for 1 h, and then slowly warmed to −40° C. in 2 h. The reaction was quench with 1 N HCl (pH<1). THF was removed and the residue was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes) to afford 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (3.60 g, 87.5%) as a light brownish oil. LCMS tR=1.29 Min. Mass calculated for, M+ 1694.1, observed LC/MS m/z 170.1 (M+H) the resulting reaction mixture was stirred at −78° C. for 1 h slowly warmed to −40° C. in 2 h The reaction was quench with 1 N HCl (pH<1) THF was removed the residue was extracted with EtOAc washed with brine dried over Na2SO4 concentrated The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of CH3CN (48.7 mmol, 2.54 mL) in 10 mL of THF was added dropwise to a solution of nBuLi (48.7 mmol) in 15 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of methyl tetrahydro-2H-thiopyran-4-carboxylate (24.3 mmol, 3.90 g) in 10 mL of THF was added dropwise and the resulting reaction mixture was stirred at −78° C. for 1 h, and then slowly warmed to −40° C. in 2 h. The reaction was quench with 1 N HCl (pH<1). THF was removed and the residue was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes) to afford 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (3.60 g, 87.5%) as a light brownish oil. LCMS tR=1.29 Min. Mass calculated for, M+ 1694.1, observed LC/MS m/z 170.1 (M+H) the resulting reaction mixture was stirred at −78° C. for 1 h slowly warmed to −40° C. in 2 h The reaction was quench with 1 N HCl (pH<1) THF was removed the residue was extracted with EtOAc washed with brine dried over Na2SO4 concentrated The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N,N-diisopropylamine (1.51 g, 2.1 mL, 15 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (6 mL, 15 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of tetrahydro-thiopyran-4-carboxylic acid methyl ester (1.60 g, 10 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred at −78° C. for 20 min. Acetaldehyde (1.32 g, 1.7 mL, 30 mmol) was then added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C. and ice-cold hydrochloric acid (2 M) was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the aqueous phase and the mixture was extracted with diethyl ether. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:3 to afford the title compound (1.77 g, 87%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO): δ 0.96 (d, J=6.5 Hz, 3H), 1.46-1.73 (m, 2H), 2.12-2.28 (m, 2H), 2.43-2.57 (m, 4H), 3.50-3.58 (m, 1H), 3.63 (s, 3H), 4.85 (d, J=5.8 Hz, 1H). LCMS (m/z) 227.1 [M+Na], Tr=1.53 min. the reaction mixture was stirred at −78° C. for 20 min The cooling bath was removed the reaction mixture was stirred at room temperature for 1 h The reaction mixture was cooled to 0° C. ice-cold hydrochloric acid (2 M) was added Sodium chloride was added to saturate the aqueous phase the mixture was extracted with diethyl ether washed with brine The organic solution was filtered through a hydrophobic frit the filtrate was evaporated The residue was purified by silica gel chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of CH3CN (48.7 mmol, 2.54 mL) in 10 mL of THF was added dropwise to a solution of nBuLi (48.7 mmol) in 15 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of methyl tetrahydro-2H-thiopyran-4-carboxylate (24.3 mmol, 3.90 g) in 10 mL of THF was added dropwise and the resulting reaction mixture was stirred at −78° C. for 1 h, then slowly warmed to −40° C. in 2 h. The reaction was quench with 1 N HCl (pH<1). THF was removed and the residue was extracted with EtOAC, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.45 in 50% EtOAc) to afford compound 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (3.60 g, 87.5%) as a light brownish oil. HPLC-MS TR=1.15 min (UV 254 nm, 5 min method); mass calculated for formula C8H11NOS 169.1 observed LCMS m/z 170.1 (M+H). the resulting reaction mixture was stirred at −78° C. for 1 h slowly warmed to −40° C. in 2 h The reaction was quench with 1 N HCl (pH<1) THF was removed the residue was extracted with EtOAC washed with brine dried over Na2SO4 concentrated The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.45 in 50% EtOAc)