2,2-dimethyl-3-(oxan-2-yloxy)propan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: DMSO (2.69 mL, 50.97 mmol) was added dropwise to a solution of oxalyl chloride (2.87 mL, 33.98 mmol) in dichloromethane (85.0 mL) at −78° C. After several minutes, neat 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.2 g, 16.99 mmol) was added dropwise and after stirring for 1 h at −78° C., triethylamine (9.5 mL, 68.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 30 min. Sat. NH4Cl was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and washed with brine. The organic layers were combined, dried over Na2SO4 and concentrated to give a pale liquid. The crude liquid was passed through a short silica gel column and eluted with 50% ethyl acetate in hexanes to provide 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (3.09 g, 97%) as a pale liquid after removal of solvents under reduced pressure. After several minutes to warm to room temperature stirred for 30 min the organic layer was separated The aqueous layer was extracted with ethyl acetate washed with brine dried over Na2SO4 concentrated to give a pale liquid eluted with 50% ethyl acetate in hexanes

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

Procedure: To a solution of neopentyl glycol (6.0 g, 57.6 mmol) and 3,4-dihydro-2H-pyran (2.64 mL, 28.94 mmol) in 2:1 THF/dichloromethane (135 mL) was added p-TsOH.H2O (100 mg, 0.53 mmol) and the reaction stirred overnight. Solid NaHCO3 was then added and after rapid stirring for 15 min the reaction was filtered and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes provided 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.21 g, 59%) as a pale liquid. after rapid stirring for 15 min the reaction was filtered concentrated to give a pale liquid Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes

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

Procedure: To a solution of neopentyl glycol (6.0 g, 57.6 mmol) and 3,4-dihydro-2H-pyran (2.64 mL, 28.94 mmol) in 2:1 THF/dichloromethane (135 mL) was added p-TsOH.H2O (100 mg, 0.53 mmol) and the reaction stirred overnight. Solid NaHCO3 was then added and after rapid stirring for 15 min the reaction was filtered and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes provided 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.21 g, 59%) as a pale liquid. after rapid stirring for 15 min the reaction was filtered concentrated to give a pale liquid Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a stirred solution of 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol (20 g, 106 mmol) an TEA (44.4 mL, 319 mmol) in dry dichloromethane (300 mL) cooled in an ice bath to 0° C.±5° C. was added a solution of sulfur trioxide pyridine complex (50.7 g, 319 mmol) in anhydrous DMSO (300 mL) in one portion. There was an exotherm to 27° C. The bath was removed and the mixture allowed to stir for 20 minutes at room temperature after which time conversion was complete by TLC. The reaction was quenched with 225 mL of saturated NaHCO3, concentrated on the rotovap to remove dichloromethane and extracted with 3×200 mL of ethyl acetate. The combined extracts were washed once with 250 mL of 10% citric acid, dried over MgSO4 and concentrated. Drying under vacuum gave 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanal as an oil. Contains ˜40% DMSO by NMR: 1H NMR (400 MHz, CDCl3) δ 9.6 (s, 1H), 4.6 (m, 1H), 3.8 (d, 1H), 3.5 (m, 1H), 3.38 (d, 1H), 1.8-1.4 (min, 6H), 1.06 (s, 3H), 1.04 (s, 3H). to 27° C The bath was removed The reaction was quenched with 225 mL of saturated NaHCO3 concentrated on the rotovap to remove dichloromethane extracted with 3×200 mL of ethyl acetate The combined extracts were washed once with 250 mL of 10% citric acid dried over MgSO4 concentrated Drying under vacuum

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

Procedure: To solution of LiAlH4 (397 mL, 397 mmol) in THF (250 mL) cooled in an ice bath to 0° C. was added methyl 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanoate (82 g, 378 mmol) in THF (250 mL) via addition funnel keeping the internal temperature below 6° C. When addition was complete the reaction was allowed to warm to room temperature and stir overnight. The mixture was cooled in an ice bath and quenched with H2O (16 mL, 888 mmol), then after 5 minutes, 10 N NaOH (16 mL, 160 mmol), and after another 15 minutes, H2O (48 mL, 2664 mmol). The mixture was allowed to stir for 30 minutes, then filtered with a THF rinse. The filtrate was concentrated and azeotropically dried with toluene. Further drying under vacuum gave 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol as a colorless liquid: 1H NMR (400 MHz, CDCl3) δ 4.58 (m, 1H), 3.85 (m, 1H), 3.6 (d, 1H), 3.5 (m, 2H), 3.4 (m, 1H), 3.2 (d, 1H), 2.8 (t, 1H), 1.8 (m, 2H), 1.6 (m, 4H), 0.85 (s, 6H). via addition funnel the internal temperature below 6° C When addition The mixture was cooled in an ice bath after 5 minutes to stir for 30 minutes filtered with a THF rinse The filtrate was concentrated azeotropically dried with toluene Further drying under vacuum

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

Procedure: DMSO (2.69 mL, 50.97 mmol) was added dropwise to a solution of oxalyl chloride (2.87 mL, 33.98 mmol) in dichloromethane (85.0 mL) at −78° C. After several minutes, neat 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.2 g, 16.99 mmol) was added dropwise and after stirring for 1 h at −78° C., triethylamine (9.5 mL, 68.0 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 30 min. Sat. NH4Cl was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and washed with brine. The organic layers were combined, dried over Na2SO4 and concentrated to give a pale liquid. The crude liquid was passed through a short silica gel column and eluted with 50% ethyl acetate in hexanes to provide 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propionaldehyde (3.09 g, 97%) as a pale liquid after removal of solvents under reduced pressure. After several minutes to warm to room temperature stirred for 30 min the organic layer was separated The aqueous layer was extracted with ethyl acetate washed with brine dried over Na2SO4 concentrated to give a pale liquid eluted with 50% ethyl acetate in hexanes

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

Procedure: To a solution of neopentyl glycol (6.0 g, 57.6 mmol) and 3,4-dihydro-2H-pyran (2.64 mL, 28.94 mmol) in 2:1 THF/dichloromethane (135 mL) was added p-TsOH.H2O (100 mg, 0.53 mmol) and the reaction stirred overnight. Solid NaHCO3 was then added and after rapid stirring for 15 min the reaction was filtered and concentrated to give a pale liquid. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes provided 2,2-dimethyl-3-(tetrahydro-pyran-2-yloxy)-propan-1-ol (3.21 g, 59%) as a pale liquid. after rapid stirring for 15 min the reaction was filtered concentrated to give a pale liquid Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes